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Annals of Oncology 18 (Supplement 11): xi37–xi55, 2007

session C: early and doi:10.1093/annonc/mdm425

advanced breast cancer


Fabio Puglisi, Enrico Pegolo, Cinzia Puppin, Claudia Andreetta, Stefania Russo, Recchia F, Candeloro G, Necozione S, Rea S.
Gaetano Pascoletti, Alessandro Minisini, Mauro Mansutti, Barbara Alessi, Giovanni Oncologia, Ospedale Civile, Avezzano, Epidemiologia Clinica, Universita‘ degli
Cardellino, Andrea Piga, Gianpiero Fasola, Carla Di loreto Studi, L’Aquila, Fondazione Carlo Ferri per Lo Studio dei Tumori, Monterotondo,
Dipartimento di Oncologia, Azienda Ospedaliero-Universitaria di Udine Roma, Italy

Background: Mesenchyme-specific genes are highly expressed by various types of Background: Objective of the present study was the evaluation of the clinical
human cancers. Recent lines of evidence suggest that periostin, a myoepithelial/basal outcome of 130 consecutive, high risks, pre-menopausal, early breast cancer

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gene, may play a role in the biology of breast cancer. Periostin is involved in metastatic patients, treated with an LH-RH analogue as ovarian protection, during adjuvant
process by taking part in mechanisms of adhesion and migration of epithelial cells. chemotherapy.
Furthermore, periostin seems to have a role in tumor angiogenesis. Patients and methods: Following surgical treatment, patients received an LH-RH
Aim: We aimed at investigating the immunohistochemical expression of periostin in analogue for 2 years and an adjuvant chemotherapy, which was tailored to the
breast cancer and its correlation with established biological and prognostic factors. individual biologic features. Characteristics: median age, 43 years (range 27-50),
Methods: We performed immunohistochemical analysis of periostin in a consecutive 78 estrogen receptor positive (ER+) and 52 ER negative (ER-), 83 stage II disease,
series of 206 tumor samples from 200 patients with early breast carcinoma. The and 47 stage III. All patients had their serum estradiol suppressed to values <40 pg/ml.
intensity of immunoreactivity was scored as 0, 1, 2 or 3 denoting negative, weak, Adjuvant chemotherapy included the following drugs in various combination:
moderate and strong staining, respectively. Therefore, for statistical analysis, the methotrexate, cyclophosphamide, 5-fluorouracil, taxanes, anthracyclines, platinum
periostin expression level for each case was putatively defined as positive if the analogues and high-dose chemotherapy with autologous peripheral blood
predominant intensity was ‡1. We also analyzed immunohistochemical expression progenitor cell transplantation in 11 patients with more than 10 positive axillary
of estrogen and progesterone receptors, Ki-67 (MIB-1), HER-2/neu, VEGF-A, nodes. 104 patients were irradiated. An aromatase inhibitor was given to ER-positive
VEGFR-1 and VEGFR-2. patients, after chemotherapy, during the administration of the LH-RH analogue up
to 2 years.
Results: Periostin was found to be highly expressed by carcinoma cells, whereas it was
absent in normal breast epithelium. The pattern of expression was mainly cytoplasmic, Results: After a median follow-up of 79 months, amenorrhea was observed in no
although in some cases (12%) a nuclear reactivity was observed. A cytoplasmic patient below 40 years and in 49% of patients over 40 years. Four pregnancies were
expression was found in 108 out of 189 (57%) evaluable cases. Interestingly, observed: 3 at term and 1 voluntary abortion. Projected recurrence-free survival rates
a significant correlation was found between periostin expression and VEGF-A and at 5 and 10 years were 83% and 76%, while projected overall survival rates at 5 and
VEGFR-1 (Spearman’s rank test rho =0.36, p <0.0001 and rho=0.25, p=0.0005, 10 years were 94% and 85%, respectively.
respectively). Notably, when periostin expression was examined on the nuclear Conclusions: These data show that in pre-menopausal patients with high risk early
compartment, a significant correlation was observed also with VEGFR-2 (rho =0.43, breast cancer, the addition of a LH-RH analogue to adjuvant therapy and total estrogen
p < 0.0001). blockade in ER+ patients, is well tolerated, protects long-term ovarian function and
Conclusion: These results strengthen the hypothesis of a relationship between periostin seems to improve the expected clinical outcome.
and vascular endothelial growth factor system. The role of periostin in angiogenesis
and in other relevant molecular pathways in breast carcinoma deserves to be further


session C

Paolo Marchetti and Federica Mazzuca MT Ionta1, ME Cazzaniga3, S Barni 3, F Atzori1, M Cremonesi3, A Trogu1, B Frau1,
Medical Oncology, Sant‘Andrea Hospital & IDI-IRCCS, Rome; University of M Murgia1, L Minerba2 and B Massidda1
L’Aquila Oncologia Medica II, Policlinico Universitario, Cagliari1, Dipartimento di Salute
Pubblica e Biostatistica, Policlinico Universitario, Cagliari2 and Oncologia
Background: Quality of life (QoL) is considered one of the most relevant endpoints Medica, Az Osp Treviglio-Caravaggio, Treviglio3, ITALY
in the palliative setting. Even if QoL data have been repeatedly considered of
paramount importance in breast cancer treatment, very few breast cancer trials Background: Pathological complete response (pCR) in the breast and/or in axilla after
assess QoL. Reduced or non-compliance on behalf of patients who are worse off or primary chemotherapy is strongly correlated to a better outcome and is now usually
those that worsen during treatment renders these instruments unpractical considered to be a surrogate for survival.However, the term pCR has not been applied
considering the amount of information lost, especially in the most clinically relevant in a standardized manner, making interpretation of the results difficult. Differently
cases. Thus, longitudinal studies aren’t relevant due to distortion of patient from any other classification, Sataloff defines as pCR the total (pT0) or near total
selection. Considering the difficulty in achieving patient’s full compliance when (minimal microscopic residual as pTm) disappearance of invasive tumour in breast,
filling out paper questionnaires and the fact that physicians are less able to assess assuming that there is no difference in terms of DFS and OS between the two groups
QoL than patients themselves, the relevance of an electronic device to record these (J Am Coll Surg 1995). Nevertheless, till now, no data are available in confirming this
data is evident. hypothesis. Aim of the present study was to investigate whether pT0 pts have the same
Methods: From February 2005 to June 2006, twenty-six consecutive postmenopausal prognosis of pTm, in terms of DFS and OS.
patients (median age yrs 62, Range 52-77) affected by early breast cancer and treated Materials and Methods: We analysed 45 out of 308 pts with initial clinical T2-3
with anastrozole were included into a cross-comparison study between two QoL (18 pts,40%) and T4 (27 pts,60%) BC, who achieved pCR, according to Sataloff’s
evaluation methods: the EORTC QLQ-C30 and QLQ-BR23 questionnaires and the classification (pT0+ pTm), following different kinds of neoadjuvant
electronic symptom assessment recorder (LESAR - conceived and created by Prof. chemotherapy,between 1989 and 2006. Median age was 47 years (29-68), ER-negative
Paolo Marchetti). QoL of each patient was assessed once a week for 3 consecutive 64% (29 pts), PR-negative 78% (35 pts). All pts received anthracycline-based
weeks. neoadjuvant chemotherapy, even standard (47%, q21) or intensified (53%, q14).
Results: Correlation and kappa analysis were used to compare the answers returned on Median number of administered cycles was 5 (2-6).
the EORTC questionnaires to those recorded with LESAR. The mean correlation Results: Twenty-seven pts achieved clinical CR (60 %), 18 PR (40%), 25 pT0 (55,5%)
coefficient for the first measurement was 0.90 and the kappa coefficient was 0.75; for and 20 pTm (44,5%),30 pN0 (67%) and 15 pN+ (33%). After a median follow up of
the subsequent measurements the correlation coefficient was 0.93 and the kappa 91 months (1-205), no difference has been observed between pT0 and pTm pts in terms
coefficient 0.89. A correlation was also demonstrated over time. of DFS (80% vs 80%, p=0.99) or OS (84% vs 85%, p=0.90).
Conclusions: Both the QoL evaluation methods (EORTC questionnaires and LESAR) Conclusions: Even if small number of pts and limited number of events in each group
gave similar results in postmenopausal patients with early breast cancer treated with limit firm conclusion, our results seem to demonstrate that there is no difference
anastrozole, but LESAR was better accepted by these women and recorded data are between pT0 and pTm pts, regardeless of pN status, in terms of both DFS and OS,
more readily accessible and in an electronic format. confirming Sataloff’s hypothesis.

ª 2007 European Society for Medical Oncology

session C Annals of Oncology

C5 MEDICAL ADJUVANT TREATMENT OF ELDERLY BREAST response, lends support to a paramount role of NK cells in the mechanism of action of

Cataldo S, Bonetti F, Indelli M, Urbini B, Carandina I, Pedriali M*, and Lelli G

Clinical Oncology Unit and * Pathology Unit, Azienda Ospedaliero-Universitaria,
Background: There are not explicit guidelines to standardize the treatment of the PATIENTS
different subgroups of elderly (> 65 years old) breast cancer patients.
Danova M1, Rosti G2, Dubois RW3, Chiroli S4
Materials and methods: This retrospective study included elderly patients undergoing
1Medical Oncology, IRCCS Foundation S.Matteo Pavia, Italy, 2Department of
adjuvant therapy at our institution between Jan.1999 and Dec.2005.
Oncology and Hematology, Ravenna 3Cerner LifeSciences, Beverly Hills, CA,
Results: 308 patients were evaluated, 196 from the young old (YO= 65-74 years old) USA 4Amgen, SpA Milan Italy
group, 112 from the old-old + oldest-old (OO= ‡75 years) group. The OO
group patients were characterized by bigger size tumors, less aggressive histologies,
Background: FN is one of the major adverse events which can occur during
larger estrogen receptors expression (ER), less use of chemotherapy (CT) and more use
chemotherapy (CT) and is often responsible for severe adverse events. There has been
of endocrine therapy (OT). Disease free survival (DFS) correlates to the absence of
a great interest in the economics of G-CSFs over the past decade, and several economic
nodal involvement (median not reached vs. 76 months, p=0.0000), ER positivity

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analyses have been published on this topic. The aim of this pharmacoeconomic study
(median 104 vs. 54 months, p=0.0259), HER-2 hyperexpression (median not
was to evaluate the cost-effectiveness of pegfilgrastim vs filgrastim given as primary
reached vs. 89 months, p=0.0256), and the use of adjuvant radiotherapy (median
prophylaxis (6- OR 11 days) in Italian BC patients (pts) receiving adjuvant
314 vs. 79 months, p=0.0014), that also correlates to overall survival (OS, median
chemotherapy associated with ‡20% FN risk.
314 vs. not reached, p= 0.0028). Comparing CT alone with OT and with CT+OT,
a significative DFS (median 54 vs. 161 vs. 314 months, p=0,0007 for CT vs. OT, Methods: Pharmacoeconomic evaluation was based on an analytic decisional model by
p=0,0083 for CT vs. CT+OT) and OS (median 54 vs. 384 vs. 314 months, p=0,0214 means of a specific software TreeAge Pro 2006 (TreeAge Software, Inc), which takes
and 0,0017) gain rise up, while CT+OT vs. OT does not provide any significative into account the possible consequences of FN, i.e. death and reduction/delay of CT
benefit (DFS : p=0,7598; OS: p=0,3517). Stratifying for age groups (YO vs OO), dose, according to literature available data. Further parameters for the model were:
median DFS was 314 vs. 79 months, p=0,1182; median OS was not reached vs. 89 costs of pegfilgrastim and filgrastim, hospitalization, percentage of RDI<85%, RR
months, p=0,0176. <85% with pegfilgrastim vs filgrastim, long term mortality due to RDI<85%, impact of
age on RDI<85%.
Conclusions: A possible explanation of our results is that the apparent advantage of
adjuvant OT on CT in elderly patients is more influenced from the biological Results: FN case-fatality was assumed to be 3.4% in the base case. At 6 days the RR of
characteristics of disease than from therapeutic choices. Further studies are necessary, FN, filgrastim vs pegfilgrastim was 2.5, and the absolute risk for filgrastim was 17.5%; at
specially in the OO subgroup. 11 days they were respectively 1.79 and 12.5%. Forty % of pts who experienced
a neutropenia event received <85% RDI vs. 9% of pts who do not. The percentage of
pts with RDI<85% at 6 days was 11.1 vs 14.2, and at 11 days 11.1 and 12.7 for
pegfilgrastim and filgrastim respectively, and these results support the long term
C6 NK FUNCTION AND CLINICAL TRASTUZUMAB ACTIVITY IN survival in the former group. At 6 days the cost-efficacy was =C 3,316 vs 3,524
METASTATIC BREAST CANCER PATIENTS respectively for pegfilgrastim and filgrastim and, at 11 days, =C 3,316 vs 5,045. Results
were quite insensitive for the age (45 vs 65 yrs), RDI related variables, cost of CT,
Beano A, dSignorino E, Polimeni MA, Mistrangelo M, Spadi R, Vandone AM, number of cycles (4 or 6) and discount rate (3-10%).
Donadio dM, Matera, P. Lista, I. Facilissimo, R. Napolitano, L, Ciuffreda
UOA Oncologia Medica, Ospedale San Giovanni Battista, Torino. dLaboratorio Conclusions: At 6 and 11 days pegfilgrastim is competitive with filgrastim use. Primary
di Immunologia dei Tumori, Dipartimento di Medicina Interna, Università degli prophylaxis with pegfilgrastim for Italian BC pts undergoing CT associated with ‡20%
studi di Torino risk of FN is cost-effective compared with filgrastim.

Background: Trastuzumab is a monoclonal antibody selectively directed against Her2

and approved for the treatment of Her2 overexpressing breast cancer patients. Its C8 INCREASED RISK OF CENTRAL NERVOUS SYSTEM
proposed mechanisms of action include also a role in mediating antibody-dependent METASTASES (CNSm) IN PATIENTS (pts) WITH BREAST CANCER
cellular cytotoxicity (ADCC), through triggering of the FccRIII on natural killer (NK) (BC) TREATED WITH TRASTUZUMAB (T): RESULTS OF A
cells. This study addressed the correlation between overall NK function and clinical POOLED ANALYSIS
trastuzumab activity.
Subjects and methods: Between March and September 2006 22 patients in treatment M. C. Garassino, Serena Di Cosimo, M Dimaiuta, D. Generali, C. Bareggi, G. Gullo,
with trastuzumab alone (8 mg/kg load and then 6 mg/kg every 3 weeks until disease M. Cinquini, N. La Verde, G. Farina & V. Torri
progression) as maintaining therapy after chemotherapy were analysed for clinical and
immunological responses. According to RECIST criteria, 14 patients obtained The incidence of CNSm ranges from 10 to 16% among women carrying a diagnosis
a response to trastuzumab, while 8 patients had disease progression. Patient’s of metastatic BC, whereas in early stages is <0.1%. Patients with HER2-positive BC
peripheral blood mononuclear cells were tested for cytotoxic activity against a standard have been reported to show higher CNSm rates; whether T may increase such risk
NK target (the MHC class I-negative K562 cell line) and against trastuzumab-coated remains controversial. In order to evaluate the possible correlation between the
MCF-7 (Her2-negative) and SKBR-3 (Her2- positive) human cell lines in a 4-h development of CNSm and the T-based treatment in BC, we performed a pooled
Cr-release cytotoxicity assay in the presence of grading concentrations of effector analysis of all published randomised clinical trials, reporting CNS events, with the
cells. administration of the HER2 monoclonal antibody in adjuvant or metastatic setting.
Results: NK activity was significantly (p<0.05) higher in responder compared to non A Medline search was conducted and four papers were considered for analysis (N9831-
responder patients at all the four effector:target (50:1 to 6:1) ratios tested. NK activity B31-HERA-Slamon-2001). Crude odds ratios for CNSm and other metastasis
of non responder patients was significantly lower than that of 25 sex and age matched occurrence were used for estimating the relative risk of events associated to
controls (p<0.02) and this was not merely due to chemotherapy- or tumor-associated therapy. Overall risks (ORs) were extracted from each study and used for
immunosuppression, since the values of responder patients did not significantly differ comparison between groups. Conditional logistic analysis was adopted, using
from those of controls. ADCC activity against Her2-positive SKBR3 cells was also studies as strata. The incidence of CNSm progression was higher in
significantly higher in responder compared to non responder patients (p<0.05) and trastuzumab-based therapy (70% of risk increase) arm in all studies (OR=0.59)
markedly so when compared to controls (p<0.001). with particular regard to the adjuvant setting. However, trastuzumab appears to be
Conclusions: The fact that, as shown here, normal levels of FccR-independent and efficacious (61% of risk reduction) in controlling disease progression to other sites
higher than normal levels of FccR-dependent cytotoxicity are required for trastuzumab (OR 2.60).

Table 1.

SLAMON 2001 ADVANCED 2.9 23 137 234 16 192 230 0.686 0.352 1.335 3.577 2.317 5.524
B31 ADJUVANT 2.4 21 62 864 11 160 872 0.513 0.246 1.070 2.907 2.132 3.964
N9831 ADJUVANT 1.5 12 38 808 4 86 807 0.330 0.106 1.029 2.417 1.628 3.588
HERA ADJUVANT 1.0 21 106 1694 15 220 1693 0.712 0.366 1.386 2.238 1.756 2.851
OVERALL 77 343 3600 46 658 3602 0.589 0.406 0.853 2.597 2.213 3.048

xi38 | session C: early and advanced breast cancer Volume 18 | Supplement 11 | October 2007
Annals of Oncology session C
Although we are aware of the limits related to the study such as the effect of cells. Survival analysis and gene expression profile are still ongoing. Taken together our
competing risks and the short follow-up of the adjuvant trials, this is the firs data support the hypothesis of a specific tumor drug sensitivity related to BRCA1
metanalysis showing that a particular subtype of BC treated with T-based therapy status. CDDP shows high activity in BRCA1-defective breast cancer cells and should
might progress to CNS. Intrinsic molecular mechanisms are warranted to be elucidated be evaluated further as a ‘‘novel’’ agent for treatment of patient with hereditary breast
and they will be our further purpose of investigation. cancers. Clinical trials are ongoing in this specific area.

A. Gambardella, S. Serra, V. Petrella, C. Mocerino, A. Santoriello*, A. Silvestri CANCER
Internal Medicine Division. Department Of Gerontology, Geriatrics And
Metabolic Disease* Geriatric Surgery Division. Second University Of Naples A. Zambelli, N. Gibelli, P. Baiardi, V. Fregoni, L. Ponchio, GA. Da Prada, P. Preti,
Naples, Italy L. Pavesi
Medical Oncology Division 1 Fondazione Salvatori Maugeri, IRCCS, Pavia-Italy
Introduction: In recent years, more and more elderly patients undergo screening
for early breast cancer detection. However, often these patients are not admitted Introduction: The HER2 extracellular domain (H-ECD) level is increased in the sera of

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to invasive examination or to radical surgical treatment. patients affected by refractory metastatic breast cancer overexpressing HER2/neu.
Methods: To evaluate this complex problem we have lead a retrospective study on Circulating levels of H-ECD have been reported to predict for response to
diagnostic and therapeutic approach of elderly patients (pts) with suspicious breast chemotherapy and outcome. However, the role of H-ECD as tumor marker, is poorly
lesions. defined.
Results: In the last five years we have observed 303 women, range 70 -85 years, with Patients and methods: From Jan 1999 to Jan 2003 sera of 103 consecutive refractory
suspicious breast lesions, all submitted to echography and mammography. Of these 264 metastatic breast cancer, overexpressing HER2, were tested using ELISA assays (Bayer/
patients (median age 73.2) have accepted a fine needle biopsy and 226 pts (age 74.3) Oncogene Science Diagnostic). Serial evaluations of H-ECD (cut-off 15 ng/ml) were
presented cytology positive for neoplastic cells. obtained before palliative chemotherapy, at the end of treatment and in case of
After comprehensive geriatric assessment (CGA) and anaesthesiologic examination progression.
194 pts (age 71.4) were admitted to surgical treatment. The pts with severe comorbidity Correlation with serum level of Ca15.3 (cut-off 35 U/ml) and with response to
and cognitive impairment were excluded and for them radiotherapy and/or hormonal chemotherapy were investigated.
therapy were proposed. Results: Among the 103 metastatic breast cancer patients, 13 obtained a response (CR/
A conservative surgery was reserved to 52% of pts and a nodal dissection to 78% PR) after chemotherapy 60 had stable disease and 30 patients progressed. We observed
of them. a significant correlation between serum level of H-ECD and Ca15.3 (p<0.001 r=0.418).
We also evaluated the tumor characteristics in relation with age and we report Moreover the same correlation was observed as regard to the response to chemotherapy
the data in following table: with significant evidence of increased levels of H-ECD in case of PD (p=0.022 r=0.174),
H-ECD normalization in case of CR/PR (p=0.01 r=0.448), stabilization in SD (p=0.009
pT age T1 (55%) 70.5 T2 (40%) 71.3 T3 (5%) 72.9 r=0.112).
Conclusions: Increased levels of H-ECD seem to be a useful marker for the prediction
pN age Positive (65%) 72.8 Negative (35%) 70.8
of chemotherapy response and for the prognosis in refractory metastatic breast cancer
ER/PgR age Positive (83%) 71.5 Negative (17%) 70.5
receiving palliative chemotherapy. Further observations are needed to confirm these
Grading age G1(31%) 73.1 G2 (52%) 72.5 G3 (17%) 70.5
preliminary data.
c-erbB2 age 3+ (27%) 70.2 2+ (20%) 70.6 1+ (22%) 72.6 Negative
(31%) 73.2

