CANCER DE MAMA

Phase I dose-escalation and pharmacokinetic study of ispinesib, a

kinesin spindle protein inhibitor, administered on days 1 and 15 of a
28-day schedule in patients with no prior treatment for advanced
breast cancer.
Gomez HL, Philco M, Pimentel P, Kiyan M, Monsalvo ML, Conlan MG, Saikali KG, Chen MM, Seroogy
JJ, Wolff AA, Escandon RD.
Anticancer Drugs. 2012 Mar;23(3):335-41.

Abstract
The objective of the study was to evaluate the safety, pharmacokinetics, and antitumor activity of
ispinesib, a kinesin spindle protein inhibitor. Patients with locally advanced or metastatic breast cancer
who had received only prior neoadjuvant or adjuvant chemotherapy were treated with escalating doses of
ispinesib administered as a 1-h infusion on days 1 and 15 every 28 days until toxicity or progression of
disease. Doses were escalated until dose-limiting toxicity was observed in two out of six patients during
cycle 1. A total of 16 patients were treated at three dose levels: 10 mg/m (n=3), 12 mg/m (n=6), and 14
mg/m (n=7). Forty-four percent of the patients had locally advanced disease and 56% had metastatic
disease; 50% were estrogen receptor positive, 44% were progesterone receptor positive, 25% human
epidermal growth factor 2 were positive, and 31% triple (estrogen receptor, progesterone receptor,
human epidermal growth factor 2) negative. Sixty-nine percent of patients were chemo-naive. The
maximum tolerated dose was 12 mg/m and dose-limiting toxicity was grade 3 increased aspartate
aminotransferase and alanine aminotransferase. The most common toxicities included neutropenia (88%;
38% grade 3 and 44% grade 4), increased alanine aminotransferase (56%), anemia (38%), increased
aspartate aminotransferase (31%), and diarrhea (31%). No neuropathy, mucositis, or alopecia was
reported. Among the 15 patients evaluable for antitumor activity, there were three partial responses, one
confirmed by the response evaluation criteria in solid tumors (7% response rate). Nine patients (60%) had
stable disease lasting at least 42 days, with four (27%) lasting for at least 90 days. Disease stabilization
(partial responses+stable disease) was observed in 11 (73.3%) patients. In conclusion, ispinesib was well
tolerated when administered on days 1 and 15 every 28 days. Limited activity was observed with this
schedule in patients with previously untreated advanced breast cancer.

Lactate dehydrogenase B: a metabolic marker of response to

neoadjuvant chemotherapy in breast cancer.
Dennison JB, Molina JR, Mitra S, Gonzlez-Angulo AM, Balko JM, Kuba MG, Sanders ME, Pinto JA,
Gmez HL, Arteaga CL, Brown RE, Mills GB.
Clin Cancer Res. 2013 Jul 1;19(13):3703-13. doi: 10.1158/1078-0432.CCR-13-0623. Epub 2013 May 22.

Abstract
Although breast cancers are known to be molecularly heterogeneous, their metabolic phenotype is less
well-understood and may predict response to chemotherapy. This study aimed to evaluate metabolic
genes as individual predictive biomarkers in breast cancer.
mRNA microarray data from breast cancer cell lines were used to identify bimodal genes-those with
highest potential for robust high/low classification in clinical assays. Metabolic function was evaluated in
vitro for the highest scoring metabolic gene, lactate dehydrogenase B (LDHB). Its expression was
associated with neoadjuvant chemotherapy response and relapse within clinical and PAM50-derived
subtypes.
LDHB was highly expressed in cell lines with glycolytic, basal-like phenotypes. Stable knockdown of
LDHB in cell lines reduced glycolytic dependence, linking LDHB expression directly to metabolic function.
Using patient datasets, LDHB was highly expressed in basal-like cancers and could predict basal-like
subtype within clinical groups [OR = 21 for hormone receptor (HR)-positive/HER2-negative; OR = 10 for
triple-negative]. Furthermore, high LDHB predicted pathologic complete response (pCR) to neoadjuvant
chemotherapy for both HR-positive/HER2-negative (OR = 4.1, P < 0.001) and triple-negative (OR = 3.0, P
= 0.003) cancers. For triple-negative tumors without pCR, high LDHB posttreatment also identified
proliferative tumors with increased risk of recurrence (HR = 2.2, P = 0.006).
Expression of LDHB predicted response to neoadjuvant chemotherapy within clinical subtypes
independently of standard prognostic markers and PAM50 subtyping. These observations support
prospective clinical evaluation of LDHB as a predictive marker of response for patients with breast cancer
receiving neoadjuvant chemotherapy.

A randomized phase II study of lapatinib + pazopanib versus lapatinib

in patients with HER2+ inflammatory breast cancer.
Cristofanilli M, Johnston SR, Manikhas A, Gomez HL, Gladkov O, Shao Z, Safina S, Blackwell KL,
Alvarez RH, Rubin SD, Ranganathan S, Redhu S, Trudeau ME.
Breast Cancer Res Treat. 2013 Jan;137(2):471-82.

Abstract
This multi-center Phase II study evaluated lapatinib, pazopanib, and the combination in patients with
relapsed HER2+ inflammatory breast cancer. In Cohort 1, 76 patients were randomized 1:1 to receive
lapatinib 1,500 mg + placebo or lapatinib 1,500 mg + pazopanib 800 mg (double-blind) once daily until
disease progression, unacceptable toxicity, or death. Due to high-grade diarrhea observed with this dose
combination in another study (VEG20007), Cohort 1 was closed. The protocol was amended such that an
additional 88 patients (Cohort 2) were randomized in a 5:5:2 ratio to receive daily monotherapy lapatinib
1,500 mg, lapatinib 1,000 mg + pazopanib 400 mg, or monotherapy pazopanib 800 mg, respectively. The
primary endpoint was overall response rate (ORR). Secondary endpoints included duration of response,
progression-free survival (PFS), overall survival, and safety. In Cohort 1, ORR for the lapatinib (n = 38)
and combination (n = 38) arms was 29 and 45 %, respectively; median PFS was 16.1 and 14.3 weeks,
respectively. Grade 3 adverse events (AEs) were more frequent in the combination arm (71 %) than in
the lapatinib arm (24 %). Dose reductions and interruptions due to AEs were also more frequent in the
combination arm (45 and 53 %, respectively) than in the lapatinib monotherapy arm (0 and 11 %,
respectively). In Cohort 2, ORR for patients treated with lapatinib (n = 36), lapatinib + pazopanib (n = 38),
and pazopanib (n = 13) was 47, 58, and 31 %, respectively; median PFS was 16.0, 16.0, and 11.4 weeks,
respectively. In the lapatinib, combination, and pazopanib therapy arms, grade 3 AEs were reported for
17, 50, and 46 % of patients, respectively, and the incidence of discontinuations due to AEs was 0, 24,
and 23 %, respectively. The lapatinib-pazopanib combination was associated with a numerically higher
ORR but no increase in PFS compared to lapatinib alone. The combination also had increased toxicity
resulting in more dose reductions, modifications, and treatment delays. Activity with single-agent lapatinib
was confirmed in this population.

Behaviour of breast cancer molecular subtypes through tumour

progression.
Castaneda CA, Andrs E, Barcena C, Gmez HL, Corts-Funs H, Ciruelos E.
Clin Transl Oncol. 2012 Jun;14(6):481-5.

Abstract
INTRODUCTION Breast cancer (BC) becomes more aggressive throughout disease progression. Clinical
stage is correlated with patient outcome. We hypothesised that BC molecular subtypes are associated
with a poor prognosis in advanced clinical stages. We analysed the distribution and behaviour of
molecular subtypes at different BC tumour size and variation of molecular subtype in recurrent lesions.
We studied 1647 consecutive patients with non-metastatic invasive and microinvasive (Tmi) BC treated
from January 1997 to December 2007. Patients were categorised by tumour size and molecular subtype.
A chi-square method was used for multiple group comparisons. Kaplan-Meier product limit method was
used to calculate overall survival and disease-free survival.
Median follow-up was 7.2 years. For patients with invasive BC the median age was 56 years. Four
hundred and fifteen patients recurred and 225 died. Larger tumours were more frequently of triplenegative (TN) subtype than small ones or Tmi lesions. Any molecular subtype change from primary
tumour to recurrent lesions is more likely to happen from a good prognosis to a subtype of worse
prognosis than the opposite. Larger tumours of luminal A, luminal B and TN, but not HER2 subtype, are
more likely to carry aggressive markers and to have worse outcomes than small ones.
We found accumulation of TN subtype, migration to a poor prognosis subtype and increasing
aggressiveness of luminal and TN subtypes throughout tumour progression. Tumours belonging to the
HER2 subtype behave aggressively regardless of the primary size.

Phase I and pharmacokinetic study of lonafarnib, SCH 66336, using a

2-week on, 2-week off schedule in patients with advanced solid
tumors.
Castaneda C, Meadows KL, Truax R, Morse MA, Kaufmann SH, Petros WP, Zhu Y, Statkevich P, Cutler
DL, Hurwitz HI.
Cancer Chemother Pharmacol. 2011 Feb;67(2):455-63.

Abstract
This phase I study was performed to determine the safety profile, maximum tolerated dose (MTD) and
biological activity of lonafarnib (SCH 66336). Single-dose and multi-dose pharmacokinetics were
conducted.
Twenty-one patients with advanced solid tumors were enrolled. Each patient received single-dose
administration on day 1, cycle 1 then switched to a twice daily (BID) dosing regimen on days 2-14 of a 28day cycle; subsequent cycles continued BID dosing on days 1-14. Dose-limiting toxicity (DLT) was
assessed during the cycle one; toxicity evaluation was closely monitored throughout the treatment.
Radiographic scans were completed to assess tumor response. Blood and urine pharmacokinetics were
evaluated on days 1 and 14 in cycle 1. SCH 66336- induced farnesylation inhibition was assessed via
conversion of prelamin A to lamin in buccal mucosa.
DLT and most common adverse events were diarrhea, fatigue, nausea and anorexia. No grade 3 or 4
hematological toxicities were observed. Nineteen of 21 patients were evaluable for response; short-term
stable disease was observed in 5 patients. SCH 66336 systemic exposure increased with dose; however,
drug accumulation was higher than projected. Renal excretion of parent drug was negligible. Farnesyl
transferase inhibition was detected at the 200 and 300 mg BID doses.
The MTD and recommended phase II dose is 200 mg BID on days 1-14 of a 28-day dosing regimen. The
plasma concentration profile suggests the pharmacokinetics of SCH 66336 is dose and time dependent.
Farnesyl transferase target inhibition was observed at doses of lonafarnib recommended for further study.