In 78 high risk patients adjuvant chemotherapy was proposed and 65 of them accepted C12 BRAIN METASTASES IN PATIENTS TREATED WITH
it. The chemotherapy was completed in 42 patients. TRASTUZUMAB FOR METASTATIC BREAST CANCER (ABC):
Conclusion: Our retrospective study demonstrated that a careful collaboration is
necessary to optimizing the management for the elderly patients with early breast
Eliana Berardi1, Virginio Flipazzi2, Monica Giordano3, Giovanna Luchena3,
cancer leading to a surgical risk stratification and to choice of the best possible Elisabetta Menatti1, Ornella Fusco1, Fabio Malugani1, Mario Fiumanò1, Alessandro
Oncology Unit Ospedale Civile Sondrio, 2Ospedale Sacco, Milano, 3Ospedale
S. Anna, Como
BRCA1-DEFECTIVE BREAST CANCER CELLS Background: The HER-2 protein, overexpressed in the 25% of primary breast
carcinoma, is an independent prognostic indicator of a subset of cancers that are at
Pietragalla A, Cucinotto I, Neri P, Di Martino T, Ventura M, Bulotta A, Calimeri T, high risk of early recurrence, regardless of tumor grade, estrogen/progesterone receptor
Propato M, Barbieri V, Eramo O, Salvino A, Rotundo M. S, Caraglia M, Mazza M, status, and lymph node status. These patients have a shorter disease-free survival than
Tassone P. and Tagliaferri P others. Clinical studies have shown that administration of Trastuzumab, a mAb
Medical Oncology Unit, University of ‘‘Magna Græcia’’, Campus ‘‘Salvatore directed against HER-2 protein, significantly inhibits the growth of breast tumour cells
Venuta’’, Catanzaro, Italy in patients with higher levels of HER-2 protein overexpression assessed by Hercep Test.
Methods: We registered an high incidence of brain metastases (BM) in patients
BRCA1-related breast tumors represent a distinct clinical entity. The HCC1937, receiving Trastuzumab. For this reason we reviewed all cases that developed since
BRCA1-defective cell line and its derivative cell clone (HCC1937/WT), where normal 2001 BM during Trastuzumab plus Chemotherapy treatment for advanced breast
BRCA1 has been reconstituted by cDNA-transfection, are a interesting model to carcinoma (ABC). All patients had visceral metastases, Performance Status 0-2 and
analyze the relationships between BRCA1-related carcinogenic pathways and the 3+ HER-2 overexpression.
sensitivity/resistance to chemotherapeutics agents. Previously,we demostrated an
Results: Among 43 consecutive patients who had received Trastuzumab, 14 (32.5%)
increased antitumor activity of cisplatin (CDDP) in BRCA1-defective cells and developed BM during treatment. Patients relapsed at CNS at a median of 25,8 months
a reduced sensitivity to paclitaxel when compared to sporadic breast cancer cells
after diagnosis of ABC and 7,3 (2-13) months from beginning Trastuzumab. All the
(MDA-MB 231, MCF-7) and to the BRCA1-reconstitute clone in vitro.Here, we BM presented neurological symptoms at the diagnosis. All stopped Trastuzumab
investigated the in vivo activity of CDDP and the differential sensitivity mechanism
treatment and shifted to other chemotherapy or/and WBRT/radiosurgery. Three of
by DNA microarray. In vivo effects of CDDP were studied using HCC1937 and them are still alive.
BRCA1/WT cells for animal xenografts. Mice bearing tumors subcutaneusly were
treated with cisplatin 5 mg/kg or vehicle, i.p. weekly, for 4 weeks. Tumors were Discussion: ABC to the CNS is common among patients receiving Trastuzumab,
measured every 3 days and survival analysis was performed by Kaplan Mayer curve.Cell including patients responding to therapy outside the CNS. This may be due to
cycle analysis from retrieved tumor tissues was performed using a cycle-test. Gene predilection for the CNS by HER-2+ tumor cells and/or poor penetration of the CNS
expression profile was performed by Affimetrix Technology.We first evaluated the by Trastuzumab and Taxanes. For this reason it’s important to have in clinical practice
in vitro chemosensitivity of HCC1937 and HCC1937/WT to CDDP;a dose-dependent for Her2 overexpressed breast carcinoma new drugs, e.g. Lapatinib, able to pass BEE.
reduction of cell growth was mainly observed in HCC1937 cells when compared
with BRCA1-reconstitute cells.We next studied the in vivo actvity of CDDP in our
xenograft model.A significant (p<0.005) reduction of the tumor volume was observed C13 HER2/NEU EXPRESSION IN RELATION TO CLINICO-
in CDDP treated mice when compared to controls.The antitumor activity of CDDP PATHOLOGICAL FEATURES OF BREAST CANCER PATIENTS
was significantly higher in the HCC1937 bearing mice than in HCC1937/WT mice.
In vivo data on cell cycle showed a cell-cycle arrest with an increase in the G0-G1 phase Adele Traina, Biagio Agostara, Lorenzo Marasà, Stella Adamo, Rosalba Amodio,
in HCC1937 cells obtained from treated mice when compared with HCC1937/WT Cecilia Dolcemascolo, Maurizio Zarcone, Giuseppe Carruba

Volume 18 | Supplement 11 | October 2007 doi:10.1093/annonc/mdm425 | xi39

session C Annals of Oncology

Experimental Oncology, Clinical Oncology, and Pathology Units, Department of site-specific familial breast cancer (FBC), early-onset breast or ovarian cancer <35 years
Oncology, ARNAS-Civico, Palermo, Italy; Department of ‘‘Igiene e and <45 years, respectively (EO-BC/OC), male BC (MBC), site-specific familial ovarian
Microbiologia’’ of Palermo University cancer (FOC). After genetic counselling and written informed consent, BRCA1/BRCA2
analysis of structural alterations (point mutations and genomic rearrangements) was
Many studies suggest that the assessment of HER2/Neu expression might be helpful in performed in cancer probands.
decision making to treat breast cancer patients. Nevertheless, clinical studies have Altogether, 29% BRCA1/2 predisposing mutations were identified: BRCA1+ 18%
yielded so far conflicting results. We have retrospectively evaluated HER2/Neu (19 point mutations and 2 genomic rearrangements); BRCA2+ 11% (all point
expression in relation to clinical-pathological features of the disease in a series of 1,480 mutations). In FB/OC, 65% BRCA1+: 100% in the 9 FB/OC with >2 OCs; 43% (6
breast cancer cases, all collected by Breast Cancer Registry in Palermo, between January BRCA1+) in 14 FB/OC with one OC. In FBC 20% BRCA1/2+ (19/96): 6% (6/96)
1999 and December 2004. The expression of the HER2/NEU oncogene was assessed by BRCA1 mutations (4 point mutations, 4/96, 4%; 2 genomic rearrangements, 2/96, 2%);
immunohistochemistry and scored on a scale of 0 to +3 as per the FDA 14% (13/96) BRCA2 point mutations.
recommendations. The HER2/Neu expression levels were related to tumor size, nodal In EO-BC probands, 28% BRCA1/2+ were detected: 7/32 (22%) point mutations
status, estrogen (ER) and progesterone receptors (PR), and age at diagnosis. A highly and 2/32 (6%) genomic rearrangement, all in the 23 EO-BCs with FB/OC (38%, 9/24).
significant (P<0.001) correlation of high HER2/Neu expression and a negative ER/PR In MBC, 20% BRCA2+ in probands with FBC. BRCA1/BRCA2 mutations were
status was observed. In addition, patients having G3 tumors and/or axillary nodal detected in 15% case index BC >35 years (8/55).
involvement showed elevated HER2/Neu expression (P<0.001), while no significant No BRCA1/BRCA2 mutation was identified in 11 BC probands in the absence of
association could be found with the other variables. Furthermore, 596 patients having B/OC positive family history (8 EO-BCs and 3 MBC). In the subgroups of FBCs 2-3,

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a follow-up ‡5 years showed an overall survival (OS) of 85% after 60 months. 16% BRCA1/2 mutations were detected (10/63): 32% in the EO-female FBCs 2-3 (6/
HER2/neu 3+ patients had a significantly worse OS with respect to patients having a 19); 8% in the female FBCs 2-3 (3/38).
0-2+ HER2/Neu status (87% vs 78%, respectively). In these last HER2/Neu 0-2+ Present data confirm the expected >10% risk of BRCA1/2 related-predisposition in
patients, the node-positive patients had a significantly shorter OS (P=0.0009) with families selected according to recommended criteria and indicate two main subgroups
respect to node-negative ones, while in HER2/Neu 3+ patients this difference becomes of at-risk families: EO or MBC with >2 BCs and FBOC with 44% BRCA1/2 mutations
not significant (P=0.565). As regards N0 patients, HER2/Neu 3+ patients show a trend, (31/70); female FBC 2-3, EO-BC and MBC without BC family history accounting for
though not significant (P=0.081), to have a shorter OS as compared to HER2/Neu 0-2+ 41% of at-risk families with <10% BRCA1/2 mutations (3/49, 6%).
patients (82% vs 92%, respectively). In addition, HER2/Neu 3+ patients having
a negative ER/PR status show a significantly lower OS (66%) with respect to HER2/Neu
0-2+ patients having a positive ER/PR status (88%) after 5 years. This combined C16 EXPRESSION OF THE LEPTIN SYSTEM AND HYPOXIA-
evidence indicates that a refined recognition of the association of HER2/Neu with other INDUCIBLE FACTOR 1a; IN HER2-POSITIVE AND HER2-NEGATIVE
parameters may be helpful for breast cancer patients prognosis and treatment and may BREAST CANCER
also provide a basis to develop ‘‘individualized’’ therapeutic strategies.
Elena Fiorio1,2, Andrea Remo3, Alessandra Auriemma1,2, Marianna Terrasi1,4,
Annamaria Molino2, Anna Mercanti1,2, Maria Franco Bonetti3, Gian Luigi Cetto2,
Sbarro Institute for Cancer Research and Molecular Medicine, Temple
ACTIVITY OF AN ALL ORAL COMBINATION University, Philadelphia, USA, 2Department of Medical Oncology, University of
Verona, Italy, 3Department of Anatomia Patologica, University of Verona, Italy,
G. Metro, A. Fabi, P. Papaldo, G. Ferretti, P. Carlini, I. Sperduti, A. Felici, 4
Section of Medical Oncology, Department of Surgical Oncology, University of
F. Cognetti and M. Milella Palermo, Italy
Division of Medical Oncology-Istituto Regina Elena - IFO, Roma
The obesity hormone leptin (Ob) has been implicated in tumorigenesis, especially in
Background: Cap is an oral, tumor-activated fluoropyrimidine with established the development of breast cancer (BC). The mitogenic, angiogenic, and antiapoptotic
activity in anthracycline- and taxane-pretreated MBC. Cel is a selective COX-2 activities of Ob are mediated through the leptin receptor (ObR). Data obtained in
inhibitor with recognized anti-tumor properties in various animal models of breast HEK293T cells engineered to coexpress ObR and the oncoreceptor HER2 suggested
cancer. Interestingly, Cel has been successfully combined with fluoropyrimidine-based that Ob can transactivate HER2 via ObR. To address this putative interaction, we
regimens, resulting in a lower-than-expected gastro-intestinal (GI) toxicity and hand- studied whether simultaneous expression of Ob, ObR and HER2 can occur in human
foot syndrome (HFS). breast cancer. Because in breast cancer cells Ob and ObR can be induced by hypoxia
Methods: Patients received Cap 2000 mg/m2 daily for 14 days, q3 wks and Cel 200 mg and HER2 has been found associated with hypoxia-inducible factor 1 alpha (HIF-1a)
b.i.d., continuously. we also explored associations among Ob, ObR, HER2 and HIF-1a.
Results: Fourty women were enrolled. Median age was 57.5 years (range 33-82), and The abundance of Ob, ObR and HIF-1a was evaluated by immunohistochemistry in
median performance status (WHO) was 1 (range 0-2 ). The majority of patients (75%) 59 BCs (31 HER2-positive, 28 HER2-negative). The expression of Ob and ObR was
had visceral localization as dominant metastatic site. Median number of previous classified as positive (at least +) or negative (below +), and of HIF-1a as low (0-2%) or
chemotherapy lines for metastatic disease was 3 (1-4). All patients had been exposed to high (>2%). The relationships among Ob, ObR, HIF-1a and the clinicopathological
antracycline-including regimens either in adjuvant or metastatic setting while 87.5% of features, i.e., grading (G1, G2, G3), tumor size (diameter in mm), node involvement
patients had received prior taxanes. The median number of cycles delivered was 6 (positive or negative), vascular invasion (positive or negative), ER and PgR expression
(range 1-18). All patients were evaluable for safety and activity. Seven patients obtained (positive or negative) were analyzed using the v2 test.
a partial response (17.5%) and stable disease was observed in 17 patients (42.5%) Ob and ObR were coexpressed in 78% of tumors and were correlated (p<0.001)
providing an overall tumor control rate of 60%. At a median follow up of 13 months in all BCs and in HER2-positive (p=<0.001) and HER2-negative (P=0.045) subgroups.
(1-32 months), median duration of response was 13 months (range 11-17), median In all BCs, the expression of Ob and/or ObR was associated with tumor size (Ob:
time to progression (TTP) was 5 months (CI 95%: 3-7) and median overall survival was p=0.04; ObR: p=0.05) and node positivity (ObR: p=0.04; Ob/ObR: p=0.02).
18 months (CI 95%:11-25). Cap-Cel combination was generally well-tolerated: grade Furthermore, the expression of Ob occurred more frequently in large (>10 mm),
2-3 treatment-related adverse events were hand-foot syndrome (23%), neutropenia node-positive tumors (trends p=0.06 and p=0.08, respectively). The simultaneous
(15.5%), diarrhea (10,5%), nausea (7,5%), asthenia (7,5), liver toxicity (7,5%) and expression of Ob/ObR and HER2 was found in 39% of BCs, but the Ob/ObR
gastric pain (5%). No grade 4 toxicities and no treatment-related deaths were observed. system was also frequent in HER2-negative BCs. High expression of HIF-1a correlated
with Ob/ObR (p=0.03). ObR and Ob/ObR did not correlate with HER2, grading,
Conclusions: Cap-Cel combination yielded a response rate comparable to that of single VI, and ER/PgR.
agent Cap. However, the addition of Cel to Cap resulted in increased TTP. The good In summary, Ob and ObR are often coexpressed and a subset of Ob/ObR-positive
tolerabity profile of this association suggests that Cel might also attenuate Cap-related tumors exhibits concomitant expression of HER2. Thus, interactions between Ob/ObR
toxicities such as GI events and HFS. and HER2 might occur in breast cancer, where activation of Ob/ObR could impede
anti-HER2 treatments. The presence of Ob/ObR correlated with high levels of HIF-1a,
suggesting that hypoxia might upregulate this system. However, Ob/ObR and HER2
C15 IDENTIFICATION OF FAMILIES SELECTED FOR BREAST were not significantly associated, implying that independent mechanisms regulate these

Sidoni T, De Marchis L2, Midulla C2, Capalbo C1, Giusti R, Paris I5, Assalone P2, C17 USE OF NON PEGYLATED LIPOSOMIAL DOXORUBICIN
Rocchi A2, Ronzino G4, Di Seri M2, Tomao S2, Meggiorini M. L6, Lanza R2, (MYOCET) ASSSOCIATED WITH CYCLOPHOSPHAMIDE OR
Scambia G3, Ficorella C, Marchetti P5, Cortesi E2, Frati L2, Gulino A1, Giannini G1 DOCETAXEL AS FIRST LINE TREATMENT IN METASTATIC BREAST
and Ricevuto E CANCER
Medical Oncology, Department of Experimental Medicine, University of L’Aquila
Lorenzo Livi1, Icro Meattini1, Alessio Bruni1, Alessia Petrucci1, Andrea Rampini1,
Between march 2002 and december 2006, 119 unrelated families at risk for breast (BC) Annamaria Mileo1, Lisa Paoletti1, Angela Sardaro2, Simona Borghesi1 and
and/or ovarian cancer predisposing syndrome were selected according to the following Giampaolo Biti1
criteria of a priori risk >10%: breast and/or ovarian cancer family history (FB/OC), Radiotherapy Unit University of Florence, 2 Radiotherapy Unit University of Bari

xi40 | session C: early and advanced breast cancer Volume 18 | Supplement 11 | October 2007
Annals of Oncology session C
Background: The aim of this study was evaluate the activity and safety of non- (28-73). Patients with endocrine responsive disease were 65,5%; 57,6% of patients had
pegylated liposomal doxorubicin (Myocet) and Docetaxel or non-pegylated liposomal visceral metastatic disease. We considered three subsequent determinations in 163
doxorubicin and Cyclophosphamide combination as first line treatment in patient with patients evaluable.
metastatic breast cancer (MBC). Results: Overall mean CgA levels [mean (95% confidence interval, C.I.)] at first,
Patient and methods: fourteen patients with median age of 54 years were treated with second and third sample was respectively125 ng/ml (2-832), 163 ng/ml (2-1111), 137
Myocet 60 mg/mq and Cyclophosphamide 600 mg/mq every three weeks. Twenty ng/ml (1-955). The correlation between CgA levels and disease response showed that,
patients with median age of 48.5 years were treated with Myocet 30 mg/mq and regardless of treatment type, patients with disease progression had mean CgA levels
Docetaxel 75 mg/mq every three weeks. Both of two groups after four cycles underwent higher than patients with stable or responsive disease (p=0,59). Moreover, supposing
restaging to evaluate the clinical response. interaction between CgA secretion and specific treatment, we considered patients
Results: All the patients were assessable for response. No patient has complete response subgroups: in hormonotherapy treated patients mean CgA value progressively increase,
in both groups. Patients treated with Myocet and Cyclophosphamide achieved in whereas it remains steady in chemotherapy treated patients (p=0,17). Regarding the
21.5% (3 out of 14) partial response (>50% decrease of measureable disease), in 42.9% disease sites, CgA levels were significantly higher in patients with non visceral
(6 out of 14) stable disease and in 35.6% (5 out of 14) progression of disease. Median of metastatic disease than in patients with visceral disease (p=0,008). Since visceral
progression free survival was 8 months. Grade 2 neutropenia occurred in 42.9% of metastatic disease patients rarely undergone to hormonotherapy alone, we could
patients and cardiac failure Grade 1 in 7%, no palmar-plantar erythrodysesthesia was suppose an hormonotherapy impact on neuroendocrine phenotype. Median survival
observed. assessed by Kaplan-Meyer survival curves was significantly lower for patients with
Patients treated with Myocet and Docetaxel achieved in 35% (7 out of 20) partial baseline CgA level supranormal than for patients with normal baseline (22,7 vs 25,8

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response (>50% decrease of measureable disease), in 40% (8 out of 20) stable disease mounths, p 0,007).
and in 25% (5 out of 20) progression of disease. Median of progression free survival Conclusion: This data suggest that the neuroendocrine phenotype is a dynamic
was 13.8 months. phenomenon, similarly to prostatic cancer.
Grade 2 neutropenia occurred in 30% of patients and cardiac failure Grade 1 in 5%,
palmar-plantar erythrodysesthesia was observed in two patients (10%).
Conclusions: combination of Myocet and Docetaxel improve progression free C20 EVALUATION OF THE PREDICTIVE EFFECT OF HER-2
survival respect Myocet and Cyclophosphamide as first line treatment in MBC with POSITIVITY ON THE EFFECTIVENESS OF BREAST CANCER
acceptable toxicity. ADJUVANT TREATMENT

Guarino S, Menegatti E, Bonetti F, Indelli M, Urbini B, Modena Y, Carandina I,

POLYMORPHISM IN BREAST CANCER CELLS Clinical Oncology Unit and * Pathology Unit, Azienda Ospedaliero-Universitaria,
Ferrara, Italy
Marianna Terrasi1,2, Elena Fiorio3, Antonio Russo2, and Eva Surmacz1
1 Introduction: HER-2 is rising up as factor predicting the response to several drugs
Sbarro Institute for Cancer Research and Molecular Medicine, Temple
University, Philadelphia, USA, 2Section of Medical Oncology, Department of employed in the treatment of early and advanced breast cancer beside its negative
Surgical Oncology, Palermo, Italy, 3Department of Oncology, University of prognostic value.
Verona, Italy Patients and methods: This retrospective study was carried out in order to evaluate the
predictive role of HER-2/neu amplification/ hyperexpression on effectiveness of breast
Leptin, a hormone produced mainly by the adipose tissue, regulates energy balance cancer adjuvant treatment.
acting in the brain. In addition, leptin can stimulate mitogenic and angiogenic Results: We evaluated 840 patients, of which 256 with HER2 positive (HER2+, 30,5%)
processes in peripheral organs. Recent data suggested that leptin can be involved in and 584 with HER-2 negative (HER2-, 69,5%) cancers. Median follow-up was 33
breast cancer progression, as it can induce proliferation, survival and anchorage- months. HER2+ tumors were more frequently associated with a greater size (p=0,003),
independent growth of breast cancer cells and is abundant in breast cancer tissues. The nodal envolvement (p=0,004), poor differentiation (p=0,0001), high proliferative
mechanisms of leptin overexpression in breast cancer are not clear. The G to A index (p=0,0001) and lack of expression of hormonal receptors (p=0,0001) comparing
substitution at -2548 in the leptin gene (Lep-2548G/A allele) in adipocytes correlated to those with HER2-. We did not see any significative differences in disease free survival
with a two-fold increase of leptin secretion and elevated circulating leptin levels. (DFS) between HER2+ (median 215 months) and HER2- (median 123 months,
Furthermore, the occurrence of Lep-2548G/A in leukocytes correlated with increased p= 0,4900). Tamoxifen therapy did not result in significative differences between the
susceptibility for different neoplasms, including breast cancer. However, molecular two groups (median DFS not reached, p=0,4593). Anthracycline-based chemotherapy
bases underlying this association have never been investigated. Here we asked whether did not provide significative differences between HER2+ and HER2- (median DFS
occurrence of Lep-2548G/A in breast cancer cells could modulate transcriptional resp. 185 vs. 87 months, p=0,6476).
activation of the leptin gene. Conclusions: In our study HER-2/neu amplification/ hyperexpression is associated
Lep-2548G/A was identified in MDA-MB-231 breast cancer cells, while it was absent in with other negative prognostic factors with statistic significance even if survival analysis
MCF-7 cells. DNA analysis revealed that Lep-2548G/A mapped near binding site for did not feature HER-2+ as a negative prognostic factor. These results are partly
a transcriptional factor SP-1 and contained a motif for binding a transcriptional explained by the short median follow-up (< 3 years).
repressor nucleolin. Thus, we focused on the impact of Lep-2548G/A on the
functional interactions of SP-1 and nucleolin with the leptin gene promoter.
Chromatin immunoprecipitation assays demonstrated that the existence of Lep-
2548G/A improved efficient recruitment of SP-1 to DNA, especially under insulin C21 GYNECOLOGIC SIDE EFFECTS OF TAMOXIFEN (TAM) IN THE
treatment, while SP-1 loading with or without insulin on DNA containing Lep- ADJUVANT TREATMENT OF BREAST CANCER: A RETROSPECTIVE
2548G/G was minimal. In contrast, nucleolin binding to Lep-2548G/A was OUTCOME STUDY
downregulated in response to insulin, while it was not regulated on Lep-2548G/G.
These results were confirmed by DNA affinity immunoprecipitation with specific Indelli M, Travasoni F, Santini A, La Torre L, Querzoli P*, Martinello R**, Simone G**
Lep-2548G/A and control probes. Enhanced loading of SP-1 near Lep-2548G/A was and Lelli G
paralleled by higher basal and insulin-induced expression of leptin mRNA in Clinical Oncology Unit, * Pathology Unit, **Ginecology Unit, Azienda
MDA-MB-231 cells. In conclusion, the occurrence of Lep-2548G/A can enhance basal Ospedaliero-Universitaria, Ferrara, Italy
and insulin-induced leptin expression in breast cancer via SP-1- and nucleolin-
dependent mechanisms. Background: Nowadays side effects of TAM on female genital apparatus is an actual
issue because of its still wide use in breast cancer adjuvant therapy and its mostly
discussed efficacy in avoiding cancer in high risk women.
C19 CHROMOGRANIN A AS PROGNOSTIC TOOL IN METASTATIC Materials and methods: We carried out a retrospective study of 591 patients
BREAST CANCER undergoing adjuvant endocrine therapy with TAM at our institution. We evaluated the
main endocrine therapy side effects, subjective and not: flushing, leukorrhoea, spotting,
Polimeni MA, Beano A, Mistrangelo M, Spadi R, Ardine M, Donadio M, metrorrhagia. We also considered endometrial disease occurrences such as invasive
I Chiappino, N Birocco, R Volpatto, V Contu, Ciuffreda L. SC Oncologia Medica, diagnostic techniques (cytology, biopsy), carcinomas, hysterectomies.
ASO S. Giovanni Battista, Torino Results: Flushing was the most common TAM side effect, followed by leukorrhoea and
Background: Human chromogranin A (CgA) is a member of the Granin family, vaginal bleeding. Flushing and leukorrhoea are more common in post-menopausal
mapping on chromosome 14. Its role in the physiopathology of neuroendocrine cells is women (p=0,001). 28% of patients underwent one invasive diagnostic evaluation at
yet unknown, as the biologic and clinical meaning of neuroendocrine phenotype in least (median 1.7, range 1-7). In 43% of cases no disease was histologically retrieved,
non-neuroendocrine carcinomas. The aim of present study is evaluating CgA levels as whereas among benign diseases (54%) atypic hyperplasia rate was 2%. Among the 27
prognostic tool in metastatic breast cancer (MBC). hysterectomies 5 endometrial, two ovarian, two cervix, and one metastatic breast
Patients and methods: From January to September 2006 we evaluate CgA serum cancers were diagnosed.
levels with IRMA method once every four weeks in 165 MBC patients. We Conclusions: We confirmed a low rate of endometrial cancer. The high invasive
considered altered CgA levels upper to 100 ng/ml. All patients achieve specific diagnostic techniques rate needs a careful evaluation in the absence of defined
antitumoral treatment (chemo- or hormonotherapy). Median age was 47 years endometrial thickness ultrasounds cut-off in asymptomatic women.

Volume 18 | Supplement 11 | October 2007 doi:10.1093/annonc/mdm425 | xi41

session C Annals of Oncology

ADVANCED(LA) AND/OR METASTATIC(M) BREAST CANCER(BC) Federica Merlin1, Tiziana Prochilo1, Antonella Savio2, Francesco Metelli3, Basem
Kildani1, Giordano Domenico Beretta1
Cecilia Nisticò, MD1, Emilio Bria, MD1, Federica Cuppone, MD1, Armando Ospedale Sant‘Orsola Fatebenefratelli, Medical Oncology, Brescia, ITALY,
Carpino, MD2, Isabella Sperduti, PhD3, Giuseppe Toglia, MD2, Vanja Vaccaro, Ospedale Sant’Orsola Fatebenefratelli, Pathology, Brescia, ITALY, 3Ospedale
MD1, Simona Barberi, MD1, MS3, Diana Giannarelli, PhD3, Francesco Cognetti, Sant’Orsola Fatebenefratelli, Sugery, Brescia, ITALY
MD1, Edmondo Terzoli, MD1
1Department of Medical Oncology, Regina Elena National Cancer Institute, Background: Approximately 35-40% of all new breast cancer occurred in women aged
Rome, Italy; 2Cardiology, Regina Elena National Cancer Institute, Rome, Italy; 70 years or more. Direct data on pathology and biology characteristics and optimal
3Biostatistics, Regina Elena National Cancer Institute, Rome, Italy treatment in older patients are limited. The aim of this retrospective study was to
analyzed biologic, clinic characteristics, treatment and survival in 182 breast cancer
Background: Trastuzumab for HER-2 positive advanced and adjuvant BC has changed patients (pts), recruited in a single institution.
the natural history of the disease. Nevertheless, an increased incidence of unexpected Patients and methods: Between January 1994 and September 2006, 182 consecutive
cardiotoxicity has been observed when T has been added to anthracyclines and taxanes. patients had a histologically confirmed diagnosis of breast cancer. Median age was 77
The weekly adiministration of EP plus G-CSF in unselected MBC pts did provide a low (range 70-94), about 40% of pts were aged 80 or more.

Downloaded from at UCHSC Denison Memorial Library Box A-003 on February 13, 2011
rate of cardiac toxicity in a previous phase II study (Nisticò, Anticancer Drugs 2007). In
Results: In 70% of pts, initial local treatment consisted of mastectomy, 27% underwent
order to assess the cardiotoxicity of T plus weekly ET in HER-2 pts, a feasibility-phase
quadrantectomy or tumorectomy. Lymph-node metastases were detected in 71 of 131
II study was designed.
(72%) patients. Tumors were stage T1-T2 in 73 %, mostly cases (101/182) were Grade
Methods: Untreated HER-2 positive (FISH/CISH amplification or +++ Dako Test) 2-3 and 78% of the tumors were hormone-sensitive. At a median follow-up of 38
LABC or MBC pts were planned to receive weekly T (4-2 mg/kg/week) on day 1, and E months after diagnosis (range 5-137), only 21 (11%) patients dead of disease (11,5%)
(25 mg/m2/week) plus P (80 mg/m2/week) on day 2, plus G-CSF support, for 16/24 and 16 pts dead for other causes. Breast cancer specific survival’s analysis demonstrated
weeks in LA/M setting respectively, in absence of significant toxicity or progression. statistical significance for the following factors: stage T, positive axillary nodes, steroid
Exclusion criteria: significant cardiac disease or L-FEV<50%. The rate of pts with status and high expression of c-erb2 (p>0,005). Stage T4 tumors (40 pts), had
L-FEV reduction >10% after 12 weeks of treatment was the chosen primary endpoint. associated unfavorable factors (ER/PgR negative, G3 and high proliferative index).
According to an optimal 2-stage Simon model, with a power of 90% at a 5% At univariate analysis, Hercep-test score 3+ indicated worse overall and disease-specific
significance level, assuming a toxicity rate of 30% as unacceptable, and less than 10% as survival; this data was significantly associated with non hormone-sensitive tumors,
acceptable, an initial step with 15 pts was required; after 11 pts with no toxicity, positive nodal status, stage T4 and G3.
a second step with further 21 pts (total: 36) was planned. Secondary end-points were
Conclusions: Also our results show that in elderly women breast cancer has more
non-cardiac toxicity and activity rates.
frequently biological favorable characteristics, but in pts with more aggressive tumors
Results: Fiftheen pts were enrolled between May 2004 and March 2007. Pts features: (T4 or Hercept-test 3+) disease specific survival is worse. In our study, about 30% of
median age=47 (range 37-69); LABC/MBC=4/11; positive hormonal receptor 8/7; women, because of clinical condition and comorbidity, didn’t received standard
menopausal pre/post=7/8; PS 0/1=14/1; number of met sites 1/2/3=7/6/2. Median treatment. We are really convinced that the goal in treating breast cancer in older
baseline- and post-week-12-L-FEV was 69% (range 64-77) and 65% (range 61-76), patients is considered, in decision making, not only age or age-related conditions but
respectively. Three pts had a >10% L-FEV reduction (20%), with an overall median also the characteristics of tumor and all new treatments available.
L-FEV reduction of 5.2%, with a median number of courses of 13 (range 8-24). No
EKG alteration or specific symptoms were present. At a median follow-up of 17
months, 13 pts were evaluable for response. Eight response (61.5%, 95% CI 9-87) were C25 INVASIVE BREAST CANCER AND AGE-RELATED
achieved, with a 9-months median duration of response. Except for severe alopecia, no PROGNOSTIC FACTORS
other grade 3-4 toxicity were documented.
R. di Rocco, A. Romiti, C. Amanti, D. Di Stefano, C. Renzi*, P. Pasquini*, I. Sarcina,
Conclusions: From both a symptomatic and non-symptomatic (L-FEV reduction)
V. Durante, C. D‘Antonio, P. Marchetti
cardiac toxicity perspective, the weekly administration of T plus EP seems safe. Due to the
Sant’Andrea Hospital, IDI-IRCCS* Rome, Italy
low L-FEV reduction rate, the second step of the present study is currently ongoing.

Background: About 6% of breast cancers occur in women below 40 yrs of age. In this
C23 MAMMOGRAPHIC SCREENING IN VERONA: IMPACT ON group, several studies reported both a more aggressive tumour behaviour and/or
CLINCAL, PATHOLOGICAL AND SURGICAL VARIABLES OF A a different distribution of some clinico-pathological features. Aim of the study: to
HOSPITAL CASE SERIES OF 4645 PATIENTS evaluate specific pathological parameters, such as tumor size and grade, node status,
ER, PgR, HER2-neu, P53 and Ki67, with respect to patient’s age.
A. Mercanti1, E. Fiorio1, A. Auriemma1, A. Caldara 1, S. Cingarlini 1, R. Micciolo2, Patients and methods: We reviewed the charts of 712 patients diagnosed with
A. Santo1, G. L. Cetto1, A. Molino1 invasive breast carcinoma, at our institution, over a period of 10 yrs: 68 (9.5%) were <
Department Oncology, University of Verona, Italy; 40 yrs old at diagnosis (mean: 35.6 yrs ± 3.8 SD). A control group of 138 women,
‡40 yrs of age (mean 57yrs ± 12.7 SD), with comparable disease stage, was selected.
Background: The mammographic screening was introduced in Verona in July 1999; Relapse rate and disease free survival (DFS) were calculated in the two groups.
the target is female population between 50 and 69 years old of age and the Immunohistochemical analysis was used for ER, PgR, HER2-neu, P53 and Ki67
mammography has performed every two years. determination. Statistical analysis included: the Fisher’s exact test for univariate
analysis, Cox regression model for multivariate analysis and Kaplan-Meier method to
Patients and methods: Data are collected from the University and Civic Hospitals of calculate DFS. p value <0.05 was considered significant.
Verona, and the impact over the time of the mass screening’s introduction is evaluated
on clinical, pathological and surgical variables. The chi-squared test and multinomial Results: Hormone receptors were more frequently expressed in older women
logistic regression are used to perform a time related difference. (p<0.05 for ER and PgR) while HER2-neu overexpression (3+) (p<0.05), Ki67 value
(p<0.01) and tumour grade (p<0.01) were higher in tumours of younger women.
Results: We compare clinical, pathological and surgical variables in pre- screening P53 expression showed no significant difference between the two groups. At a median
versus post screening period. follow-up time of 25 months, 11 (16.2%) and 5 (3.6%) relapses were observed in the
The proportion of cases diagnosed with in situ disease increase from 10.7% to 16.9% younger and older patients, respectively (p<0.05). 5-yr DFS was 76% and 95.2% in
(p<0.001). younger and older women, respectively (p=0.09). Younger age and node status were
Invasive breast cancers show an increase in pT1 stage (62.9% vs 69.7%; p<0.001), independent relapse risk factors in univariate and multivariate analyses (HR= 6.03, IC
particularly those of dimension <10 mm (31.1% vs 40%, p<0,001). 95%: 1.01-36.08, p<0.05 and HR 11.60, IC 95%:1.27-105.49, p<0.05 respectively).
We do not found a statistical significance for the impact on age at diagnosis.
There is a considerable increase in asymptomatic breast cancers both in invasive Conclusions: Our findings demonstrate a peculiar distribution of some pathologic
tumours (32.6% in pre-screening period versus 47.6 in post screening period, p<0.001) parameters, probably associated with a more unfavourable outcome, in younger breast
and, mostly, in in situ carcinomas (58.4% vs 80.7%, p<0.001). cancer patients.
There is a marked shift from demolitive to conservative surgery for both invasive
(31.5% vs 45.7%; p<0,001) and in situ carcinoma (49% vs 81.9%; p<0,001); collaterally C26 SAFETY AND ACTIVITY OF TRASTUZUMAB (TRA)
complete axillary dissection for both invasive (90.6% to % 70.5%; p<0,001) and, CONTAINING THERAPIES AS TREATMENT OF METASTATIC BREAST
mostly, in situ carcinoma (65.1% vs 21%; p<0,001) decreases. CANCER (MBC): A FIVE-YEAR EXPERIENCE
Conclusions: Mammographic screening has both a direct efficacy for screen-detected
breast cancers and an indirect efficacy making the women awareness about the Rosalba Rossello1, Barbara Adamo1, Tindara Franchina1, Claudia Garipoli1,
importance of early breast cancer detection. Monica Iorfida1, Vincenzo Festa1, Erika Montalto1, Maria Rosaria Valerio2, Antonio
Our hospital datas prove both these effects and their impact on breast cancer Russo2, Vincenzo Adamo1
variables in operated patients. Dipartimento di Patologia Umana, U.O. Oncologia Medica e Terapie Integrate,
We observe an increase of asymptomatic diagnosis, in situ carcinomas and smaller A.O.U. Policlinico ‘‘G. Martino’’, Messina. 2Dipartimento di Oncologia, Sezione
invasive tumours; the immediate consequence is a less invasive surgery and a better prognosis. di Oncologia Medica, Università di Palermo

xi42 | session C: early and advanced breast cancer Volume 18 | Supplement 11 | October 2007
Annals of Oncology session C
Background: HER2 over-expression has been reported in 20%-30% of BC. TRA is Measurement of the left ventricular ejection fraction (LVEF) was carried out before
widely used as treatment of choice for HER2-positive MBC. the first and after the fourth cycle. All patients completed cycles without dose
Purpose: To evaluate safety and activity of TRA containing therapies in HER2 positive reduction. After the fourth cycle patients underwent modified radical mastectomy
MBC patients (pts). (8 pts) or conservative surgery (16 pts). Radiotherapy was performed on patients
who underwent conservative surgery or in T4 tumours. Stage after surgery was: Stage
Patients and methods: 70 pts (median age 57 (31-81 yrs), ECOG PS/pts 0/56, 1/12, 2/2;
0 in 3pts, I in 7 pts, IIA in 5pts, IIB in 5 pts; IIIA in 4 pts. Her-2/neu pos in 9 pts and neg
ER+ 57%, PR+ 40%, 49/70 pts with visceral disease and 41/70 with metastases in two or
in 15 pts. ER/PR status was ER-/PR-in 10 pts; ER+/PR+ in 9, ER+/PR- in 5. We
more sites), treated with TRA from May 2001 to June 2006, were included in our
obtained: 6 CR; 14 PR; 4 SD. G1 thrombocytopenia occurred in 6 pts and G1 anemia
retrospective analysis. TRA was administered alone in 12 pts and in combination in 58
in 10 pts. Main non-haematologic toxicities were: G1 nausea (10 pts), G2 fatigue
pts: 48% with vinorelbine, 29% with docetaxel and 23% with paclitaxel. Previous
(10 pts) and alopecia (all pts). No congestive heart failure was observed. The
treatments for metastastic disease were hormonotherapy in 11 pts (16%) and 1 or more
combination of EPI and NVB is safe and effective in LABC pts. G-CSF offers
lines of chemotherapy in 25 pts (36%).
important benefits in terms of CT dose maintenance and haematological toxicity
Results: First line treatment: RR 41%, SD 47%, with TTP 8 months (1-44); Second line: prevention.
RR 23%; SD 62% with TTP 9 months (3-23); beyond second line: RR 22%; SD 78%
with TTP 9 months (4-19). OS was 19,2 months (3-62). Median cumulative TRA dose
was 5286 mg (464-17940 mg). TRA was well tolerated. The median LVEF was at
baseline 62% and 59% at the end. Relevant adverse events were: only one asymptomatic
LVEF decrease to 40% (baseline 60%) requiring treatment discontinuation, 6 reversible

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asymptomatic LVEF decrease (10% to 15%), 2 reversible tachycardia, 1 G3
Grazia Palomba1, Antonio Cossu2, Mario Budroni2, Eitan Friedman3, Antonio
hyperbilirubin, and 2 transient increase transaminases.
Farris4, Antonio Contu2, Marina Pisano1, Paola Baldinu1, Maria C. Sini1, Maria P.
Conclusion: Trastuzumab containing therapies in MBC are safe with a remarkable Satta1, Milena Casula1, Francesco Tanda4, Giuseppe Palmieri1
activity even in heavily pretreated women. Patients should benefit from continued 1
Istituto di Chimica Biomolecolare-CNR, Sassari; 2Azienda USL 1, Sassari;
Trastuzumab therapy, as shown by the maintenance of TTP even beyond second line 3
Chaim Sheba Medical Center, Tel-Hashomer, Israel; 4 Università degli Studi di
treatment. Sassari

C27 TRASTUZUMAB DISCONTINUATION DUE TO Background: The BRCA2-8765delAG mutation was firstly described in breast cancer
CARDIOTOXICITY IN WOMEN WITH HER2-POSITIVE OPERABLE AND families from French-Canadian and Jewish-Yemenite populations; it was then reported
ADVANCED BREAST CANCER: A SINGLE INSTITUTION EXPERIENCE as a founder mutation in Sardinian families. We evaluated both the prevalence of the
BRCA2-8765delAG variant in Sardinia and the putative existence of a common
Stefania Redana, Giorgio Valabrega, Renato Palmiero, Cinzia Ortega, Luisa Omini, ancestral origin through a genotype analysis of breast cancer family members carrying
Massimo Aglietta, Filippo Montemurro such a mutation.
Istituto per la Ricerca e la Cura del Cancro, Candiolo, Torino, Italy Methods: Eight polymorphic microsatellite markers (D13S1250, centromeric, to
D13S267, telomeric) spanning the BRCA2 gene locus were used for the genotype
Background: Trastuzumab-related depression of myocardial contractility is of concern analysis. Screening for the 8765delAG mutation was performed by PCR-based
and makes cardiac function monitoring mandatory during treatment. We sought to amplification of BRCA2-exon 20, followed by automated sequencing.
compare treatment discontinuation because of trastuzumab-related cardiotoxicity in Results: Among families with high recurrence of breast cancer (> 3 cases in first-degree
women treated with trastuzumab-based therapy for advanced or operable breast cancer relatives), those from North Sardinia shared the same haplotype whereas the families
(adjuvant setting). from French Canadian and Jewish-Yemenite populations presented distinct genetic
Patients and methods: The medical charts of 113 patients with advanced disease and of assets at the BRCA2 locus. Screening for the BRCA2-8765delAG variant among
30 with operable disease were retrospectively analysed. All 143 patients underwent unselected and consecutively-collected breast cancer patients originating from the
regular monitoring of left-ventricular ejection fraction by ultrasonography and, if entire Sardinia revealed that such a mutation is present in the northern part of the
required, by multiple gated acquisition scan. In patients with operable breast cancer island only [9/648 (1.4%) among cases from North Sardinia versus 0/279 among cases
trastuzumab was started after the completion of chemotherapy and, if administered, of from South Sardinia].
radiation therapy and continued for 1 year. For these patients, we adopted the criteria Conclusions: The BRCA2-8765delAG has an independent origin in geographically and
of the Agenzia Italiana del Farmaco (AIFA) protocol which called for definitive ethnically distinct populations, acting as a founder mutation in North but not in South
trastuzumab stoppage in the case of congestive heart failure (CHF), LVEF drop Sardinia. Since BRCA2-8765delAG occurs within a triplet repeat sequence of
‡45%, or LVEF drop <50% with an absolute reduction compared to the baseline AGAGAG, our study further confirmed the existence of a mutational hot-spot at this
value £10% during treatment. genomic position (additional genetic factors within each single population might be
Results: 10 patients, 5 with advanced (4%) and 5 with operable disease (20%), stopped involved in generating such a mutation).
treatment because of cardiac toxicity (7%, 95% C.I. 4-12%). Of patients with advanced
disease, 2 developed congestive heart failure and 3 had an asymptomatic decline in
LVEF >20% or below the threshold of normality. Of patients receiving trastuzumab in C30 ROLE OF VACUUM-ASSISTED BIOPSY (MAMMOTOME) IN
the adjuvant setting one developed symptomatic CHF, and 4 experienced an EARLY DETECTION OF BREAST CANCER
asymptomatic reduction in LVEF. The Cox Proportional Hazard analysis showed that
the risk of trastuzumab stoppage was higher in patients treated in the adjuvant setting Pagni P. 1, Spinelli GP. 2, Miele E.1, Tomao F.1, Caprio G.1, Russillo M.1, Rossi L.2,
(HR 3.674, p=0.02). Ielapi T.2, Codacci Pisanelli G.1, Tomao S.2
Department of Experimental Medicine, ‘‘Sapienza’’ University, Rome, Italy;
Conclusion: Trastuzumab is discontinued more frequently in the adjuvant than in the 2
Department of Experimental Medicine, University of Rome‘‘Sapienza’’-Polo
metastatic setting on account of cardiotoxicity. This is due in part to stricter cardiac-
safety criteria adopted for patients with early disease. However, shorter time between
anthracycline-based chemotherapy and trastuzumab in the adjuvant setting is likely to
concur. Strategies aimed at increasing compliance to adjuvant trastuzumab by Background: The role of vacuum-assisted biopsy tecnique (Mammotome) in detection
reducing the risk of cardiotoxicity-related treatment stoppage are needed. of early breast cancer (eBC) is still under evaluation. This minimal invasive device has
similar diagnostic accuracy of conventional core biopsy with few traumatisms and
aesthetical consequences. However mammotome can understimate some pathologies
C28 NEOADJUVANT CHEMOTHERAPY WITH EPIRUBICIN- such as atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS). The
VINORELBINE AND G-CSF IN LOCOREGIONALLY ADVANCED aim of our study is to evaluate advantages of eco-guided mammotome biopsy in early
BREAST CANCER: OUR EXPERIENCE detection and eventual complete excision of BC.
Patients and methods: Form January 2003 to January 2006, 229 female patients (pts)
Savarino A, Fabiano E, Maniaci V, Puliafito I, Sauta M. G, Bene A with breast lesions were studied. The average age was 48 years (range 19–75).
ASL 1 Agrigento; Human Pathology Department-Medical Oncology and Performance status (ECOG) was 0/1. The previous ultrasound examination showed
Innovative Therapies Unit, University of Messina regular lesions in 173 pts (75,6%), irregular nodules in 39 pts (16,9 %), poly-lobate
nodules in 13 pts (5,6%) and dishomogeneous echostructure in 4 pts (1,7%). In 181
Neoadjuvant chemotherapy (NACT) has shown to be a valid help in the treatment patients a rx mammography was also performed. All patients underwent biopsy under
of locoregionally advanced breast cancer (LABC) because it reduces the use of echographic guidance using Mammotome with 11-Gauge needle.
radical breast surgery. Epirubicin (EPI) and Vinorelbine (NVB) have demonstrated Results: Hystology of biopsies carried out with Mammotome confirmed the
to be the most active drugs. The aim of our study is to evaluate complete response benign nature (fibroadenoma) of all 173 pts with echographically regular nodules.
(CR), partial response (PR), stable disease (SD) and toxicity after 4 cycles of EPI/NVB. There were 12 positive malignant pathology (10 ductal, 2 lobular infiltrating
From January to November 2006, twenty-four women with mean age of 48 years carcinoma), 17 benign sclerosis adenosing lesions, 4 ADH and 4 fibroadenomas
old (32-69) were enrolled in this study. Clinical stage at diagnosis was T2:9 pts, T3: 7 diagnosed in pts with irregular nodules. The remaining biopsies showed NOS
pts, T4:8 pts. Lymphonodal status was N0:2 pts, N1: 10 pts, N2: 9 pts, N3: 3 pts. benign lesions. The procedure was well tolerated and no side effects were reported.
Patients received EPI 100 mg/m2 i.v. day 1 plus NVB 25mg/m2/die from days 1 to The only complication of Mammotome biopsy is represented by haematoma in
5 every 3 weeks for 4 cycles, with 300 lg of G-CSF as prophylaxis from day 8 to 13. a low percentage of pts.

Volume 18 | Supplement 11 | October 2007 doi:10.1093/annonc/mdm425 | xi43

session C Annals of Oncology

Conclusion: Mammotome biopsy of echographically evidenced lesions of the breast, in C32 BIS CLINICAL BENEFIT OF FULVESTRANT IN HEAVILY
our experience, is preferable if suspicion of malignancy is high. Comparing with FNAC PRETREATED PATIENTS WITH METASTATIC BREAST CANCER
it gives more informations in terms of invasivity, grading, histotype and hormonal
receptors. It is a well tolerated procedure with little discomfort for the patient. Today Giuseppa Scandurra, Guido Carillio, Rosa Anna Aiello, Maurizio Chiarenza,
this device could be considered as an innovative technique for the diagnosis of BC Antonella Mazzola, Marco Alı̀, Gloria Barone, Filippo Greco, and Michele Caruso
against it incisional and excisional biopsy and FNAC too. Department of Medical Oncology, Humanitas Centro Catanese di Oncologia,
Catania, Italy

Fulvestrant is a steroidal estrogen receptor (ER) antagonist with no agonistic activity,

C31 THE USEFULNESS OF 99MTC-TETROFOSMIN PLANAR providing possible advantages over tamoxifen and other selective estrogen receptor
SCINTIMAMMOGRAPHY AND SPECT IN THE EVALUATION OF modulators (SERMs) in the treatment of hormone-sensitive breast cancer. The once-a-
NEOADJUVANT HORMONE OR CHEMOTHERAPY RESPONSE IN month administration of fulvestrant 250 mg in 5 mL intramuscular injection produces
LOCALLY ADVANCED PRIMARY BREAST CANCER (LAPBC) down regulation of ER levels through the bind to receptors and rapid loss of ER protein
in the tumour.
Giuseppe Madeddu,1 Antonio Farris,2 Francesca Chessa,1 Daniela Sanna,1 Maria Since November 2005 to January 2007 we tested objective response, clinical benefit,
Pittalis,2 Carlo Putzu,2 Susanna Nuvoli1 and Angela Spanu1 and safety of fulvestrant administered as maintenance or disease progression therapy in
Depts. of 1Nuclear Medicine and 2Oncology. University of Sassari. Sassari. Italy heavily pretreated patients with metastatic breast cancer. Among 66 enrolled patients,

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56 of them were evaluable for the above end-points. Fifty-five female and one male
patient entered the study, ECOG PS 0-3, median age 59 years (range 32–87), estrogen
Aim: To evaluate and compare the usefulness of 99mTc-tetrofosmin planar and progesterone receptor positive in 100% and 16%, respectively, HER-2/neu
scintimammography (SM) and SPECT in monitoring neoadjuvant hormone or overexpressed in 23%, bone metastasis as only site of disease in 14% of cases. All the
chemotherapy response in LAPBC patients. patients had already received on average two endocrine therapy lines (range 1–4) and
Methods: 24 LAPBC patients were studied before and after completing hormone (8 three chemotherapy schedules (range 1–6) including anthracyclines and taxanes.
cases) or chemo (16 cases) neoadjuvant therapy prior to surgery. In all cases, following With a median treatment duration of 5 months (range 2–18), we observed 3 partial
740 MBq 99mTc-tetrofosmin i.v. injection, both conventional planar SM and SPECT responses (5%) and 30 disease stabilizations (54%) for at least 6 months. The clinical
were acquired using a dual-head gamma camera with HR parallel hole collimators. benefit rate was 59%. Partial responses occurred in patients with soft tissue or visceral
In 10 cases planar SM with a new developed small field of view high spatial resolution disease. A PS improvement was often recorded in the elderly patients (more than 70
(1.6 mm) DBC (LumaGEM 3200S/12k) mounted on a modified mammography unit years), compared with poor benefit in the younger women (less than 50 years),
allowing similar projections of mammography and breast compression during probably because of more frequent HER-2/neu overexpression in the latter group.
acquisition was also acquired. Planar and SPECT findings were evaluated visually, Fulvestrant was well tolerated and none of patients reported noteworthy side effects.
mutually compared and correlated with definitive histopathological findings. Interestingly, we couldn’t always find a direct correlation between clinical benefit and
Results: Four patients had complete pathologic positive response, while residual tumor reduction of tumour markers, that probably reflects the slow and progressive drug
was ascertained at histology in 28 patients. No uptake areas were detected at both steady state reachable after 3 to 6 months of treatment.
conventional planar SM and SPECT, excluding residual tumor after therapy in 3/3 Fulvestrant represents an effective and optimally tolerated therapy in heavily
(100%) cases. DBC planar SM was performed in 1 of these 4 cases resulting true pretreated patients with endocrine responsive metastatic breast cancer.
negative. Conventional planar SM detected residual tumor in 17/21 (80.9%) cases,
resulting false negative in 2 with a pT1c tumor and in 2 patients with subcentimetric
multiple and scattered tumor foci. SPECT was true positive in 19/21 (90.5%) cases, but C34 PRELIMINARY RESULTS OF A DOSE-FINDING STUDY OF
missed both subcentimetric tumors which were also false negative at conventional PTK787/ZK222584 (PTK/ZK) IN COMBINATION WITH WEEKLY
planar SM. However, these latter 2 carcinomas were identified only at DBC planar SM VINORELBINE (V) AND TRASTUZUMAB (T) AS TREATMENT OF
which was true positive also in the other 7 patients with macroscopic residual tumor in PATIENTS (PTS) WITH METASTATIC BREAST CANCER (MBC)
whom the procedure was performed. OVEREXPRESSING HER-2/NEU, PREVIOUSLY TREATED WITH AT
Conclusion: Both conventional planar SM and SPECT proved useful diagnostic tools
in monitoring neoadjuvant hormone or chemotherapy response in LAPBC. SPECT
G. Gasparini1, M. R. D’Andrea1, F. Cacciamani1, F. Salerno1, G. Filippelli2,
appears more sensitive than conventional planar SM in detecting residual tumor;
M. Lucia2, V. A. Lonoce1, and R. Sarmiento1
however, our preliminary data seem to suggest that sensitivity can further increase by 1
U.O. Oncologia Medica A.C.O. San Filippo Neri, Roma; 2Oncologia Medica
high resolution DBC planar SM, especially in subcentimetric tumor foci.
Ospedale ‘‘S. Francesco di Paola’’, Paola (CS)

Overexpression of HER2 in human cancer is associated with increased expression of

vascular endothelial growth factor (VEGF). The anti-HER2 monoclonal antibody
C32 EVALUATION OF HER-2 STATUS ON CIRCULATING TUMOR trastuzumab (T) inhibits tumor growth and VEGF expression. The combination of
CELLS (CTCS) IN PATIENTS WITH BREAST CANCER vinorelbine (V), and T, is an active and safe 2nd-line treatment for MBC patients (pts),
overexpressing HER-2/neu. PTK/ZK is a potent, selective and orally active inhibitor of
M Pestrin, S Bessi, M Truglia, F Galardi, S Cappadona, C Biagioni, W Claudino, VEGF-R tyrosine kinases. Based on the observation that HER2-induced VEGF
D Pozzessere, L Biganzoli, A Giannini and A Di Leo expression results in increased angiogenesis and that blockade of HER2 receptor and
Translational Research Unit, Dept. of Oncology, Hospital of Prato, Istituto VEGFR may result in superior antitumor efficacy, we have designed a Phase I dose-
Toscano Tumori finding study testing the combination of V, T, and PTK/ZK in HER-2/neu + MBC pts.
1ary objective of the study: MTD of the combination. 2ary objectives: safety,
Introduction: Recent studies suggest that HER-2 status of HER-2 negative primary pharmacokinetics (PK) and activity. The study design is based on 4 dose levels (DL): V
tumors could change during disease progression. The HER-2 status might be reassessed starting from 20 to 30 mg/mq (d 1-8-15, q 28), PTK/ZK from 500 mg/daily to 1250
at the time of starting treatment. Evaluation of HER-2 on CTCs isolated from blood mg/daily. 7 pts have been enrolled so far (median age: 54): median n. of metastatic
samples could represent a real-time analysis of the protein status. sites: 2; ER/PgR status negative (5/7), ER+/PgR- (2/7), HER-2/neu positive (3+ by
Patients and methods: Study aims were to evaluate the correlation between: HercepTest in 6/7, FISH test amplified in 1 pt). First 3 pts were treated according to
1.CTCs number and disease features the study design; no DLT was found; 3 more pts were then enrolled at the 2nd DL and no
2.HER-2 status on CTCs and primary tumor DLT was also found. One pt has been enrolled at the 3rdDL. Combination therapy has
Blood samples were obtained from 47 patients with breast cancer at different phases generally been well tolerated, being the most common toxicities observed: nausea G1
(2 neoadjuvant, 7 adjuvant and 38 metastatic). CTCs were immunomagnetically (2/7), muscoloskeletal diffusal pain G1 (2/7), pruritus G1 (1/7), non febrile neutropenia
separated and fluorescently stained using the CellSearch Kit. CTCs stained positive G3 (2/7). 5 pts are evaluable for response: 1 RC and 4 SD have been observed. PK
for DAPI and CK8,18 and/or 19. The HER-2 status was assessed using the Tumor analysis is also being conducted, by collecting blood samples on days 15 and 18 of the
Phenotyping Reagent. Definition of HER-2 positivity was: primary as per standard cycle 0 (V and T alone), and on days 14, 15 and 18 of the 1st cycle (V, T, and PTK/ZK).
criteria; CTC ‡ 50% positive cells. The PK analysis of both V and PTK/ZK is centralized and is ongoing.
Results: CTCs could be detected in 1, 5, 31 patients in neo-adjuvant, adjuvant and
metastatic settings, respectively. The median CTCs number was 7/7,5 ml (range: 0-14), C35 MODULATION OF g/d T-LYMPHOCYTES BY ZOLEDRONIC
3/7,5 ml (range: 0-5), 6/7,5 ml(range: 0-60.000), respectively. Correlation between ACID (ZA): RESULTS IN 23 DISEASE FREE PATIENTS WITH EARLY
HER-2 status on CTCs and primary tumor was performed in 24 cases and we found BREAST CANCER HISTORY
non-concordant results in 33% of cases: 39% of HER-2 negative primary tumors had
HER-2 positive CTCs and 17% of HER-2 positive primary tumors had HER-2 negative Daniele Santini1, Federico Martino2, Maria Elisabetta Fratto1, Bruno Vincenzi1,
CTCs. Sara Galluzzo1, Chiara Agrati2, Paola Piacentini2, Vittorio Altomare3, Federica
Conclusions: We found CTCs in all disease phases. Moreover, our study suggests that Turchi2, Fabrizio Poccia2 and Giuseppe Tonini1
a subset of HER-2 negative patients develops HER-2 positive CTCs. Clinical evaluation Medical Oncology, University Campus Bio-Medico, Rome 2 National Institute
of anti-HER-2 compounds in the subset of patients carrying HER-2 negative primary for Infectious Diseases Lazzaro Spallanzani, IRCCS, Rome 3 Breast Surgical
tumor and HER-2 positive CTCs is warranted. Unit, University Campus Bio-Medico, Rome

xi44 | session C: early and advanced breast cancer Volume 18 | Supplement 11 | October 2007
Annals of Oncology session C
Introduction: Amino-bisphosphonates are potent activators of human c/d T cells both follow-up) and 1032 were without metastases at diagnosis (52 deceased, 791 alive e 186
in vitro and in vivo. ZA is able to activate c/d T cell effector functions also in patients lost during follow-up).
with advanced solid tumors. We conducted an osservational perspective study aimed to Conclusions: Such structured database allows to obtain several informations in
evaluate immunomodulating properties of a single-dose of zoledronic acid on c/d T order to design retrospective studies, obviously knowing their limits, such as the need
cells in a selected patient subset. of high numbers of patients to evidence subtle differences. Nevertheless retrospective
Material and methods: 23 breast cancer patients without any evidence of macroscopic studies are able to observe the real cohort status so defining the impact of different
disease and with diagnosis of osteopenia (Total T score </= -2) during inhibitor factors in order to plan prospective studies later. They also may influence sanitary
aromatase treatment received a single-dose of zoledronic acid 4 mg. For each patient policy choices and available resource distribution.
blood withdrawals for total and c/d T lymphocytes evaluation (by cytofluorimetric
analysis) were obtained before ZA infusion and 7, 28, 56, 90 and 180 days after.
Results: No significant modifications in the absolute number of total lymphocytes, of C38 CLINICAL USE OF THE SERUM MARKER HER-2/NEU IN
the different subsets and no of Vd1 and Vd2 T lymphocytes at the different timepoints PATIENTS WITH BREAST CANCER
have been identified. Kinetics of the different c/d T cells subsets were determined:
a significant decrease of Naı̈ve Vd2 T lymphocytes after 180 days (p<0,01) and Dalu D, Cattaneo MT, Piazza E, Piva S, Gambaro A, Tosca N, Gabris A,
a significant progressive decrease of Central Memory subset after 28 (p<0,05), 90 Filipazzi V, Esani G, Ferrario, Somma L, Sarnataro C, Zambelli S, Damiani E
(p<0,01) and 180 days (p<0,01) was observed. ZA induced also a significant reduction Oncology Department, Sacco Hospital, Milan
of Effector Memory Vd2 T lymphocytes after 56 (p<0,01) and 90 days(p<0,05).

Downloaded from at UCHSC Denison Memorial Library Box A-003 on February 13, 2011
Moreover, we observed that population could be divided in 2 subsets characterized by Background: Her-2/neu is the extracellular domain of the membrane receptor Her-2,
a different c/d T lymphocyte kinetics: ‘‘responder patients’’ with a significant decrease overexpressed in cancer cells. Its levels appear to be increased in aggressive breast
of c/d T lymphocytes total number and of Effector Memory and ‘‘no-responder cancer and in patients who do not respond to therapy.*
patients’’ without any significant modulation of c/d T lymphocytes. Methods: We selected 51 patients, from 37 to 79 years of age. The first group was made
Conclusions: A single dose of ZA has been shown, for the first time in literature, to up of 31 patients with early-stage breast cancer and the second group of 20 patients
exert long-lasting activation of effector subsets of c/d T lymphocytes in healthy with advanced Her-2 positive (2+ and 3+) breast cancer that were starting a course of
patients. Data on functional analysis to verify a hypothetical constitutional anergy of c/ chemotherapy (CMF, FEC or Trastuzumab). We considered the levels of Her-2/neu
d T cells in no-responder patients will be presented during the meeting. before and after surgery and before and after chemotherapy. We evaluated the levels of
serum Her-2/neu using the automated ADVIA Centaur Immunoassay System (cut-off
=12,7 ng/ml) and the expression of the tissue antigen HER-2 using the
C36 NEO-ADJUVANT CHEMOTHERAPY (NACT) FOR BREAST immunohistochemical method HercepTest DAKO Corp.
Results: In the first group of patients who underwent surgery we observed a reduction
in the number of patients who had levels of Her-2/neu above the cut-off point after
Ruscelli S, Masini C, Cortesi L, De Matteis E, Di Emidio K, Proietto M, Iacchetta F,
surgery (67 % before surgery and 33 % after surgery) and a reduction of the average
Braghiroli B, Pesce E, Federico M
level of Her-2/neu (15,6 ng/ml before surgery and 11,8 ng/ml after surgery). Also in the
Cattedra di Oncologia Medica II, Dipartimento di Oncologia ed Ematologia,
second group of patients we recorded a reduction of the average levels of Her-2/neu:
Università degli Studi di Modena e Reggio Emilia
from 63 ng/ml, before chemo-therapy (range 8,7 – 283,5), to 31 ng/ml after the
treatment (range 7,7 – 39), the number of pts with levels above the cut-off falled
Background: NACT was initially proposed in locally advanced inoperable disease and from 81% to 27%.
also in operable BC to achieve downstaging of the tumour, avoiding mastectomy. These variations poor correlate with the clinical response to chemotherapy.
Moreover NACT offers the chance to use the tumour as an in vivo measure of response.
Conclusions: We observed a reduction in the levels of Her-2/neu in both groups of
Patients and methods: We analysed 256 cases of invasive BC treated at Modena Cancer patients but the correlation with clinical response was poor.This would enable us to
Center between 1988 and 2005 with NACT, focusing on the rate of tumour reduction arrange a closer follow-up or identify the patients who are not responding to treatment.
and rate of breast-preserving surgery. Moreover we also compared the outcome of * Diana Luftner ‘‘Serum HER-2/neu in the management of breast cancer patients.’’
patients treated with NACT with 4665 treated with surgery up-front. Clinical Biochemistry 36 (2003).
Results: At time of diagnosis tumour size was < 2 cm (T1) in 14 patients (5.5%),
between 2 and 5 cm (T2) in 111 (43.4%), more than 5 cm (T3) in 34 (13.3%) and
locally advanced (T4) in 97 (37.9%); axillary nodes were clinically positive in 171 C39 TRIPLE-NEGATIVE BREAST CANCER: OUR EXPERIENCE
patients (67.8% ) including 113 (42.9%) N1, 33 (12%) N2, and 25 (9.1%) N3. 227
tumours were infiltrating ductal carcinomas (89%), 137 were G3 (54.4%), 59 (23%) Alessandro Bertolini, Elisabetta Menatti, Ornella Fusco, Eliana Berardi,
were RE- and 77 (30%) PR -. The more frequent regimens were ADM-including in Fabio Malugani, Mario Fiumanò
139 cases (54%), ADM and Taxanes in 75 (29%) and CMF in 23 (9%). A downstaging Oncology Unit Ospedale Civile Sondrio
was achieved in 63 patients with clinical T2 (57%), in 32 T3 (94%) and in 47 T4 (48%).
Surprisingly, only 68 patients (27.3%) underwent conserving surgery. Five-year Background: Triple-negative breast cancers are defined by a lack of expression of
recurrence free survival rate was 56%, being 66% and 51% for patients treated with estrogen, progesterone, and ERBB2 receptors. This subgroup accounts for 15% of all
conserving surgery and mastectomy, respectively (p=0.08). Comparing patients treated types of breast cancer and for a higher percentage of breast cancer arising in African
with NACT with those treated up-front with surgery, we found that the 5-year and African-American women who are premenopausal. Triple negative tumors are
recurrence free survival was 65% vs 92% (p<0.001) for patients in stage I, 66% vs 81% associated with a shorter survival. Patients with BRCA1 mutations develop
(p=0.02) in stage II and 46%vs 62% (p<0.001) in stage III. predominantly triple negative tumors.
Conclusions: Our data show the inefficacy of the NACT to achieve downstaging of the Method: We reviewed in our database as prognostic factors women with breast cancer
tumour. Moreover, the outcome of responders suggests that the downstaging achieved history in the last four year. We decided to look for triple negative population and to
with NACT did not overcome the adverse prognostic effect of disease extension before observe outcome after treatment.
NACT. Results: We observed 170 breast cancer, 19/170 (11.2%) of these were triple negative.
They have: ductal histological type in 18 pts and lobular in 1 pt. Grade: G3 18 pts and
G2 1 pt. Their stage at diagnosis was: I 9 pts, IIA 2 pts, IIB 6 pts, IIIA 1 pt and IIIC 1 pt;
C37 PROGNOSTIC AND PREDICTIVE FACTORS RELATED TO the adjuvant treatment was CMF+RT in 8 cases, AC+T in 6 cases, FEC in 3 cases,
BREAST CANCER CLINICAL HISTORY: AN OUTCOME STUDY Taxotere in 1. 5/19 (26.3%) progressed during follow up with median PFS 20 months.
On the contrary the group not triple negative progressed for 10.6% (16/151). Some of
Donati D, Giuliani J, Guarino S, Urbini B, Margutti G, Indelli M, Durante E*, them were HER2 positive.
Querzoli P*, Beccati D*, Guerzoni F**, Bonetti F, Carandina I, and Lelli G
Clinical Oncology Unit, *Breast Cancer Program, **Pathology Unit and **Health Conclusion: According to literature triple negative population in near to 15% of all
Statistics, Azienda Ospedaliero-Universitaria, Ferrara, Italy patients and they have a poor prognosis. In our study we have less patients because the
entire group is selected by need of treatment. The outcome of the group is different
from the general population. We think that lymphnode stage, grading, and tumor size
Introduction: Prognostic factors correlate to the final therapeutic outcome are still the most useful prognostic markers, but also other factors must be now
independently from the therapy; predictive factors are those that correlate with cancer considered.
therapy efficacy. Outcome studies evaluate the most reliable parameters that may
define the long term result of different strategies.
Materials and methods: Computer clinical record-chart of breast cancer patients C40 THE MEANING OF TIME FOR BREAST CANCER PATIENTS
visited for the first time at our institution between 1/1/1999 and 31/12/2005 were
enriched with bio-pathologic data. Data were copied on paper forms at first and then Cinzia Bonforte, Giuseppe Pastura, Giuseppa Scandurra, Vincenzo Adamo
inserted into a computer database. Each patient form contemplates 181 items. They are Dipartimento di Patologia Umana, U.O. Oncologia Medica e Terapie Integrate,
arranged to automatically calculate overall, disease free and progression free survival A.O.U. Policlinico ‘‘G. Martino’’, Messina
for each patient.
Results: Database includes data concerning 1227 patients. Among these, 195 were Purpose: To re-consider changes occurring into the meaning of time in cancer
metastatic at diagnosis (104 deceased, 69 alive with metastases and 22 lost during experience.

Volume 18 | Supplement 11 | October 2007 doi:10.1093/annonc/mdm425 | xi45

session C Annals of Oncology

Methods: Qualitative study by narrated interviews with a sample of 6 women, Results: At a median follow-up of 7,5 years (range 3,8–8,5 years) 13 pts (52%) relapsed
conducted in DH and interpreted using Bergson’s theory. Finding: Three times and 11 pts (44%) died. The most common sites of recurrence were lung, liver and
emerged: time-changing, feelings of dis-integration, length of time prospected to the bones; 6 pts developed brain metastases and in 2 cases a bone marrow infiltration was
end of life. documented. No toxic deaths and no long term toxicities (except irreversible
Result: Women felt a break into their experience of time which has changed, in amenhorrea in all the premenopausal pts) were observed. No secondary malignancies
particular feelings about length, which gave continuity and connected present with the occurred. Overall, the median relapse-free survival is 65,1 months, while the median
past and future, are changed. Patient’s need to tell their history from the beginning overall survival has not been reached yet. 3/5 (60%) HER-2 positive pts relapsed.
showed the importance to integrate cancer memory into life-memory of patients. Conclusions: In our experience high-dose sequential chemotherapy with
Conclusion: Using Bergson’s theory, we may assume that the idea of a chronological autologous stem cells support is a safe treatment with no toxic deaths and no
time scanned is relative. In cancer experience, dimension of time is changed in deep. long-term toxicities. This regimen should therefore be further investigated if
There is a disagreement between objective time, beaten by rhythm toward illness, translational research will be able to identify subgroups of pts with the highest
and a subjective one, a time of mind, following the personal history of patients and probability to benefit from intensive chemotherapy.
their possible end. Time subjective is not discontinued, it is the result of complete
history of individual representation, that is, first of all, history of body experience.
In fact we ‘‘haven’t’’ a body. We ‘‘are’’ it. It’s important to underline, assuming
memory as unit of this time, that it doesn’t exist in body-memory, the presence of C43 MALE BREAST CARCINOMA, A MONO INSTITUTIONAL
cancer. So time subjective is disturbed by need to integrate this experience. EXPERIENCE

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Research implication: Although some articles of breast cancer investigating on time Paola Bergnolo, Antonella Boglione, Simona Chiadò Cutin, Paolo Pochettino,
now exist, future research into the experience of breast cancer is necessary. Orietta Dal Canton, Cristiano Oliva, Manuela InguÌ, Ferdinando Garetto,
Clinical implication: Health professional need to be aware to give patients, possibility Alessandro Comandone
to re-consider the meaning to cancer into their life-time. U.O.A Oncologia, Ospedale Gradenigo, Torino

C41 SAFETY OF ZOLEDRONIC ACID IN BONE METASTATIC Male breast cancer is a rare disease not completely understood. Principles of
management of this tumour derived from trials done in women. We describe our
experience about treatment of male breast cancer.
Patients (pts) and methods: A total of 16 men with diagnosis of breast carcinoma were
Giuseppa Ferraro, Nicola Caristi, Marcello Maugeri Saccà, Concetta Arcanà,
treated in our Institution since 1998. The median age is 61 (46-72). 15 tumours were
Barbara Adamo, Roberta Briguglio, Mariangela ZanghÌ, Vincenzo Adamo
Dipartimento di Patologia Umana, U.O. Oncologia Medica e Terapie infiltrating ductal carcinomas, 1 was DCIS (ductal carcinoma in situ); G2: 8 pts, G3:
7pts, 1 G unknown.
Integrateate, A.O.U. Policlinico ‘‘G. Martino’’, Messina
HER2 overexpression was measured by immunostaining in 6 pts and was negative in
all of them.
Background: Zoledronic acid is a new nitrogen-containing-bisphosphonate showing
Staging of disease at the time of diagnosis: pTis: 1, pT1c pN0: 3, pT2pN0: 2, pT1c
a good activity in pain and skeletal events related to metastatic bone disease, with
a favourable safety profile. pN1: 2, pT2 pN1: 4, pT2 pN2: 1 pT3 pN2: 1, pT4 pN2: 2. All of them received radical
mastectomy and axillary dissection.
Materials and Methods: We retrospectively evaluated the safety of a standard dose Tumours were estrogen receptors positive > 10% in 13 pts, 12 pts received hormonal
(4 mg every 3 or 4 weeks in 15 minutes infusion) of zoledronic acid in 68 bone therapy (all of them received tamoxifen, one patient refused hormonal therapy).
metastasized breast cancer patients treated from January 2004 to January 2007. Median Adjuvant chemotherapy was administered in 13 men; 10 pts received anthracycline-
number of administrations was 14 (range 4-68). 37 patients (54,4%) received based regimes (4 of them also taxanes) and 3 were treated with CMF.
chemotherapy and 51 (75%) received hormonotherapy. Skeletal related events (SRE),
5 pts relapsed: 2 nodes, 1 chest wall, 2 bone metastasis, all received chemotherapy for
were defined as spinal cord compression, pathologic bone fractures, bone surgery, bone
radiotherapy and hypercalcaemia. Bone pain was evaluated with VAS pain scale. metastatic disease (3 died for disease). Median follow-up is 26 months (4-103), overall
survival is 46 months (4 – 119).
Results: Among 68 evaluable patients, 31 (45,5%) experienced one SRE and 6 (8,8%) In our series none have a family history of breast cancer, but 4 (25%) pts showed
had more than one SRE. Only 3 patients (4,4%) did not obtain a good pain control. We another neoplasm before diagnosis of breast cancer: 1 testicular seminoma, 2 prostate
observed 5 (7,3%) hypocalcaemia, 5 (7,3%) acute reactions, such as pyrexia and carcinoma and 1 pts seminoma and prostate carcinoma. These data accord to those of
myalgia, 4 (5,8%) increased serum creatinine levels (1,6 to 2,2 mg/dl), 2 (2,9%) literature on the correlation between gonadal disfunction, due to disease or for
periodontal pain and 1 (1,4%) conjunctivitis. Despite this good safety profile, 2 treatment, and male breast cancer.
patients (2,9%) developed osteonecrosis: 1 patient had osteonecrosis of the jaw (ONJ) The treatment of male breast carcinoma was suggested by the standard of care for
and 1 had double osteonecrosis of jaw and maxilla. Both patients underwent dental women, large studies are necessary to improve information about previous neoplasm,
extraction during zoledronic acid treatment, being in the course of a third-line course and cure of the disease.
chemotherapy. Theese patients received 18 and 29 zoledronic acid administrations,
respectively. Patients developing ONJ had weight loss and worsening of PS.
Conclusions: our data confirm a good safety profile of zoledronic acid. ONJ was a rare
but important side effect, heavily affecting QoL of patients. C44 PHASE II TRIAL OF NON-PEGYLATED LIPOSOMAL
AUTOLOGOUS HAEMATOPOIETIC STEM CELLS SUPPORT IN VERY V. Safina1, N. Giuntini1, L. Coltelli1, F. Martella2, R. Di Marsico1, E. Bejtja1,
Istituto Toscano Tumori. Department of Oncology. Azienda ASL 6, Livorno

Alessandra Bernardi, Nicoletta Cacciari, Francesca Sperandi, Claudio Zamagni

Anthracyclines and taxanes are the most active drugs in metastatic breast cancer
and Andrea Angelo Martoni
(MBC) treatment. Mostly patients receive anthracycline-based therapy in adjuvant
Medical Oncology Unit S.Orsola-Malpighi Hospital, Bologna, Italy
setting and dose-cumulative cardiotoxicity represents a limit to re-treatment in
metastatic disease. Myocet demostrates better cardiac tolerability than conventional
Background: Results of randomized phase III trials of high-dose chemotherapy anthracyclines and interesting activity in combination with taxanes. We therefore
with autologous haematopoietic stem cells support (HDCT) in the adjuvant treatment designed a phase II study to define the activity and tolerability of Myocet 60 mg/sqm
of breast cancer were mainly considered negative and this therapeutic approach has iv d1 combined with Taxotere 37,5 mg/sqm iv d1,8 q21 for six courses in MBC
been abandoned by many. However several questions about the role of HDCT in this patients previously treated with an anthracycline-based chemotherapy. Up to day
setting remain unanswered and a meta-analysis is ongoing. 16 patients have been enrolled in the study (median age of 56 years and a median
Methods: Twenty-five consecutive high risk early breast cancer pts with at least 45 number of 2 metastatic sites). All patients had received epirubicin-based adjuvant
months of follow-up treated in our institution with HDCT are included in the present treatment (median cumulative dose 420 mg/sqm) and had left-ventricle ejection
analysis. Median age was 44 (range 24-59 years) and 15 pts were premenopausal. The fraction (LVEF) above 50%. So far 75 courses have been administered (median number
median number of axillary lymph-nodes metastases was 13 (range 3-49) and the of cycles for pt: 6) and the main toxicities observed were: neutropenia G3/G4 6%/8%
pathological stage was IIB in one pt, IIIA in 3 pts, IIIB in one pt and IIIC in 20 pts. (with 2 episodes of febrile neutropenia); diarrhoea G3 1%; mucositis G3 1%. No other
The 10-year risk of relapse of pts with disease characteristics similar to those of our haematological or non haematological noteworthy toxicities were reported.
study population is about 80-85%. Estrogen and/or progesterone receptors were No significant reduction of LVEF was registered by ultrasound monitoring
positive in 15 pts and negative in 10 pts. HER-2 status was known in 18 pts and 5 pts performed every two cycles. In one case LVEF fell below 50% after the fourth cycle, but
(28%) were positive (HER-2 3+ (IHC) and/or FISH). The HDCT regimen used was rapidly recovered. 14/16 pts are evaluable for activity (one too early and one withdrawn
cyclophosphamide 7g/m2 plus G-CSF (followed by apheresis of peripheral from protocol because of drug infusion reaction). 8 patients (57.1%) obtained partial
haematopoietic stem cells), methotrexate 8 g/m2 followed by thiotepa 600 mg/m2 and response, 5 patients (35.8%) had a stable disease and 1 patient (7.1%) progressed
melphalan 160 mg/m2 or by mitoxantrone 60 mg/m2 and melphalan 180 mg/m2 and during treatment. The study is still ongoing considering the promising activity and the
stem cells reinfusion. good profile of tolerability of the combination. Supported by A.R.C.O. foundation.

xi46 | session C: early and advanced breast cancer Volume 18 | Supplement 11 | October 2007
Annals of Oncology session C
C45 SAFETY AND EFFICACY OF INHALED IL-2 THERAPY IN PRE- Medical Oncology Division,Cosenza,Italy
PULMONARY METASTASES Background: MBC is a chronic disease and no treatment may be considered as the
standard approach.Capecitabine(C) and Docetaxel (D) have demonstrated synergy in
Marco Burgio, Fernanda Bellomo, Giuseppe Bronte, Annapaola Carreca, Dario both preclinical and clinical studies in MBC, but not in clinical practice.
Piazza, Sergio Rizzo, Salvatore Russo and Ignazio Carreca
Methods: From February 2005 to September 2006, 13 consecutive pts with median age
Medical Oncology Unit, University of Palermo, Palermo, Italy
44 (range 26-68), ER+ 50%PG+65%HER2 3+ 30%,performance status 2 or better
(ECOG), adequate bone marrow, renal, hepatic and cardiac function ; no prior
Introduction: Inhaled interleukin(IL)-2 therapy has been reported to prevent chemotherapy for metastatic disease; previous adjuvant chemotherapy (8 with
progression of pulmonary metastases of renal cell carcinoma, melanoma, breast and anthracyclines and 5 CMF) received six or eight cycles: D75 mg/m2 i.v. on day 1 + C
ovarian cancer. Several patients have been treated with inhaled IL-2 therapy as single 850 mg/m2 p.o. bip on days 1-14 each q3w and in HER2 3+ Trastuzumab 8 mg/kg
therapy or in combination with systemic immunotherapy and/or chemotherapy with loading dose and 6 mg/kg each q3w, or until unacceptable toxicity. Routine medication
minimal toxicity. for D was given. Primary endpoint was ojective response according to WHO criteria.
Patients and methods: Twelve elderly breast cancer patients (median age 66.5, range Results: Disease sites were 3 LN, 2 chest wall, 2 bone,7 lung, 9 liver. Mean age was
60-77), with radiologically documented progressing pulmonary metastases after at least 44(range 26-65)A total of 95 cycles was given, with median 6 (range 2-10). 6 pts had
two lines of prior systemic chemo- and/or hormonal therapy, were enrolled. All G2/3neutropenia,0 febrile neutropenia,5 G3 hand-foot syndrome, 9 G1/2 stomatitis
patients had to be able to comply with inhalation technique, and were not candidates and diarrhea, 6 G1/2, 5nausea/vomiting, 7 asthenia.With median follow-up of 28 wks

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for other treatment options. Before treatment all patients were evaluated for (range 7-52).
Comprehensive Geriatric Assessment (CGA), ECOG PS and QoL (EORTC-QLQ-C30). There were 3 RC((23%),5 RP(38.6%), 2 SD(15.4%) and 3 PD(23%).All the RC
The protocol included twice-daily inhalation of nebulized IL-2 at a maximum dose and 3 RP were observed in anthracycline naı̈ve, 2 RC and 2 RP were observed in HER
of 18 million IU/day, 5 days a week. Treatment was continued until progression, life 2+ Trastuzumab administered. Median response duration was 25 wks and median
threatening toxicity, or patient refusal. Response was assessed only in the targeted TTP was 30 wks.
pulmonary lesions using the Response Evaluation Criteria in Solid Tumors (RECIST)
Conclusions: DC combination is a efficacious frontline-therapy also in clinical
system. Toxicity was determined following WHO criteria.
practice, with high RR in pts anthracycline naı̈ve MBC, and an important treatment
Results: 3 pts achieved a partial pulmonary remission, 4 pts experienced stabilization of option for women with anthracycline-pretreated, with the manageable toxicity profiles.
pulmonary disease. One patient discontinued treatment because of cough and dyspnea.
Most of the pts did not show respiratory symptoms under inhalation therapy; few pts
showed slight fever. Only mild leucopenia and thrombopenia (WHO grade 1) were
observed. No patient experienced severe adverse events. QoL scores improved C48 CORRELATION BETWEEN PLASMA D-DIMER LEVELS AND
significantly compared with pretreatment scores. AXILLARY LYMPHNODE STATUS IN OPERABLE BREAST CANCER
Conclusions: Our data suggest that inhaled IL-2 therapy is associated with minimal
toxicity and is effective in delaying progression of pulmonary metastases in advanced V. Fregoni1, L. Regolo2, A. Zambelli1, G Da Prada1, P. Preti, L. Ponchio1,
breast cancer pts heavily pretreated. Inhalation therapy may be applied to almost all L. Pavesi1, A. Costa2
elderly patients with co-morbidities. Under treatment all pts enjoy a good QoL. This long- 1
Divisione di Oncologia Medica 2IRCCS Fondazione S Maugeri, Pavia, Italy
term safety treatment might contribute to turn progressive cancer into a chronic disease.
In patients bearing solid tumours, several mechanisms may induce activation of the
C46 EFFECT OF FULVESTRANT TREATMENT ON COMPLETE coagulation process. The extent of such activation has been reported as correlating with
BLOOD LIPID PROFILE IN HORMONE-SENSITIVE METASTATIC tumour stage and prognosis in some malignancies. D-dimer is a stable end-product of
BREAST CANCER PATIENTS fibrin degradation, and levels of D-dimer are elevated by enhanced fibrin formation
and fibrinolysis. Consistently, D-Dimer levels are increased in patients with various
Andrea Camerini1, Domenico Amoroso1, Ornella Garrone2, Sara Donati1, Gianna solid tumours.
Tartarelli1, Maura Vincenti3, Chiara Valsuani1, Olimpia Siclari1, Cheti Puccetti1, Some authors have suggested a tight correlation between early tumour metastasis,
Romana Prosperi Porta4, Marianna Rondini1, Paolo Pronzato5, Alessandro lymphovascular invasion, and plasma D-dimer levels in operable breast cancer patients.
Sgambato6 However, the usefulness of combining plasma D-dimer levels with sentinel lymph node
Medical oncology, Ospedale Versilia - AUSL 12 Viareggio; 2Medical oncology, biopsy (SNB) in primary breast cancer is still unclear. The aim of our study is to verify
Ospedale Santa Croce e Carle - Cuneo; 3Medical oncology, Ospedale degli a possible correlation between quantitative D-dimer levels (Instrument Laboratory)
Infermi - Biella; 4Medical oncology, Ospedale S. Chiara - Pisa; 5Oncologia and lymph node involvement, in particular focusing on sentinel node (SN) status.
medica A, IST - Genova; 6Universita Cattolica - Roma One hundred forty-two breast cancer patients were enrolled in the study. All patients
(aged 29-84) underwent preoperative D-dimer plasma evaluation before surgery.
Background: Fulvestrant (F) is a pure anti-estrogen agent available for post- 40 out of 142 patients (28 %) underwent axillary lymph node dissection, while 102/
menopausal hormone-sensitive advanced breast cancer (ABC) treatment. Aim of the 142 patients (72%) were eligible for SNB technique.
study is to analyze the effect(s) of F on lipid profile, endometrial mucosa and The median D-dimer level of the whole series was 210 ng/ml (range 45-709)
coagulation indices (CI). D-dimer levels resulted higher in patients with nodes involvement as compared with
nodes negative patients. However this difference did not reach the statistical
Patients and methods: 31 pts (mean age 64.5 ± 9.8 yrs) with hormone-sensitive ABC
significance (p=0.37), both for patients with multiple metastatic axillary nodes
were enrolled. All patients (data on 28 pts) received at least one previous hormone-
(p=0.27) and for patients with single SN involvement (p=0.60).
treatment (HT) course, with 89.3% receiving ‡2 HT courses. Last HT was
In conclusion, we found no statistical correlation between D-dimer plasma levels
exemestane in 17/28, letrozole in 6/28 and other in 5/28 with a median withdrawal time
and clinical stage in breast cancer patients. Such lack of correlation does not support
of 18 days (range 3–1456). All pts but three received at least one previous CT regimen,
the hypothesis that D-dimer plasma might be related to lymphovascular invasion and
with 60% receiving ‡2 CT regimens. Complete fasting lipid blood profile and CI were
clinical stage.
assessed before F administration, every 3 months and at discontinuation time.
Endometrial mucosa thickness was evaluated by trans-vaginal echography before F
administration and at end-study time. All patients referred no significant dietary
changes during treatment. Body weight and body mass index did not vary during study. C49 DIFFERENT TRASTUZUMAB SCHEDULE ALLOWS
Pts receiving statins were excluded. SAVING MONEY
Results: Pts received a median of 5 F injections (range 3-19). We observed SD in 12 and
E. Pazè, D. Perroni
PD in 16/28 pts with a mean time to progression of 6.5 ± 3.9 months. Total cholesterol
Ospedale Civile, Saluzzo (CN)
(C) levels significantly decreased during treatment (222.9 ± 50.2 vs 204.7 ± 43.5 mg/dl;
p = 0.0047) together with LDL-C (129.4 ± 43.9 vs 117.4 ± 40.2 mg/dl; p = 0.012).
Instead, HDL-C (64.9 ± 17.7 vs 65.3 ± 18.3 mg/dl; p = ns) and triglycerides (140.2 ± The availability of new very expensive drugs is challenging health systems because of
62.4 vs 137.9 ± 59.4 mg/dl; p=ns) did not vary. Reduction of C and LDL-C was the economic burden on budgets. Some strategies have been devised in order to use
independent from the type of last HT or the treatment duration. Mean endometrial targeted therapies appropriately, but still ways to reduce costs are needed.
mucosa thickness and CI value did not vary. Trastuzumab is a new drug used in advanced and early breast cancer. It was initially
used at a dose of 2 mg/kg/week, but proportionally higher doses and longer intervals
Conclusions: We observed a clear lipid lowering effect of F. We suggest a possible effect
proved to be pharmacokinetically equivalent and safe, and now it is commonly
of F on lipid metabolism.
administered at a dose of 6 mg/kg every 3 weeks. For a 60 kg woman this schedule
translates into administering 360 mg per cycle. Being the drug marketed in 150 mg
C47 ACTIVITY AND SAFETY OF FRONTLINE DOCETAXEL AND strength vials, 3 vials are needed to prepare the appropriate dose for each cycle.
CAPECITABINE COMBINATION THERAPY IN PATIENTS WITH We think that a strategy to minimise drug wastage is flexibility in the frequence with
METASTATIC BREAST CANCER(MBC) which the treatment is administered. We administer Trastuzumab at a fixed dose of
300 mg per patient, and we schedule the administrations so that every patient receives
S. Ceniti, V. Liguori, S. Turano, R. Biamonte, R. DeSimone, A. Filice, C. Manfredi, the 2 mg/kg/weekly dose intensity. For instance a 60 kg woman will therefore receive
C. Mastroianni, A. Rovito, C. Viscomi and S. Palazzo 300 mg every 17-18 days, so for one year treatment it translates into using 44 vials of

Volume 18 | Supplement 11 | October 2007 doi:10.1093/annonc/mdm425 | xi47

session C Annals of Oncology

drug (2 · 22 administrations) rather than 52 (3 · 17 administrations) with 15% of patient with IDC with FF would benefit from an anthracycline-containing
costs saving. chemotherapy.
A table with most common body weights and corresponding intervals can be easily
drawn (see below).
Kg 6 mg/kg/3w Vials for Vials for Intervals (days) N. cycles in Vials for Costs PATIENTS
1 cycle 1 year with 300 mg 1 year 1 year saving
fixed dose M. Panella*, A. Di Leo*, S Santini*, E. Cantisani*, M. C. Villani , S. Bonini ,
55 330 mg 3 52 19 20 40 23% I. Bessi , S. Nepi , A. C. Marinià, and A. Bevilacqua§
60 360 mg 3 52 17–18 22 44 15% *Dipartimento Oncologico- USL 4 di Prato, Ospedale di Prato, Istituto Toscano
65 390 mg 3 52 16 23 46 12% Tumori,  Associazione Progetto Aurora Donna Onlus, àU.O. Recupero ed
70 420 mg 3 52 15 25 50 4% educazione funzionale, §C.Ri.D.A – Centro di Riabilitazione Ambulatoriale

Introduction: Cancer represents for the patient and the family an event that involves all
aspects of life: the patient’s relationship with his/her own body, the meaning of pain,
disease, death, social and professional relationships.
Objectives: The main objective of this project is improving the quality of life in patients

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Laura Pisanu, Davide Adriano Santeufemia, Giovanni Maria Fadda, Giovanni with breast cancer through the integration of a multidisciplinary staff, and the patient’s
Sanna, Maria Giuseppa Sarobba, Carlo Putzu and Antonio Farris family in a way that is completely supportive of the patient.
Cattedra di Oncologia Medica, Università di Sassari, Sassari, Italy An innovative aspect is the clinical management of the activities of all professionals
involved in the cure and rehabilitation process, in synergy with volunteer services and/
or associations, where breast cancer patients can talk in a confidential environment
Purpose: To investigate the effect on endometrium thickness of third generation
with volunteers who have lived with and been through cancer.
aromatase inhibitors (AIs), administered as adjuvant switched therapy in
postmenopausal women with endocrine-responsive breast cancer and abnormal Methods and instruments: The plan foresees the active involvement of several
uterine bleeding (AUB) or transvaginal ultrasonography (TU) proven of asymptomatic professional figures and the active participation of the patient. Main steps of the plan
Tamoxifen-induced endometrial thickening. are as follows: 1. Experimentation of the integrated program in the defined and
structured ‘‘continued assistance’’ 2. Diagnosis that finds its fulcrum in the
Materials and methods: 35 postmenopausal women who was taking adjuvant
‘‘Acceptance’’ of the disease 3. Rehabilitation program foresees: specialist visit(s),
tamoxifen 20 mg/day (> or =12 months, < or = 48 months) and developed AUB and/or
functional evaluation before and after treatment, psychological counseling, survey of
asymptomatic endometrial thickness >9 mm were switched to an AI. 8 patients (23%)
needs (indicated by the staff), individual rehabilitative treatment, informative/
were switched to Anastrozole, and 20 (57%) and 7 (20%) women were treated with
formative seminaries and meeting of patients, relatives, hospital staff and volunteers.
Letrozole and Exemestane respectively. All patients underwent endometrial
All steps are monitored and aim at effectuating the necessary corrective actions in
investigation before the start of AIs therapy and, thereafter, at 10 month intervals.
order to improve the services rendered.
Endometrial assessment was based on TU; hysteroscopy and endometrial biopsy were
performed if necessary. Conclusions: The project is ongoing. At the meeting we will present the early results of
this rehabilitation program.
Results: Median age of women was 67 years. The mean Tamoxifen intake duration was
27± 13 months. The mean endometrial thickness at baseline TU was 13± 4 mm.
Hysteroscopy with endometrial biopsy was performed in 24 patients (68,5%): C53 VINORELBINE (VNB) AND 5FLUOROURACIL (5FU)
benignant uterine abnormalities were diagnosed in 3 cases (8,6%). The average period COMBINATION IN PATIENTS WITH ANTHRACYCLINE AND
of endometrial surveillance after the start of AIs therapy was 10±.8 months and TAXANE-PRETREATED METASTATIC BREAST CANCER (MBC):
a progressive decrease of endometrial thickness (mean 8±.6mm) was observed in 21 A PHASE II STUDY
(68%) woman (p=001). Of those 13 (62%) where switched to letrozole, 5 (23%) to
exemestane and 3 (15%) to anastrozole. During AIs administration no endometrial Cristiano Oliva, Manuela InguÌ, Paola Bergnolo, Paolo Pochettino, Simona Chiadò
pathology was found in all patients. Cutin, Antonella Boglione, Manuela Biscardi, Ferdinando Garetto, Orietta Dal
Conclusions: When administered as switched therapy after tamoxifen withdrawal, AIs Canton, Alessandro Comandone
may reverse tamoxifen-associated endometrial thickening. UOA Oncologia, Ospedale Gradenigo, Torino

VNB and 5FU are effective drugs in MBC. Anthracyclines and Taxanes are often used in
C51 TOPOISOMERASE II ALPHA EXPRESSION IN INVASIVE adjuvant setting or as first line treatment. Patients (pts) with MBC undergo often
To evaluate safety and efficacy of the combination of VNB and 5FU we started
Antonino Mafodda, Raffaella Giuffrida, Marzia Mare, Giusi Blanco, Stefania a phase II study in pts with MBC previously treated with Anthracyclines and Taxanes.
Munaò, Lorenzo Memeo, Dario Giuffrida From 12/2002 to 12/2006 43 pts (median age 59; range 38-76) were treated with
Dipartimento di Oncologia Sperimentale, Istituto Oncologico del Mediterraneo, the combination of bolus Folinic Acid (FA) 100 mg/m2 intravenous (IV), bolus 5FU
Viagrande (CT) 400 mg/m2 IV, and 24 hours continuous infusion 5FU 600 mg/m2 on days 1-2, and
VNB 25 mg/m2 on day 1 every 14 days for 6 months. 432 cycles of CT were administered
Invasive ductal carcinoma (IDC) with fibrotic focus (FF) is a rare, recently described (median 12, range 3-12). 22 pts (51,2%) completed the 6 months treatment.
subtype of IDC with aggressive characteristics and significantly poorer survival. FF is Patients were all pretreated with Anthracyclines and Taxanes in adjuvant setting or
composed of fibroblasts and various amounts of collagen fibers, and they occupy for metastatic disease. Most common sites of metastatic spread were: bone 26, liver 22,
almost the entire center of the IDC. IDCs with FF exhibit significantly greater tumor lymph nodes 15, lung 12, local recurrence 8. 23 pts (53,5%)received this therapy as first
angiogenesis and higher tumor cell proliferative activity and the presence of FF is an line CT, 16 as 2nd and 4 as 3rd. PS (ECOG) was 0-2 (median 0). We recorded
independent prognostic parameter. IDCs with FF are characterized by higher neutropenia G3 19 times (4,4% of cycles), fatigue G3 in 5 cases and G3 mucositis in 4.
frequencies of Her2 protein expression, abnormal nuclear accumulation of p53 and 4 pts interrupted CT cause intolerable toxicity (1 liver toxicity, 1 febrile neutropenia,
aneuploidy than those without FF. In addition, the former show significantly higher 1 chronic constipation, 1 protracted G3 mucositis).
proliferation activity than the latter. These findings indicate that the presence of FF in 12 pts (27,9%) achieved a partial response, 21 (48,8%) had no changes and
IDCs is an important histological parameter for predicting the outcome of patients 10 (23,3%) experienced disease progression.
with IDC of the breast. After a median follow up of 15,6 months, median time to progression was 9,2
Recent clinical trials have suggested that patients whose breast tumors overexpress months and median overall survival was 17,3 months.
HER2 may derive particular benefit from anthracycline-containing chemotherapy In our phase II study VNB and 5FU demonstrated an interesting activity with an
compared to that without anthracycline. It has been proposed that the HER2 acceptable toxicity in Anthracyclines and Taxanes pretreated pts with MBC. The regimen
amplification might mask an underlying TOP2A amplification that occurs frequently warrants development with administration of oral VNB and fluoropyrimidine derivates.
and concurrently with HER2 amplification probably due to the close genomic position
on chromosome 17. Topoisomerase II alpha, is a direct molecular target of
anthracycline and is potentially useful as a predictive marker of response to C54 DOSE-DENSE ‘‘MYTAX’’ REGIMEN IN BREAST CANCER: A
anthracycline therapy. DOSE-FINDING STUDY
Therefore we studied Topoisomerase II alpha expression by immunohistochemistry
in five cases of IDC with FF selected from the files of our institution. M. Mancini1, K. Cannita1, A. Santomaggio1, M. Tudini1, F. De Galitiis2,
Patient’s age ranged from 43 to 71 (mean, 60 years); all cases showed an high A. I. Rispoli1, F. Martella1, G. Porzio1, M. Pelliccione1, P. Lanfiuti Baldi1, A. Bafile3,
proliferation index (Ki-67>20%) while 4 of 5 demonstrated Her-2 overexpression, in P. Marchetti3, C. Ficorella1, E. Ricevuto1
line with the previous findings about IDC with FF and 3 of 5 were positive for both ER Medical Oncology, S. Salvatore Hospital, University of L’Aquila
and PR.
We found that Topoisomerase II alpha was overexpressed in all the 5 cases studied, Background: We describe the toxicity of dose-dense TLC-D99 and Docetaxel (TXT) in
and if this data will be confirmed by larger cohorts of patients, it would suggest that breast cancer patients (pts).

xi48 | session C: early and advanced breast cancer Volume 18 | Supplement 11 | October 2007
Annals of Oncology session C
Methods: Nine pts were enrolled in the dose-finding study and treated with a fixed Results: The clinical response rate was 79 %. All patients but 5 proceeded to surgery, all
TXT dose (50 mg/m2) days 1 and 15, and TLC-D99 at three dose levels, 40-45-50 patients but 3 were treated with modified mastectomy. All patients received 3 o 4 cycles
mg/m2 days 1 and 15 every 2 weeks, using an intra- and inter-patient approach. Dose- of adjuvant chemotherapy, in addition hormonotherapy was given to patients with
limiting toxicity (DLT) was defined as G3-non haematological or G4 haematological. hormone-receptor positive tumors after completion of chemotherapy. Non-
Cardiac monitoring was planned with LVEF and Precursor Brain Natriuretic Peptide hematological toxicity was generally moderate with grade 3-4 toxicity in 11 % of the
(PBNP). cycles; most common non-hematologic toxicities were nausea and vomiting, alopecia
Results: Disease extension: metastatic breast cancer (MBC), 5; locally advanced BC, 2; mucositis and asthenia. Hematological toxicity grade 2-3 was observed in 14 % of the
T2-T3 BC, 2. Previous chemotherapy: untreated, 6 pts; adjuvant chemotherapy, 3 pts. patients.
Patients enrolled for each dose-level: I, 7; II, 8; III, 8. Newly treated patients: I does- Conclusion: The preliminary data seems to show a safe and highly effective
level, 7; II dose-level, 2. Total valuable cycles, 53: I dose-level, 14; II, 19; III, 20. Total combination treatment for patients with advanced inoperable breast cancer. If these
DLTs in 3 patients, 33%, and 3 cycles, 6%: 2 cardiac, characterized by a 19% LVEF results will be confirmed, we extending this approach to the management of patients
decrease and an arrhythmia with symptoms; one G4 hematologic resistant to G-CSF. with earlier stages of breast cancer.
DLTs at single dose-level per patients and cycles, respectively: I, 14% (1/7 pts) and 7%
(1/14 cycles); II, no DLT in 8 pts and 19 cycles; III, 25% (2/8 pts) and 10% (2/20 cycles).
Cumulative G3-4 toxicities by patients and cycles, respectively: cardiac arrhythmia C57 FOUR YEARS OF EXPERIENCE WITH COMBINED WEEKLY
11% and 2%, cardiac general (symptomatic FEV decrease), 11% and 2%; alopecia 89% NON-PEGYLATED LIPOSOMAL DOXORUBICIN AND TAXANE IN
and 49%; neutropenia resistant to G-CSF, 11% and 2%. Cardiac DLTs were observed in BREAST CANCER SECOND-LINE TREATMENT

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2 pts >65 y old. G2 toxicities by patients and cycles, respectively: asthenia 44% and
20%, stomatitis/mucositis 11% and 2%, nausea 33% and 11%. Median rDI of TLC- M. S. Rosati, M. L. Basile, P. C. Sacco, L. Cerbone, G. Pasciutti, T. Falbo,
D99 was 22,5 mg/m2/w and TXT 25 mg/m2/w per patient, respectively. Objective M. Di Seri
responses in 8 assessable pts: MBC, 3 PR and 2 SD; LA-BC, one pCR; T2-T3 BC, 1 PR Dpt of Clinical Oncology, University ‘‘La Sapienza’’, Rome, Italy
and 1 SD.
Conclusion: To date, maximum tolerated dose wasn’t reached, thus the third dose- Introduction: We performed a phase II study to determine the activity and toxicity of
level (TLC-D99, 50 mg/m2) can be recommended for phase II studies. combined weekly non-pegylated liposomal doxorubicin (Myocet)and taxane as
second line treatment in patients with advanced breast cancer.
Patients and methods: Thirty-two patients with stage IV breast cancer and ECOG
C55 FULVESTRANT AND CAPECITABINE IN ELDERLY ADVANCED PS 0-1 were treated with liposomal doxorubicin (25 mg/m2) and (schedule A)
BREAST CANCER PATIENTS: THE PROPOSAL FOR AN EFFECTIVE paclitaxel (50 mg/m2) or (schedule B) docetaxel (30 mg/m2) on days 1,8 and 15 every 4
AND SAFE COMBINED TREATMENT SCHEDULE weeks for a maximum of six cycles. Twenty patients had received prior chemotherapy
with an anthracycline regimen. Twenty-seven patients had disease at multiple sites.
Giuseppe Bronte, Fernanda Bellomo, Marco Burgio, Annapaola Carreca, Hepatic and pulmonary disease were the predominant metastatic site.
Dario Piazza, Sergio Rizzo, Salvatore Russo and Ignazio Carreca Results: Seventeen patients (median age, 56 aa) were treated with schedule A and
Medical Oncology Unit, University of Palermo, Palermo, Italy fifteen patients with schedule B. G1-2 hematologic toxicities (mainly neutropenia)
occurred in 27% of cycles while G3-4 occurred in 16%. Significant alopecia G3 was
Background: Fulvestrant is the first of a new class of pure estrogen receptor common (72%) and cutaneomucous toxicities G3-4 occurred in 18% of cycles (three
antagonists. It was studied in comparison to anastrozole and tamoxifen in the 1st and patients). Except for mucositis (4% vs 32%, p< 0.05), there were no differences in
2nd line of hormonal treatment in women with advanced breast cancer. AIM: Since terms of toxicity between schedule A and B. LVEF was conserved throught all cycles.
elderly patients develop rapid and often fatal toxicity during treatment with cytotoxic Overall response (OR) was 87.5% and median time to progression (TTP) was
drugs, we tried to design a new schedule for combined chemo-endocrine therapy in 8.08 months (2.8-13.4); 4-years overall survival was 25.02 months (15.2-30.6).
elderly breast cancer patients. The target is to identify a treatment regimen that could Conclusion: Giving a combination of non-pegylated liposomal doxorubicin and
be effective and safe for pre-treated and comorbid pts with positive comorbidity score. taxane at weekly intervals as II line treatment in advanced breast cancer is an active and
Methods: 20 elderly advanced breast cancer patients (mean age 70; range 65-86) well tolerated approach with good toxicity profile. Our data encourage phase III trials.
previously treated with adjuvant endocrine therapy. Comprehensive Geriatric
Assessment (CGA) was previously performed. Primary endpoint: clinical response
rates (RR) according to WHO criteria. Secondary endpoints were toxicity profile using
NCI-CTC v2.0 and quality of life (QoL) score measured through EORTC QLQ-C30
Results: 20 pts were treated with capecitabine 1000 mg/m2 twice daily p.o. on days 1 Pasqualina Di Bitonto*, Antonio Abate*, Giacomo Vessia*, Mario De Lena**
to 14 every 21 days and fulvestrant 250 mg as a single 5 mL intramuscular injection, *Struttura Semplice di Oncologia, Struttura Complessa di Medicina, P.O.
once-monthly until disease progression. Based on CGA all patients were included into UMBERTO I, Viale Regina Margherita, ALTAMURA.** Oncologic Consultant
groups I-II, according to Balducci’s classification of frailty. None of the pts needed any
delay in drugs delivery. We observed 7 (35%) objective responses (OR) (2 complete
Background: The estrogen receptor has proven to be the single most important target
(CR); 5 partial responses (PR)). Stable disease was acquired in 8 (40%) pts. Clinical
in breast cancer over the last thirty years, changing therapeutical and preventive
benefit in 15 (75%) pts. No grade-4 toxicity was found. QoL score underwent
approach to this disease. After tamoxifen, a selective ER modulator, Aromatase
amelioration after treatment in all pts.
inhibitor (AI) have proven to be more efficacious in first and second line therapy and
Conclusions: This pilot study could identify a safe schedule for managing elderly even in adjuvant setting in post menopausal women. Fulvestrant is the first pure
comorbid breast cancer pts, that couldn’t be treated otherwise. Preliminary data are estrogen receptor degradation and has proven to be just as effective as Aromatase
encouraging, thus induce the authors to continue and enlarge the study in order to inhibitors in breast cancer patients who have had disease recurrence or progression and
confirm these first outcomes. pretreated with tamoxifen and aromatase inhibitors.
Aim: To evaluate efficacy and tolerability of Fulvestrant.
Patients and methods: From August 2006 to March 2007 we treated with Fulvestrant
C56 PRIMARY SYSTEMIC THERAPY FOR ADVANCED INOPERABLE ten post-menopausal patients with metastatic breast cancer in progression, pretreated
BREAST CANCER with tamoxifen and aromatase inhibitor.
Eigth patients were affected by a tumor with Estrogen (ER) and Progesteron
V. Palmisano, V. Leonardi, A. Pepe, A Usset, C. Arcuri, A. Laudani, G. Savio, receptor (PgR) positive. Two patients were ER positive but PgR negative. Median age
G. Rondello, A. Giresi, P. Amari and B. Agostara was 63 years (range 48-78), PS: 0-1, visceral disease in six patients, skeletal disease in
Dipartimento di Oncologia PO ‘‘M. Ascoli’’, ARNAS Civico Palermo four patients. CA 15-3 was high in 8 patients.
Results: Important side effects were not observed, but 70% of patients referred
Background: Primary systemic therapy is used in the treatment of patients with a sensation of ‘‘burst of heat’’on day three or four after Fulvestrant injection. After six
advanced inoperable breast cancer in order to downstage the primary breast tumor. months of this treatment seven patients were valuable for disease response: six had
Docetaxel and Epidoxorubicin are some of the most active agents in the treatment of stable disease whereas one had progression disease; in all patients (8) there was
breast cancer. a reduction of 50% of the marker CA15-3.
Patients and methods: Fourty five patients with histologically confirmed advanced Conclusions: These data demonstrate that Fulvestrant is a well-tolerated treatment,
inoperable breast cancer were treated with epidoxorubicin 30 mg/mq weekly and which allows marker control after prior anti-estrogenic therapies.
docetaxel 35 mg/mq weekly for 6 consecutive weeks every 8 weeks for two cycles.
Clinical tumor size and nodal status were assessed by palpation and by ultrasound
before each cycle of chemotherapy. C59 CMFVP IN HEAVILY PRETREATED ADVANCED BREAST
The main characteristics of enrolled patients were: median age 54 (range 34-62), CANCER (BC)
median initial clinical tumor size 6 cm (range 2-13), 7 patients had inflammatory breast
cancer. Axillar lymph nodes were palpable in 75 % patients; out of 56 % had hormone- Claudia Mucciarini, Giampaolo Di Carlo, Fabrizio Artioli
receptor-positive disease and 20 % of tumors showed over-expression of HER2/neu. Medical Oncology Unit, Ramazzini Hospital, Carpi, Modena, Italy

Volume 18 | Supplement 11 | October 2007 doi:10.1093/annonc/mdm425 | xi49

session C Annals of Oncology

Refractory advanced breast cancer is one of the most controversial areas for medical evalueting the role of AIs. With this intent, all RCTs where patients were randomized to
oncologist. receive standard tamoxifen or Ais (whatever strategy) were meta-analyzed.
The efficacy of second and subsequent lines of chemotherapy in this setting is Methods: A literature-based meta-analysis was accomplished, and event-based
uniformly poor. relative risk ratios (RRs) with 95% confidence interval (CI) were derived. A fixed-
Anyway women with fairly good compliance can be expected to live for a long time (FEM) and a random-effect (REM) model according to the inverse variance and
and should be offered the chance to benefit from multiple chemotherapy lines. heterogeneity test were applied as well. Absolute difference (AD) and the Number
We used a modified schedule of CMFVP in the treatment of metastatic BC patients of patients Needed to Treat (NNT) were calculated. A linear regression model
with a good performance status whose disease was resistant to various considering 5-years DFS and OS rates has been used to look for correlation, estimated
chemotherapeutic regimens, including anthracyclines and taxanes. by adopting the Pearson, R2 (parametric tests) and Spearman (non-parametric test)
We treated 10 patients with cyclophosphamide 100 mg die orally every day, coefficients.
metotrexate 25 mg/mq and 5-FU 400 mg/mq on day 1 weekly, vincristine 1 mg i.v. on
Results: In an overall sample of 10 RCTs (27653 patients), 8 RCTs reporting all data
day 1+8 and afterwards once a month, prednisone 12,5 mg/day orally for 14 days from
were eligible for the correlation analysis. AIs significantly improved DFS, with a AD
day 1 and subsequently 7,5 mg daily, until progression and/or toxicity.
ranging from 2.3 to 3.5%, which translate into 29-43 NNT; OS was significantly
Mean age was 60 years (range 54-67); ECOG PS was 0-1; all patients had multiple
prolonged in the overall an in the early switch strategy, with an AD of 0.8 and 1.61%,
metastatic sites except one that had only brain lesions; sites of involvement were as
which translate into 120 and 62 NNT, respectively.
follow : brain, lymphonodes and/or bone 50% of pts, liver, pleura and/or lung 25% of
pts. Mean number of previous chemotherapies was 5 (range 3-7). The schedule had a
Population Pts (#RCTs) RR (95% CI) p Het. AD (%) NNT

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mild toxicity, with 6 pts developing grade 2-3 neutropenia without fever, 5 pts with
a grade 2 nausea, 3 pts with a grade 2 astenia and 2 pts with a grade 1/2 neuritis.We had FEM/REM
a 25% of partial response and a 50 % of partial response/stable value of the bioumoral DFS Overall 27563 (10) 0.80 (0.76, 0.85) <0.0001 0.034 2.8 36
rate of CA 15.3 (elevated in all the pts). The response was obtained only on the 0.77 (0.69, 0.85) <0.0001
lymphonodes sites. At present, 75% of the patients is dead, the most for brain disease Up-Front 11163 (2) 0.86 (0.80, 0.94) 0.0004 0.58 2.3 43
progression. Early Switch 8776 (5) 0.76 (0.68, 0.84) <0.0001 0.14 3.5 29
In conclusion, in our experience this combination had a mild toxicity and a quite Late Switch 7624 (3) 0.67 (0.56, 0.80) 0.00001 0.28 2.5 40
low efficacy in very heavily pretreated BC patients, expecially if brain lesions are OS Overall 25109 (8) 0.89 (0.82, 0.97) 0.01 0.16 0.8 120
present. Up-Front 11163 (2) 0.95 (0.86, 1.06) 0.41 0.59 - -
Early Switch 8776 (4) 0.80 (0.69, 0.92) 0.003 0.17 1.61 62

C60 AXILLARY NODE DISSECTION AND SENTINEL LN: A A linear strong correlation between DFS and OS was present in the overall population
MONOINSTITUTIONAL EXPERIENCE (r=0.78, R2=0.60, p=0.001; Rho=0.77, p=0.001), and in the early switch strategy
(r=0.83, R2=0.68, p=0.003; Rho=0.84, p=0.002). A trend for correlation was found in
Fasola C, Filipazzi V, Gambi V, Piazza E, Damiani E, Isabella L, Ferrario the upfront strategy as well (r=0.88, R2=0.79, p=0.11; Rho=1.00), maybe not-
S, Somma L, Cattaneo MT, Tosca N, Zambelli S, Gambaro A, Sarnataro C. significant for the low number of accrued RCTs.
e Nosenzo MA Conclusions: With these data, DFS confirms to be an accurate and reliable surrogate
Oncology Department, Sacco Hospital, Milan (Italy) end-point for OS in RCTs exloring AIs as adjuvant endocrine treatment for early BC.
The predictive role of earlier DFS (3-years) estimation for ultimate/late survival
Background: We evaluated disease recurrence after surgery in breast cancer pts with or deserves a deeper analysis.
without sentinel lymph-node (LNS +/-) who did, or did not, undergo axillary node
Methods: From 2002 we recruited 103 patients:17 in pre and 86 in post menopause, on
average 63 years old (29-80), with early-stage breast cancer (T<=2,5cm),staging with C62* TIMING OF ADJUVANT CHEMOTHERAPY AND TAMOXIFEN IN
identifying the LNS, biopsying it, resection of the tumour, followed by systemic therapy WOMEN WITH BREAST CANCER: FINDINGS FROM TWO
(CT-HT) and locoregional therapy (RT). The follow-up included a chest X-ray, an CONSECUTIVE TRIALS OF GRUPPO ONCOLOGICO NORD-OVEST
abdominal ultrasound, a yearly mammogram or breast ultrasound, a clinical -MAMMELLA INTERGRUPPO (GONO-MIG) GROUP
examination, an evaluation of the tumour markers and a bone scintigraphy for the first
five years. Ultrasound of the axillary region was performed every three months for two Lucia Del Mastro1, Beatrice Dozin2, Enrico Aitini3, Tiziana Catzeddu1, Editta
years if the LNS +. Baldini4, Antonio Contu5, Antonio Durando6, Saverio Danese7, Giovanna
Results: In 76 patients (74%) the LNS -, 27 patients (27%) metastasis were found. Cavazzini3, Giuseppe Canavese8, Paolo Bruzzi2, Paolo Pronzato1 and Marco
In this second group 14 patients (52%) underwent radical surgery of the axillary Venturini1,9
region and 13 patients (48%), of whom 4 had macrometastasis, did not undergo Oncologia Medica A, Istituto Nazionale per la Ricerca sul Cancro, Genova –
surgery given the favourable prognostic factors (age, high expression of ER-PR, stage Italy. 2Epidemiologia Clinica, Istituto Nazionale per la Ricerca sul Cancro,
T, HER-2 score 0) and the patient’s desires. These 27 patients underwent adjuvant Genova –Italy. 3Presidio Ospedaliero C. Poma, Mantova, Italy. 4Ospedale S.
chemo-therapy with schedules containing anthraciclines followed by hormone, Chiara, Pisa, Italy. 5Ospedale Civile, Sassari, Italy. 6DH oncologico, Ospedale S.
according to the guidelines of S.Gallen 2003. After a median follow-up of 36 months we Anna, Torino, Italy. 7Divisione Ginecologia ed Ostetricia C, Ospedale S. Anna,
observed disease progression in 4 patients (mTTP 20 months). Two with LNS - Torino, Italy. 8Senologia Chirurgica, Istituto Nazionale per la Ricerca sul Cancro,
(2,6%)one had an axillary and the other a lung recurrence. The other two were in LNS Genova –Italy. 9Current affiliation: Oncologia Medica, Ospedale Sacro Cuore,
+ and both had a loco-regional recurrence without any difference between the surgery Negrar – Verona, Italy
Conclusions: This data suggests that lymph node involvement is not as decisive as the Purpose: The aim of the present study was to analyze the timing of adjuvant
biological characteristics of the tumour in the choice of the therapy. Even if there is no chemotherapy and tamoxifen (TAM) in breast cancer women. We evaluated the
formal indication for radical surgery with LNS -, there is not sufficient data to prove outcome of both premenopausal and postmenopausal women who were enrolled in
that, in cases LNS + for micrometastasis, immediate axillary dissection is better than two randomized trials (GONO-MIG1 and GONO-MIG5) on adjuvant chemotherapy
observation after an aggressive chemotherapy. We will continue with a follow-up at 5 and who received either concurrent or sequential TAM.
years. Patient and methods: We considered for the analysis patients who received any of the
three antracycline-based regimens used in GONO-MIG1 and MIG5 studies and
concurrent or sequential TAM. The end-point was overall survival (OS). Hazard ratios
C61* SHOULD DISEASE FREE SURVIVAL (DFS) BE USED AS of death or recurrence for treatment comparisons were estimated by Cox proportional
RANDOMIZED CLINICAL TRIALS (RCTS) EXPLORING ADJUVANT Results: We analized data of 1183 patients, 575 (48.6%) received concurrent TAM and
AROMATASE INHIBITORS (AIS) FOR BREAST CANCER (BC)? 608 (51.4%) received sequential TAM. At 10 years the OS was 83% (95%CI:79-87) and
UPDATE OF A META-ANALYSIS LOOKING AT THE MAGNITUDE OF 80% (95%CI:75-86%) in the concurrent and sequential groups, respectively. Event free
THE BENEFIT survival (EFS) was 63% (95%CI:57-70%) in the concurrent and 55% (95 CI:43-67%)
in sequential groups, respectively. No significant difference in the hazard of death
Federica Cuppone, MD1, Emilio Bria, MD1, Mariangela Ciccarese, MD2, Cecilia (HR=1.12; 95%CI:0.78-1.6, p=0.53) and recurrence (HR=1.03; 95%CI: 0.81-1.32;
Nisticò, MD1, Paolo Carlini, MD1, Isabella Sperduti, PhD3, Vito Lorusso, MD2, p=0.8) between the two groups was observed in multivariate analysis. A potential
Edmondo Terzoli, MD1, Francesco Cognetti, MD1, Diana Giannarelli, PhD3 interaction between timing of TAM and patient age was observed: a decreasing trend
Department of Medical Oncology, Regina Elena National Cancer Institute, (p=0.005) in HR of death with increasing age suggested that concurrent therapy might
Rome, Italy; 2Medical Oncology, Vito Fazzi Hospital, Lecce, Italy; 3Biostatistics, be more effective than sequential therapy in young patients.
Regina Elena National Cancer Institute, Rome, Italy; Conclusions: No outcome difference between sequential and concurrent chemo-
endocrine therapy in early breast cancer patients was observed. The potential advantage
Background: To date, DFS is considered the traditional end-point for adjuvant RCTs of the administration of TAM concomitantly with chemotherapy in young patients
in BC. Actually, its eventual correlation with OS has not been addressed in trials need further investigation in prospective trials.

xi50 | session C: early and advanced breast cancer Volume 18 | Supplement 11 | October 2007
Annals of Oncology session C
C63* IN PRE-TRASTUZUMAB ERA ESTROGEN RECEPTOR (ER)- *Ospedale Silvestrini, Perugia
HER2-POSITIVE INVASIVE BREAST CANCER (BC) HAD A POORER Background: The ELDA phase 3 study ( ID: NCT00331097) is
PROGNOSIS COMPARED TO BC WITH TRIPLE-NEGATIVE comparing weekly docetaxel vs CMF as adjuvant treatment of elderly breast cancer
PHENOTYPE patients. An amendment has been approved in December 2006 to adjust methotrexate
dose according to creatinine clearance. Safety data collected before the amendment
E. De Matteis1, L. Cortesi1, S. Ruscelli1, S. Messinese1, G. Cervo1,C Cirilli1, have been compared.
M. Federico1
Patients and methods: Early breast cancer patients, 65 to 79 years old, are eligible if
Cattedra di Oncologia Medica II, Università di Modena e Reggio Emilia, they have metastatic lymphnodes or average to high risk of recurrence according to
2001 St.Gallen criteria, PS£ 2, adequate bone marrow, renal and hepatic function.
Background: Triple negative BC (ER-, PR- and HER2-) has been recognized as an high Patients are randomly assigned to CMF (cyclophosphamide 600 mg/m2, methotrexate
risk BC that lacks the benefit of specific therapy targeting these proteins. However, also 40 mg/m2, fluorouracil 600 mg/m2, days 1-8) or docetaxel (35 mg/m2 days 1-8-15),
double negative BC (ER-, PR- and HER-2+) should be regarded as high risk BC. We both every 4 weeks.
compared the outcome of triple and double negative BC treated at Modena Cancer Results: Data of 101 patients, 53 in the CMF and 48 in the docetaxel arm, median age
Center (MCC) in the pre-tastuzumab era. 70, enrolled up to October 2006, were analysed. At least one grade 3-4 toxic event of
Patients and methods: 2191 women diagnosed with BC between 1999 and 2006, any type was reported in 40 (75.5%) and 19 (39.6%) patients with CMF and docetaxel,
resident in the Province of Modena and referred to the MCC were evaluated. Triple- respectively (exact p=0.0002). Grade 3-4 hematological events were observed in 37

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negative were compared to double negative and other BC, in terms of clinical (69.8%) vs 4 (8.3%) cases (exact p<0.0001) and grade 3-4 non-hematological toxicity
presentation and outcome. in 12 (22.6%) vs 15 (31.2%) patients, with CMF and docetaxel, respectively (exact
Results: One hundred and seventy triple-negative BC (7.8 %) and 85 double negative p=0.11). In particular, a significantly higher incidence of anemia, neutropenia,
BC (3.9%) were found and compared with 1936 hormonal sensitive BC (88.3%). thrombocytopenia and febrile neutropenia was reported in CMF arm. Among non-
Compared to triple negative BC those with double-negative BC had larger tumours hematological toxicity, constipation, mucositis, nausea and vomiting were significantly
(p=0.008), node positive status (p=0.030) and high grade (p<0.0001). Double-negative more common with CMF; diarrhoea, abdominal pain, dysgeusia, neuropathy and liver
BC had also a poorer outcome compared with triple-negative and other BC; the 5-year toxicity were significantly more frequent in docetaxel arm. No significant interaction
survival rate was 72%, 76% and 89%, respectively for double-negative, triple-negative was found between severe toxicity and baseline variables, including creatinine clearance
and other BC (p<0.001). Also the DFS was significantly shorter for double-negative and geriatric assessment.
(72%) than for triple-negative (76%) and for other BC (88%) (p<0.001). As a result, Conclusions: In the present analysis, weekly docetaxel was less toxic than CMF.
the event-free survival at 5 years was worst for double-negative (53%) than for triple- Efficacy data must be awaited to draw conclusions on the role of adjuvant weekly
negative (66%) and for other BC (77%) (p<0.001). docetaxel for elderly early breast cancer patients.
Conclusions: In the pre-trastuzumab era double-negative BC are to be considered at
higher risk than those with triple-negative phenotype in terms of recurrence, event free,
and overall survival. Our finding confirm the additional negative role of HER-2 C66* IS 3-YRS DISEASE-FREE-SURVIVAL (DFS) A RELIABLE
overexpression, that seems fortunately overcome by the availability of specific target SURROGATE END-POINT FOR PREDICTING 5-YRS OVERALL-
THERAPIES IN EARLY BREAST CANCER PATIENTS (BC PTS). Mariangela Ciccarese, MD1, Emilio Bria, MD2, Federica Cuppone, MD2, Paolo
RESULTS FROM THE NORA STUDY Carlini, MD2, Michele Milella, MD2, Isabella Sperduti, PhD3, Vito Lo Russo, MD1,
Cecilia Nisticò, MD2, Edmondo Terzoli, MD2, Francesco Cognetti, MD2, Diana
Cazzaniga ME1, Mustacchi G2, Pronzato P3, De Matteis A4, Di Costanzo F5, Rulli E6, Giannarelli, PhD3
Latini L, 1Barni S, 8Merlano M, 9Floris C on behalf of NORA Study Group 1
Medical Oncology, Vito Fazzi Hospital, Lecce, Italy; 2Department of Medical
Treviglio Hospital, 2University of Trieste, 3IST Genova, 4Pascale Institute, Oncology, Regina Elena National Cancer Institute, Rome, Italy; 3Biostatistics,
Careggi Hospital, 6Mario Negri, 7Ospedale Civile di Macerata, 8Ospedale Regina Elena National Cancer Institute, Rome, Italy
S.Croce e Carle di Cuneo, 9Ospedale Oncologico ‘‘Armando Businco’’ - ASL
8 - Cagliari
Background: DFS is considered the traditional end-point for adjuvant trials for BC.
The eventual correlation between earlier DFS (i.e. 3-yrs) with 5-yrs OS is still unclear in
Background: Chemo- and endocrine therapies administered in the adjuvant setting trials addressing the role of taxanes; if correlation exists, it would be faster to trasfer
present peculiar adverse events (AEs), mainly in the acute time. On the contrary, few new drugs from clinical research into daily practice. In this analysis, all trials evaluating
data are available about the late AEs, in particular those regarding the cognitive and the role of adjuvant taxanes for early BC have been gathered to determine the
sexual area. correlation between 3-yrs DFS and 5-yrs OS.
NORA is a cohort study aimed at investigating treatment modalities and clinical
outcome in 3515 early BC pts radically resected in 71 Oncological Italian Centers. Methods: RCTs with at least 60 month follow-up were considered eligible. A linear
regression model has been applied to explore the correlation by considering both each
Patients and methods: We collected cognitive and sexual AEs by using a dedicated single outcome pair (DFS and OS) for all arms (extracted by curves), their differences,
CRF only throughout the prospective cohort, in which we asked doctors to report the and each outcome Hazard Ratio (HR) or calculated Relative Risk (RRs), following
number and the typology of AEs per pt. We asked to fill in cognitive and sexual form 2 steps: 1) correlation between 5-yrs DFS and OS (to confirm the evidence); 2)
not before than 3 months from the start of the adjuvant therapy and every 3 months correlation between 3-yrs DFS and 5-yrs OS (predictive role). The correlation was
thereafter . 584 pts (46.8%) had at least 1 report, 326 had 3 reports. estimated according to Pearson (r) and R2 coefficients (parametric tests) and Spearman
Results: Median age of pts with cognitive disorders was 54.9 years, the one of pts (Rho) coefficient (non-parametric test). A model to calculate the target sample size to
with sexual disorders was 52.6 (44.7-80.8. At baseline, 136 pts (23.3%) reported determine 5-yrs OS benefit of 3%, 5% and 7%, respectively, was calculated as well.
cognitive AEs, 133 (22.8%) sexual ones. Among 136 pts with cognitive AEs, 63 (46.3%) Results: Data for DFS and OS were available for 10 RCTs (17067 patients). When
had memory disorders, 57 (41.9%) difficulty in concentration, 96 (70.6%) considering 5-yrs outcomes a linear correlation was found between rates (r=0.74,
behavioural and 25 (18.4%) required psychological support. Sexual disorders were: R2=0.55; p<.0001; Rho=0.83; p<.0001), and HRs (r=0.90, R2=0.81; p<.0001;
modification of the libido (51 pts, 38.5%), vaginal dryness (87, 65.4%), recurrent Rho=0.91; p<.0001). Three-yrs DFS correlates with 5-yrs OS, with both rates (r=0.81,
urinary infection (21, 15.8%) and hair loss (24, 18%). During the approximately 1-year R2=0.66; p<.0001; Rho=0.92; p<.0001), and RRs (r=0.84, R2=0.71; p=0.002;
follow up period, 89 (27.3%) and 96 pts (29.4%) reported to have had 1or more Rho=0.85; p=0.002). Moreover, a linear strong correlation between 3-yrs DFS and
cognitive or sexual disorder, respectively. Among cognitive AEs, most pts had 5-yrs OS absolute differences was found (r=0.86, R2=0.74; p=0.001; Rho=0.84;
behavioural disorders (63/89, 70.8%), whereas among sexual AEs, vaginal dizziness was p=0.002). The sample size model (on the basis of the r-coefficient=0.81), calculate
the most frequent (60/96, 62.5%). The majority of the pts reported cognitive and 2733, 863, and 389 pts to improve 3-yrs DFS of 4%, 7% and 10%, which means to
sexual AEs when treated with chemotherapy followed by hormones (47/152, 30.9% improve 5-yrs OS of 3.2%, 5.7% and 8.1%, respectively.
and 56/152, 36.8%), respectively.
Conclusions: According to this analysis, 3-yrs DFS seems reliable in predicting an
Conclusion: Late AEs coming from adjuvant treatments, even if often misunderstanding, ultimate survival advantage when adressing te role of new drugs in early BC.
represent an important medical and social issue in the strategy of BC pts. Furthermore, a smaller patient’ sample is required when DFS is chosen as primary end-
point; this allows to have relible results in a shorter time period.
A. de Matteis, F. Nuzzo, M. C. Piccirillo, S. Gori*, A. Morabito, F. Di Rella, NEOADJUVANT CHEMOTHERAPY
A. Gravina, V. Labonia, G. Landi, C. Pacilio, E. Rossi, G. D’Aiuto, R. Thomas,
M. D’Aiuto, M. Rinaldo, G. Signoriello, C. Gallo, F. Perrone Cortesi L1, Barchetti A2, De Matteis E1, Ruscelli S1, Della Casa L2, Tazzioli G3,
On behalf of the NCI-Naples Breast cancer Group Lazzaretti M. G4, Iannone A2, Federico M 1

Volume 18 | Supplement 11 | October 2007 doi:10.1093/annonc/mdm425 | xi51

session C Annals of Oncology

Cattedra di Oncologia Medica II, 2Dipartimento di Scienze Biomediche, 1
Medical Oncology and 2Breast Unit Azienda Ospedaliera of Perugia, 3Oncology
Dipartimento di Chirurgia Generale, Università di Modena e Reggio Emilia, Dept, Istituto di Ricerche Farmacologiche Mario Negri, Milan,4Pharmacology
Modena,4Divisione di Chirurgia Generale,Ospedale Carpi (Modena) Dept,5Experimental Medicine and 6Internal Medicine University of
Perugia,7Regional Cancer Center, Azienda Ospedaliera, Perugia, Italy
Background: Tumor progression is related to the malignant potential of cancer cells
and microenvironment. To better define the role of proteins secreted by tumor cells Drug resistance and severe toxicity are often limiting factors in effectiveness of
and the effect of neoadjuvant chemotherapy (NACT) in breast cancer (BC), we adjuvant CT used for treatment of EBC. Several functional single nucleotide
analyzed the bi-dimensional maps of secreted proteins in Tumor Interstitial Fluid polymorphisms (SNPs) of genes GSTT1, GSTM1, GSTP1, TS, MTHFR, RFC1,
(TIF) and in Normal Interstitial Fluids (NIF) before and after NACT. involved in the transport and metabolism of these drugs could affect the toxicity
Methods: Eleven patients with stage II and III BC treated with 4 courses of FEC90 and and treatment efficacy. We investigated whether these SNPs were associated with
4 cycles of TXT were investigated. Tumor and normal tissue samples were collected toxicity and treatment effectiveness in pts with EBC treated with CMF, FEC and
before and post NACT. Samples were incubated at 37C for 1h and secreted proteins FAC regimens.
were analyzed with 2D electrophoresis and silver stained. Spots of potential interest Methods: PCR-RFLP-analysis of germ-line polymorphism was performed for GSTP1,
were purified, digested with trypsin and analyzed with HPLC-ESI-MS/MS. RFC1 and MTHFR, while PCR assay for GSTT1, GSTM1 and TS genes. Toxicity was
graded using the WHO criteria.
Results: 140 proteins have been characterized. Glucidic metabolism (PGK1, PKM2 and
FBP1), proteasome subunits (TCP1, PSA, EF1A1, PSME1) and Rho-GDI family Results: From June 2000 to September 2005, 244 consecutive pts entered the study. GP
proteins were up-regulated in TIF while small heat shock proteins (CRYAB), frequencies were:MTHFR C677T genotype 27.5% C/C, 47.5% C/T, 25% T/T;5’UTR TS

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homeostasis regulators (CAI,II) and antioxidant proteins (PRDX2) resulted expressed genotype 32% 2R/2R, 35.2% 2R/3R, 32.8 3R/3R;RFC1 G80A genotype 23.4% A/A,
in NIF. In 9 cases, TIF and NIF samples were also collected at the surgery time showing 46.3% A/G, 30.3 % G/G; GSTP1 A313G genotype 59.4% A/A, 39.3%A/G, 1.2% G/
a correlation between pathological response and proteomic expression profile. In G;GSTT1 and GSTM1 null genotypes 20.5% and 54.1%, respectively.119 pts (48.7%)
5 patients with pathological response >50%, a sharp decrease of total TIF protein were treated with FEC, 125 pts (51.3%) with CMF. The most significant hematologic
expression was observed; in the four minor responders, the TIF pattern was almost and non-hematologic toxicities observed with CMF/FEC were neutropenia (63 pts)
unchanged. The EF1A1 protein resulted overexpressed in non-responders before and and oral mucositis (46 pts). Pts with 2R/3R TS genotype showed severe neutropenia
after NACT, while it was absent in major responders in which a dephosphorilation of G3/G4 compared to pts with 2R/2R TS genotype (p=0.038) while the same group
Rho-GDI was also present. had a lower probability of developing oral mucositis (G2/G3) (p=0.012). When
considering toxicity of any grade (G1-4), pts with RFC1 G80A genotype had
Conclusions: The proteomic characterization of interstitial fluid perfusing the breast
significantly lower risk of developing mucositis (p=0.05) compared to G80G allele.
tumor microenvironment represents a sensitive tool for the detection of differentially
At median follow-up of 2.8 years, 10 pts (4.1%) died, 217 pts (88.9%) are alive and
expressed proteins. Moreover the TIF/NIF study seems a promising novel resource for
free of tumor relapse and 27 pts (11.1%) have experienced local and/or distant
biomarker discovery and for identifying selective targets for therapeutic interventions.
recurrences. Relationships between genotypes and recurrence were also evaluated
and only GSTT1-null genotype was significantly associated with shorter
C68* EGFR, MAPK, AKT AND PTEN STATUS BY Conclusions: Our data suggest that 2R/3R TS and RFC1 G80G genotypes may have
IMMUNOHISTOCHEMISTRY (IHC): CORRELATION WITH CLINICAL a potential role to identify patients with greater risk of toxicity to CMF/FEC and that
OUTCOME IN HER2-POSITIVE (HER21) METASTATIC BREAST GSTT1-null genotype may be an important marker in predicting clinical outcome in

Stefania Gori1, Verena De Angelis1, Angelo Sidoni2, Mariantonietta Colozza1, Ivana

Ferri2, Daniela Fenocchio3, Vienna Ludovini1, Carlo Basurto1, Paola Anastasi1,
Lucio Crinò1
Medical Oncology and 3Pathological Anathomy and Histology Service, Azienda C70* BRCANESS PHENOTYPE AND METHYLATION OF BRCA1
Ospedaliera, Perugia, 2Institute of Pathological Anatomy and Histology, Perugia PROMOTER IN SPORADIC BREAST CANCERS
University, ITALY
Giorgetti G, Galizia E, Bianchi F, Piccinini G, Loretelli C, Belvederesi L, Catalani R,
T alone or in combination with CT has been shown to be an active therapy in HER2+ Gargliardini D, Ferretti C, Corradini F, Bracci R, Santinelli A, Cellerino R
MBC pts. However, not all pts will benefit and mechanisms of resistance to T are still Centro Regionale di Alta Specializzazione in Genetica Oncologica, Istituto di
poorly understood. The aims of this study were to evaluate the IHC expression of EGFR, Medicina Clinica e Biotecnologie Applicate-Oncologia Medica, Università
MAPK and Akt (two downstream effectors of the EGFR family signaling) and PTEN and Politecnica delle Marche, Ancona
their correlation with clinical outcome in HER2+MBC pts treated with T ± CT.
Methods: 133 consecutive HER2+ MBC pts were treated between 04/99 and 03/06 but Background: BRCA1 protein is involved in distinct DNA-repair processes. Hereditary
tumor tissue was available for this analysis only from 45 pts. HER2 evaluated by CB11 breast cancers diagnosed in BRCA1 mutation carriers have ‘‘triple negative’’ phenotype
was scored according to Herceptest.Tumors were considered EGFR positive if ‡1% for Oestrogen Receptor (ER), Progesterone Receptor (PgR) and ERB B2. Similar
positive tumor cells and MAPK positive and Akt positive if the percentage of positive features are present in basal-like sporadic cancers. Since genetic inactivation due to
tumor cells was ‡10%. PTEN expression was assessed by IHC on a scale from 0 to 400 somatic mutations of BRCA1 is a rare event in sporadic breast cancers, we have
(percentage of positive cells x staining intensity) as described by Hirsch F et al (JCO investigated if epigenetic mechanisms, such as methylation of its promoter, could play
21:3798;2003). a role in patients with ‘‘triple negative’’ phenotype.
Results: At median follow up of 57 months (range 5-229) from the start of T, Methods: We have retrospectively analysed two groups of sporadic breast cancer
45 pts were evaluable for TTP and OS and 42 for response to T. Median age of pts was patients: ‘‘triple negative’’ (‘‘BRCA-like’’) cases (42) and positive (‘‘BRCA-unlike’’)
53 years (23-77). We observed 27 responses (CR+PR) to T ± CT (64.28%); median TTP ones (47).
was 24 months (3.3-179.8). In 11 of the 27 responsive pts (40.7%), progression was Methylation Specific PCR and Bisulfite Genomic Sequencing on genomic DNA
observed in CNS ± other sites. Median OS from the start of T was 74 months. EGFR+ (obtained from sections of paraffin-embedded tissues and modified with sodium
tumors were 10 (22.2%), MAPK+ tumors were 16 (35.5%) and Akt+ tumors were 23 bisulfite) were used to analyze the methylation pattern of BRCA1 CpG island. BRCA1
(51.1%). Only 2 pts had PTEN expression score of 0-99 (PTEN-). We analyzed the immunohystochemical analysis (IHC) was performed in all patients, to associate the
correlation of HER2, EGFR, MAPK, Akt and PTEN status with response to T, TTP and reduction or lack of BRCA1 protein with epigenetic damage. The association between
OS. HER2 was significantly correlated with response to T (p= 0.013): in HER2 3+ methylation and type of tumours was evaluated using Chi-square test. A probability of
tumors we observed 22 (9 CR and 13 PR) out of 27 objective responses but no 5% was used as level of significance.
significant correlation was found between HER2 status and TTP and OS. EGFR, Results: BRCA1 promoter methylation was present in 18/42 (43%) of ‘‘BRCA-like’’
MAPK, Akt and PTEN status of tumors were not significantly associated with cases and in 13/47 (28%) of ‘‘BRCA-unlike’’ ones. The BRCA1 IHC was performed in
response to T, TTP and OS in our series. all available samples (table).
Conclusions: We did not find any significant correlation between EGFR, MAPK, Akt, Conclusion: We have observed that the methylation of BRCA1 promoter is higher in
PTEN status evaluated by IHC and clinical outcome in HER2+ MBC pts treated with ‘‘BRCA-like’’ tumours than in ‘‘BRCA-unlike’’ ones. Although this difference is not
T ± CT. Only HER2 status evaluated by IHC significantly correlated with response to statistically significant (p=0.133), further studies are in progress to better
T ± CT. understand the possible role of BRCA1 promoter methylation in sporadic
breast cancers.
AND SURVIVAL IN EARLY BREAST CANCER (EBC) PATIENTS (PTS) Methylation Methylated Unmethylated IHC IHC -/+ IHC ++/+++
‘‘BRCA-like’’ 42 18 (43%) 24 40 35 (87%) 5 (13%)
V. Ludovini1, S. Gori1, A. Rulli2, I. Floriani3, L. Pistola1, G. Nocentini4, V. N. Talesa5, ‘‘BRCA- 47 13 (28%) 34 47 31 (66%) 16 (34%)
S. Piattoni6, P. Anastasi1, C. Basurto1, F. R. Tofanetti1, M. Tonato7, M. Colozza1, unlike’’
L. Crinò1

xi52 | session C: early and advanced breast cancer Volume 18 | Supplement 11 | October 2007
Annals of Oncology session C
C71* BRCA1 EXPRESSION: A CORRELATIVE STUDY AMONG planning to administer new therapies targeting either HIF-1 a and/or mTOR in

Piccinini G, Galizia E, Santinelli A, Bianchi F, Loretelli C, Belvederesi L, Gagliardini D, C73* KINETIC DISTRIBUTION OF CARDIAC MARKER NT-PROBNP
Giorgetti G, Catalani R, Ferretti C, Corradini F, Bracci R, Cellerino R IN CHEMONAIVE BREAST CANCER PATIENTS RECEIVING
Centro Regionale di Alta Specializzazione in Genetica Oncologica, Istituto di ANTHRACYCLINES-BASED ADJUVANT CHEMOTHERAPY
Medicina Clinica e Biotecnologie Applicate -Oncologia Medica, Università
Politecnica delle Marche, Ancona A. Zambelli, A. Lanza, P. Sagrada, GB. Vadacca, A. Papalia, G. A. Da Prada,
V. Fregoni, L. Ponchio, P. Preti, M. De Salvo, F. Cobelli, L. Pavesi
Background: BRCA1 protein is involved in several DNA repair pathways. BRCA1 UO di Oncologia Medica 1, IRCCS Salvatore Maugeri Foundation and Università
mRNA is induced at late G1/early S phase. In sporadic breast cancers, the loss or degli Studi di Pavia, Pavia Italy
reduction of BRCA1 expression is rarely due to BRCA1 mutations and most frequently
to epigenetic events. BRCA1-associated breast cancers are usually ‘‘triple negative’’ Introduction: The natriuretic peptides are counterregulatory hormones involved in
(Estrogen Receptor-ER, Progesterone receptor- PgR, and ERBB2) and share many volume homeostasis and cardiovascular remodeling. The predictive significance of
features with the ‘‘ basal like’’ subtype. Our study aims to evaluate the possible role of plasma natriuretic peptide levels in apparently asymptomatic patients receiving
BRCA1 in sporadic breast cancers showing a ‘‘triple negative’’ phenotype. cardiotoxic chemotherapy (CT) has not been established.

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Methods: We selected 23 and 37 sporadic breast specimens on the basis of triple- The aim of the study was to describe the kinetic distribution of N-terminal pro-
negative or positive staining for ER, PgR and ERBB2. Total RNA was extracted from brain natriuretic peptide (NTproBNP) levels over time during chemotherapy to
paraffin-embedded tumours. BRCA1 mRNA was reverse transcribed and analysed elucidate factors associated with changes of NTproBNP at different time points and to
by nested-PCR. Negative samples were re-assessed by Real Time PCR. BRCA1 protein correlate with cardiotoxic events defined as symptomatic CHF or absolute decrease in
was evaluated by Immunohystochemical (IHC) assay. The association between LEVF by > 20% (or >10% points below 50%).
tumours and the expression of both mRNA and protein was evaluated by the Fisher’s Patients and methods: A total of 480 determinations of NTproBNP and
exact test. Troponin I (TnI) were performed in 20 consecutive chemonaive breast cancer patients
Results: BRCA1 mRNA and protein expression was present in 6/23 (26%) triple receiving 6 cycles (q3wks) of anthracycline-based chemotherapy and compared with
negative and in 24/37 (65%) positive tumours. BRCA1 mRNA was absent in 4/23 10 patients receiving anthracycline-free chemotherapy regimens.
(17%) triple negative and in 3/37 (8%) positive samples. Noteworthy, in 13/23 (56%) Serum concentrations of cardiac markers NTproBNP and TnI were obtained at each
triple-negative patients BRCA1 mRNA is transcribed but the protein is absent, whereas treatment cycle before chemotherapy, at the end, after 2 and 24 hours and after 21 days.
in positive ones this occurs in 10/37 (27%) patients (p=0.01, table). Echocardiography, to assess LVEF, was performed at baseline, every 3 cycles during
Conclusion: BRCA1 mRNA and IHC were positive in 26% of triple-negative and in CT and every 6 months thereafter.
65% of positive breast cancers. Even though BRCA1 IHC is not credited by high Results: After 24 months of follow up, in breast cancer patients receiving
reliability, the lack of BRCA1 protein in 56% of triple negative tumours expressing anthracyclines, we describe a slight increase of NTproBNP at the end of CT, after
mRNA suggests that there might be other mechanisms by which BRCA1 expression is 2 hours with a peak at 24hours. The median NTproBNP was 101 pg/mL at baseline
controlled at post-translational levels, such as miRNA deregulation. and 173 pg/mL at 24h.
The NTproBNP rise at 24 hours was mainly reversible, recovering normal values
Triple Negative Triple Positive (i.e. <155 pg/mL) at 21 days. No changes in TnI levels were observed.
mRNA+/IHC+ (6/23) 26% (24/37) 65% The sole patient that experienced cardiotoxicity, for an asymptomatic drop of LVEF
mRNA+/IHC- (13/23) 56% (10/37) 27% by 25%, had NTproBNP increase that persisted during the whole CT period.
mRNA- (4/23) 17% (3/37) 8.1% Conclusion: Our results show a reversible increase of NTproBNP early after
anthracycline-based chemotherapy. This NTproBNP rise is frequent and
uninformative about the cardiotoxic risk. However the lower reduction rate after
21 days could represent a marker for early detection of cardiotoxicity. The timing
of measurement will be important to consider when using NTproBNP for risk
IN THE YEARS 1998-2001
Daniele Generali, Alfredo Berruti, Stephen B. Fox, MariaPia Brizzi, Manuela Milani,
Simone Bonardi, Rossana Dionisio, Luigi Dogliotti, Alberto Bottini and M. G. Pescarenico*, F. Bozzani§, P. Sgargi§, G. Vasini, V. De Lisi§
Adrian L. Harris *Dipartimento Cure Primarie, Azienda Unità Sanitaria Locale di Parma, §Registro
Unità di Patologia Mammaria - Istituti Ospitalieri di Cremona Tumori di Parma, U. O. di Oncologia Medica, Azienda Ospedaliero-Universitaria
di Parma, Parma, Italia
Introduction: HIF-1 a, as marker of hypoxia, is involved in the selection of
more aggressive phenotype being associated with both chemo and endocrine Introduction: The biological factors are measurable parameters at the diagnosis that
resistance in BC. Letrozole is a potent and selective non steroidal aromatase inhibitor correlate with disease free and overall survival and, in absence of treatments, can
used for the treatment of estrogen positive (ER+ve) post-menopausal BC women. correlate with natural history of disease. The multivariate analysis is currently ongoing
Whether HIF-1 a expression could be modulated by AI is the subject of this to identify which factors are independent predictors and to develop and validate
investigation. HIF-1 a expression was evaluated before and after primary letrozole a single survival model for oBC.
therapy in a series of elderly ER+ve patients enrolled in a randomized prospective trial Aim: This study considers the oBC in the female population of Parma, in the period
(Bottini et al JCO 2006). 1998-2001, with age 40-74, and correlates the overall survival with some prognostic
Patients and methods: 114 women with T2-4 N0-1 and ER+ve BC were randomly factors: age, tumour size, axillary lymph-nodes involvement, histological type and
assigned to 6 months of primary Letrozole plus/minus oral ‘‘metronomic’’ biological parameters (hormonal receptor status, histological grade, Ki67 and Her2/
cyclophosphamide. Tumor response was assessed clinically with a calliper. On TMAs neu expression).
HIF-1 a and mTOR expression (an upstream regulator of HIF-1 a) were evaluated in Methods: From January 1998 and December 2001 1559 women with BC were
tumor specimens collected before and after treatment. The intensity of the staining for identified from our tumour registry. Women with distant metastases (n=58) and
TMAs marker was scored from 0 (no staining) to 2 (strong staining) in nuclear carcinoma in situ (n=247) were excluded from our study. Women were divided into
intensity for HIF-1 a expression. two groups, considering 230 cases in the group of age 40-49 and 1024 in the group of
Results: At baseline HIF-1 a expression inversely correlated with grading (p<0.01) and 50-74. Stage was known in 99% of cases, receptor status in 87%, grade in 72%, Ki67 in
nodes (p<0.01) while it did not correlate with stage, p53, bcl2, Ki67, PgR or ER a 86% and Her2/neu in 72%.
expression. HIF-1 a and mTOR baseline expression were directly correlated (p=0.01). Results: 5-year overall survival was 92% in the 1254 women. Overall poor survival was
Letrozole treatment led to a significant reduction in HIF-1 a expression (p <0.004, associated with lymph-nodes involvement (P=0.001), receptor status (P=0.01) and
Wilcoxon Rank sum test), with no difference between the arms. Reduction in HIF-1 a Ki67 expression (P=0.02). No significant difference in the mean score for age, tumour
did not show any relationship with disease response. As previously observed (Generali size, histology, Her2/neu, when considered singularly, while patients with more than
et al SABCS 2006) letrozole-based therapy was also able to down-regulate mTOR two factors among receptor status negative, Ki67 >10%, high nuclear grade, Her2/neu
pathway. Interestingly, mTOR and HIF-1 a reduction after treatment were significantly positive (+++) showed a poor 5-year overall survival rate compared with the others
associated (p=<0.03). (P= 0.01). On the other hand, in the node-negative group, no prognostic factors turned
Conclusions: Letrozole reduced HIF-1 a expression and mTOR downregulation could out significant, except the association with the tumour size (T).
be a possible mechanism. Whether these changes correlate with drug efficacy or not is Conclusions: Prognostic factors of oBC are important for overall survival. Patients
a matter of future research. However, these results should be taken into account when who had multiple unfavourable risk factor were associate with significant differences in

Volume 18 | Supplement 11 | October 2007 doi:10.1093/annonc/mdm425 | xi53

session C Annals of Oncology

median survival and the most important prognostic factors was axillary lymph nodes C77* SERUM VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF)
HELICAL AND KINASE DOMAINS OF THE PIK3CA GENE IN INVASIVE G. Catalano, M. Orditura,*F. Iovino, ^F. Ferraraccio, §G. Antoniol PhD, F. Morgillo,
BREAST CARCINOMAS (IBC) C. Belli, G. Santabarbara, T. Fabozzi, M. Fasano, M. R. Diadema, F. Ciardiello,
*F. Lo Schiavo, F. De Vita
Antonella Ferro1, Mattia Barbareschi2, Fiamma Buttitta3, Lara Felicioni3, Sabrina Division of Medical Oncology - Department of Clinical & Experimental Medicine;
Cotrupi2, Fabio Barassi3, Maela Del Grammastro3, Paolo Dalla Palma2, Antonio ^
Pathology; *Division of Oncological Surgery- Second University of Naples, Italy
Marchetti3 Enzo Galligioni1
Unit of Medical Oncology and 2 Pathology, Trento. 3 Clinical Research Center,
Background: VEGF is a potent stimulator of angiogenesis, associated with unfavorable
Center of Excellence on Aging, University-Foundation, Chieti, Italy
clinical characteristics in breast cancer. We evaluated the serum VEGF concentrations
in endocrine positive breast cancer patients and relate these results to the
Background: The PI3K-AKT pathway plays a fundamental role in signal immunohistochemical expression of VEGF by the tumor and to the other established
transduction following tyrosine kinase growth factor receptors activation. Mutations clinico-pathological prognostic markers, namely microvessel density (MVD), tumor
in the PIK3CA gene are among the most frequent mutational events in IBC. In IBC, size, grading and lymph node status.

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the PIK3CA gene is frequently mutated at ‘‘hot spots’’ in exons (E) 9 and 20,
Methods: Serum levels of VEGF were determined using a commercially available
corresponding to the helical (E542K and E545G) and kinase (H1047R) domain
sandwich enzyme immunoassay kit (Endogen VEGF ELISA kit). Four– lm tissue
respectively. Little is known about the possible clinical significance of these
sections were used for immunohistochemical procedure. The antibodies used were
mutations. We studied the association of PIK3CA mutations with pathological
a mouse monoclonal antibody against human VEGF, p53,c-erb-B2 and CD34 class II .
features and clinical outcome in a mono-institutional series of IBC patients.
Results: The mean serum VEGF levels of the breast cancer patients were significantly
Materials and methods: Frozen samples of 163 consecutive IBC with complete
elevated compared with those of the control group (294.95±113.51 vs 62.5±25.2 pg/ml;
pathological and clinical data were analyzed for mutations in E9 and E20 of the
p<0.01). Serum VEGF in ductal cancer or NOS was not significantly elevated compared
PIK3CA gene using SSCP and direct sequence analysis.
with lobular carcinoma (p=0.20). Nodal status did not appear to influence serum
Results: We identified 46 missense mutations, 24 (53%) in E9 and 21 (47%) in E20. VEGF levels (p=0.52).A significant correlation was seen between basal VEGF serum
Twelve (50%) of the 24 mutations in E9 were of the E542K type and 11 (46%) were of concentrations, microvessel density (p=0.01), neoplastic embolization (p=0.007) and
the E545K type. Twenty (95%) of the 21 mutations in E20 were H1047R substitutions. p53 status (p= 0.004). Serum VEGF levels did not show any significant correlation with
Mutations in E9 were more frequent in lobular carcinomas (42% of cases) than in tumor grade (p=0.81), multifocality (p=0.77), perineural invasion (p=0.87), Ki67
ductal carcinoma (11%) (p=0.002). There was no significant correlation between (p=0.15) and platelet count (p=0.85). A VEGF positive staining was detecteded in
PIK3CA mutations and other clinicopathological and biological variables. At 50 out of 71 ER- positive tumors (70%).In these patients VEGF expression was
univariate survival analysis PIK3CA E20 mutations were associated with prolonged significantly associated with neoplastic embolization (p= 0.041) and circulating VEGF
overall (OS) and disease free survival (DFS) while mutations in E9 were associated with levels (p=0.047). Finally 13 of 56 tumours were classified as c-ERB-b2 positive. In these
significantly worse prognosis. At multivariate analysis E9 PIK3CA mutations were the patients a significant correlation was observed with neoplastic embolization (p=0.040),
strongest independent factor to predict poor prognosis in term of DFS (P = 0.0003) serum VEGF levels (p=0.02), tissue VEGF expression (p=0.004) and CA 15-3 levels
and OS (P = 0.001). (p=0.023).We found no significant correlation between VEGF expression and other
Conclusion: Our data show that E9 PIK3CA mutations are typical of infiltrating parameters examined. Using stepwise multivariate analysis MVD, neoplastic
lobular carcinomas. Moreover, E20 PIK3CA mutations are associated with better embolization, p53 status were the only covariates that were independently associated
prognosis, while E9 mutations are independently associated with early recurrence and with serum VEGF levels.
death. This is of relevance concerning potentially therapeutic approaches, as it suggests Conclusions: Our results confirm that in primary endocrine positive breast cancer
that PIK3CA E9 mutations could be the most important targets for PI3K inhibiting serum VEGF levels are elevated and show a positive relationship with tumor VEGF and
drugs.(Submitted to CCRJ). p53 overexpression.

Ornella Garrone, Mauro Feola, Marcella Occelli, Antonella Francini, Fabrizia Albrile,
Gian Luca Visconti, Valentina Polla Mattiot, Alberto Biggi, Marco Bobbio, Sara Quercia, Claudio Zamagni, Alessandra Musto, Alessandra Bernardi,
Marco Merlano Donatella Santini, Marta Rosati, Manuela Lenzi, Stefano Fanti, Mario Taffurelli and
Ospedale S. Croce e Carle Cuneo Andrea Angelo Martoni
Medical Oncology Unit, Nuclear Medicine Unit, Pathology Unit, General Surgery
Anthracyclines are among the most used drugs in breast cancer treatment. Unit, S.Orsola-Malpighi Hospital and University of Bologna, Bologna – Italy
Unfortunately they induce a dose dependent chronic cardiotoxicity. In order to
prospectively evaluate the cardiotoxic effects of epirubicin-containing adjuvant Background: Pathological complete remission is an important goal of primary
chemotherapy in early breast cancer patients, we performed cardiac evaluation by chemotherapy because it correlates with a better prognosis in terms of relapse-free and
means of multigated radionuclide (MUGA) scan, troponin I and neurohormonal overall survival. In most of the trials published in the literature, the response to primary
assessment. chemotherapy is evaluated with physical exam, mammography and, in some cases,
Methods: Patients with early breast cancer undergoing surgical treatment followed by ultrasounds. The correlation between clinical and pathological complete response is
chemotherapy were enrolled. The chemotherapy regimen consisted of epirubicin quite poor (about 50%).
90 mg/sqm, cyclophosphamide 600 mg/sqm and fluorouracil 600 mg/sqm on day 1 The primary aim of this study is to investigate if 18F FDG PET improves the
every three weeks for 6 cycles. The presence of coronary artery disease, valvular disease, correlation between clinical and pathological response and if it is able to identify early
abnormal left ventricular ejection fraction (LVEF<50%), were considered exclusion predictive signs of response in pts treated with primary (neoadjuvant) anthracycline-
criteria. All patients underwent clinical assessment, MUGA scan, troponin I, brain and taxane-based chemotherapy for breast cancer.
natriuretic peptide (BNP), at baseline, 1 month after the last chemotherapy cycle (T1), Patients and methods: T2-4 N0-3 M0 hystologically confirmed breast cancer pts,
and then after 1 year (T2). candidates for primary chemotherapy were eligible; M1 olygometastatic patients were
Results: 52 patients median age 57 years (range 28-73) were included. Hypertension also eligible if the therapeutic program included breast surgery after chemotherapy. Pts
y/n 21/52 patients. All patients performed T1 and T2 evaluations. Statistical analysis were evaluated at baseline, every 2 courses and at the end of primary chemotherapy
was performed according to the Student Test. with physical exam, mammography, ultrasounds, breast MRI and PET scan. In the first
A significant reduction of LVEF was observed (from 62±5.5 % to 58.5±7.7 %, 10 pts PET scan was carried out before each cycle. Metabolic therapy response was
p=0.001) at T1 without any change at T2 (from 58.5±7.7 % to 58.3±6.6%, p=0.9); BNP quantitatively measured by SUVmax within the primary lesion and by relative (%)
plasma level increased (from 36.1±42.8 pg/ml to 62.5±93.3 pg/ml, p=0.005) at T1 and SUVmax decrease. Pathological response was evaluated according to Miller and Payne
remained slightly increased at T2 (from 62.5±93.3 pg/ml to 58.8±99 pg/ml, p=0.5). classification system, that ranges from grade 1 (no response) to grade 4-5 (only small
Troponin I increased at T1 (from 0.006±0.01 ng/ml to 0.05±0.04 ng/ml, p=0.0001) but clusters or individual cells residual, or no malignant cells at all).
returned at the baseline level at T2 (0.005±0.08 ng/ml). In 17/52 (35%) patients LVEF Results: Up to now 24 pts have been enrolled and 6 of them are still on chemotherapy.
reduced >5% at T2. Moreover patients with LVEF reduction at T2 did not have The present analysis is focused on the first 18 pts. Median age 50 (range 31-72), median
increased secretion of troponin I after chemotherapy (0.07±0.05 ng/ml vs 0.05±0.04 KPS 100%; stage II: 8 pts; stage III: 8 pts; stage IV (olygometastatic): 2 pts. After 6-8
ng/ml, p=0.14). courses of primary chemotherapy we observed 8 (44%) grade 4 pathological
Conclusions: The modification in LVEF and BNP developed early after anthracycline remissions. Baseline PET was pathological (focal lesion with SUVmax >2, median 10,
chemotherapy and did not recover completely after 1 year. Before chemotherapy none range 2.5-20) at primary tumor level in all pts; a complete normalization (SUV max £2)
of the analysed parameters might predict the systolic dysfunction at T2. was observed in 12/18 cases (66%) at the end of primary chemotherapy. The overall

xi54 | session C: early and advanced breast cancer Volume 18 | Supplement 11 | October 2007
Annals of Oncology session C
concordance between PET and pathological evaluation was 78% (14/18), while the A small study was conducted to determine the clinical and biological effectiveness of
concordance of PET with grade 4 pathological remission was 67%. PET overestimated TOR (60 mg/day) as a short-term pre-operative therapy in elderly patients (pts) with
pathological response in 4/18 cases (22%). After the 2nd course of chemotherapy 7/8 newly diagnosed, (ER+) operable or locally advanced (T2-T4b, N0-1) BC.
pts (87.5%) with grade 4 pathological response and 2/10 pts (20%) with grade 1 to 3 The diagnosis of BC was established by core-needle biopsy. A cut-off of 10% of
pathological response had a SUVmax decrease ‡75% (p<.01 ). stained cells was used to define ER+. Response to the treatment was based on changes
Conclusion: The correlation between FDG-PET response and grade 4 pathological in clinical measurements by callipers. After 3 months of TOR, all pts were referred to
remission is 67% (95% CI: 46-88%). An early (after 2 courses) decrease of SUVmax the breast surgeon. Blood samples were collected at baseline and monthly thereafter.
‡ 75% on primary breast lesions is significantly more frequent in grade 4 pathologic Serum oestradiol (E2), testosterone (TST), sex hormone-binding globulin (SHBG),
responders. and bone metabolism markers (BAP and ICTP) were assessed by IRMA or RIA
Forty-seven pts entered the study. The median age was 78 years (range, 65-90 years);
C79* MORPHOLOGICAL AND MOLECULAR ANALYSIS OF 72% of pts were classified as T2 without clinical nodal involvement. By WHO criteria,
CIRCULATING TUMOR CELLS (CTCS) IN BREAST CANCER response rate was 42.5% (95% CI, 28.3 to 57.8%), with further 25 pts achieving disease
stabilisation. After 3 months of therapy, a significant decrease in both circulating E2
S Bessi, M Pestrin, M Truglia, F Galardi, S Cappadona, C Biagioni, W Claudino, and TST levels was observed (median decrease 28% and 13%, respectively; paired t test
M De Stefanis, L Biganzoli, A Di Leo, and A Giannini p=0.01), with a concurrent rise (median value 77%) in SHBG levels (p=0.01). No
Translational Research Unit, Dept. of Oncology, Hospital of Prato, Istituto significant changes in serum BAP and ICTP occurred.

Downloaded from at UCHSC Denison Memorial Library Box A-003 on February 13, 2011
Toscano Tumori In conclusion, neoadjuvant TOR appears to be an effective endocrine option in this
patient population. Despite the changes in endocrine parameters, short-term TOR
induces no apparent impact on bone metabolism markers.
Background: The detection of CTCs in peripheral blood may have some clinical use for
The Authors would like to thank the ITMO office for their data management
monitoring response to therapy and disease recurrence. It is very important to use
reproducible systems to isolate and characterise CTCs.
Experimental design: 7.5 ml blood samples were collected from 47 patients with breast
cancer in different disease phases (2 neoadjuvant, 7 adjuvant, 38 metastatic). CTCs
were isolated with the CellSearch System (Immunicon Co.) by means of C81* WEEKLY PACLITAXEL AND PEGYLATED LIPOSOMAL
immunomagnetic separation, using ferrofluid nanoparticles binding anti-epithelial cell DOXORUBICIN IN METASTATIC BREAST CARCINOMA
adhesion molecules (EpCAM), and fluorescently stained with Epithelial Cell Kit.
CTCs were defined as nucleated (DAPI positive), epithelial (CK 8, 18, 19 positive) and V. Leonardi, V. Palmisano, A. Pepe, A. Usset, G. Savio, A. Laudani, C. Calabria,
negative for CD45. Concomitantly, we used Tumor Phenotyping Reagent to L. Tartaglia, P. Amari, G Carruba and B. Agostara
investigate HER-2/neu expression. Moreover, CTCs were isolated using the Profile Oncologic Department, Division of Medical Oncology, PO ‘‘M. Ascoli’’, ARNAS
Kit: slides were set up and investigated by Papanicolaou staining, Civico, Palermo
immunocytochemestry (ICC), fluorescence in-situ hybridization (FISH).
Results: CTCs could be detected in 1, 5, 31 patients in the neoadjuvant, adjuvant, and Introduction: Systemic chemotherapy has saved the life of many patients with
metastatic settings and the median CTC number was 7/7.5 ml, 3/7.5 ml, 6/7.5 ml cancer, but the maximum efficacy of cytotoxic agents is severely limited by their
respectively. adverse effects. Peg-LD has the advantage of delivering the active anthracycline
CTCs HER-2/neu expression was investigated in 33 samples (45% were negative, directly to the tumor site while exposing the patient to a lesser degree of doxorubicin-
55% positive). The morphological analysis after Papanicolaou staining showed two associated toxicities. More recently, a regimen in which Paclitaxel is infused weekly
cellular sub-types: the most representative one is characterized by small size, round cells over 1 hour produced substantial anti-tumor activity, with little myelosuppression.
with a large nucleus (high nucleus/cytoplasmic ratio)that were both isolated and in
Materials and methods: We designed a phase II trial to study the efficacy and toxicity
clusters; the other group is characterized by bigger and sometimes more elongated cells.
of Peg-LD 10 mg/m2 d1,8,15 plus Paclitaxel 70 mg/m2 weekly in metastatic breast
CTCs were also evaluated by ICC (Cytokeratins, ER, PGR, Ki67, C-erbB2) and FISH
cancer patients with high cardiologic risk. All patients were premedicated with
Pyridoxine 300 mg/daily per os and Desametasone 8 mg i.v. before each chemotherapy
Conclusions: CellSearch System, with minimal operator involvement, is a reliable, administration to prevent the palmar-plantar erythrodysesthesia (PPE). To date, 31 pts
simple, automated and standardized method to isolate and better bio-characterize have been recruited, 27 pts (87 %) evaluable for efficacy and 31 pts (100 %) for toxicity.
CTCs. Adjuvant chemotherapy had been administered in 25 pts (anthracycline-based in
16 pts); 20 pts (64.5%) have two or more sites of disease.
Efficacy: Overall, 3 CR, 14 PR have been recorded with an overall response rate of
62.8%. 6 NC and 3 PD had been registered.
A CLINICAL AND BIOLOGICAL STUDY Toxicity: Toxicity was generally manageable; the only grade 3,4 side effects recorded
were: PPE 6 %, mucositis 3 %, Leucopenia 12.6 %, AST/ALT 3 %. No cardiotoxicity
Antonia Martinetti2, Luigi Celio, Roberto Bajetta1, Angela Denaro, Ettore Seregni, was seen.
Maddalena Mancin Emilio Bajetta Conclusions: The weekly Paclitaxel and Peg-LD appears to be a well tolerated and
Medical Oncology Unit, Pharmacy Unit1, Nuclear Medicine Unit2; Fondazione effective approach in metastatic breast cancer patients with high cardiologic risk. This
IRCCS Istituto Nazionale Tumori, Milan, Italy phase II study will continue to accrue patients until 40 pts are enrolled.

Volume 18 | Supplement 11 | October 2007 doi:10.1093/annonc/mdm425 | xi55