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RECENT ADVANCES IN THE

TREATMENT OF BREAST CANCER


Djoko H. Hermanto
Hematology-Medical Oncology Division, Department of Internal Medicine
Faculty of Medicine, Brawijaya University - Dr. Saiful Anwar General Hospital
Malang

Individualizing Treatment of Women with


Breast Cancer (BC)
Factors that affects treatment option:
Menopausal status: premenopausal or post menopausal
Biological Age: younger or older patients
Molecular subtype: ER, PR, HER2, (Ki-67) status (Luminal A, lum B,

HER2+, Triple negative)


T,N Stage: types of surgery, neo-adjuvant or adjuvant treatment
Number of lymph nodes involvement
Pre-invasive or invasive BC
DCIS or LCIS
Inflammatory / non-inflammatory
Performance status
Co morbidities factors
Previous therapy and toxicities
Patient preference
1. NCCN guidelines Version 1.2014
2. Goldhirsch A, et al. Annals of Oncology 2013;24: 22062223
3. Cardoso F, et al. Annals of Oncology 2014; 00: 118.

Histological & Molecular subtypes of BC

TNM Staging System for Breast Cancer

Early BC refers to BC in stages 0, I and II,


Locally Advanced BC refers to BC in stages IIIA IIIC,
Advanced or Metastatic BC refers to BC in stages IV,
at the time of diagnosis

1. NCCN Guidelines version 3.2014


2. Kalogerakos K, et al. Cancer Therapy 2008;6:463-476

New Approach to Breast Cancer


Breast cancer treatment needs multidisciplinary

approach and team


Good relation between Radiologists, Pathologists,

Surgeons, Medical oncologists and Radiotherapist


is needed to choose the best treatment options for
every patients
Trained nurses needed to help patient and

physician in diagnosis and treatment


Supportive group and programs are needed to

increase information of patient and her quality of


life

Breast Cancer: Treatment Options


Management of BC often involves more than one

approach
Surgical option is the mainstay of the treatment of EBC1
Breast-conserving surgery (lumpectomy, or segmented

mastectomy), followed by radiation therapy2; or


Mastectomy (simple mastectomy with sentinel biopsy or
modified radical mastectomy)2.

Adjuvant Radiation therapy


Systemic therapy: neoadjuvant/ adjuvant chemotherapy.
Targeted therapy: Endocrine therapy, Anti HER2

1. Ring A, et al. British Journal of Cancer 2011;105: 189193


2. NCCN version 3.2014

Surgical option
Breast-Conserving Surgery (BCS) has become the standard

treatment for EBC.


Indications: Stage I or Stage II Breast Cancer (localized tumor)

Tumor not fixed to overlying skin or to underlying muscle


Negative surgical margins
No diffuse, inflammatory or multicentric cancer
No malignant appearing mammographic abnormalities after surgery
No previous radiation (prevents further Breast Radiation Therapy)

Lymph node involvement is not a contraindication

Lnn. must not be fixed to other lymph nodes and to surrounding tissue

Invasive ductal and lobular cancer not contraindication

Tumor must not be diffuse


Requires that negative surgical margins are achieved
1. Cordeiro. N Engl J Med 2008;359:1590-601
2. Morrow (2002) CA Cancer J Clin 2002;52(5): 277-300

Different methods of mammoplasty used to fill defects after wide lumpectomies


makes better cosmetic results

Adjuvant Radiation Therapy


Adjuvant radiotherapy is the current standard of care for:
Patients with EBC following BCS, and
Patients with a high risk of local recurrence following

mastectomy.1

According to the Oxford overview analysis (EBCTCG,

2005a): in women undergoing BCS followed by radiation


vs surgery alone, 5-year local recurrence risks were 7%
vs 26% (2P<0.00001) and a 15-year breast cancer
mortality risks were 30.5 vs 35.9% (2P=0.0002).
There is new strategies in radiation therapy for EBC

according to St Gallen International Expert Consensus


2013.2
EBCTCG : The Early Breast Cancer Trialists Collaborative Group

1. Ring A, et al. British Journal of Cancer 2011;105(2):189-193


2. Goldhirsch A, et al. Annals of Oncology 2013;24: 22062223

Highlights of the St Gallen International


Expert Consensus 2013
Radiation therapy:
The safety and efficacy of shorter courses of
whole breast radiation therapy (40 Gy in 15
or 42.5 Gy in 16 fractions) offer advantages
of convenience and cost over the previous
standard of 50 Gy in 25 fractions.

Goldhirsch A, et al. Annals of Oncology 2013;24: 22062223

Systemic Treatment
1. Neo adjuvant/ adjuvant: regimens for

HER2(-) disease and for HER2(+) disease1.


2. Endocrine therapy :
Anti estrogens: tamoxifen, toremifene and

raloxifene
Aromatase inhibitors: anastrozole, letrozole, and
exemestane
Progestin, androgens hormone, LHRH agonist

3. Targeted therapy: trastuzumab, lapatinib,

bevacizumab, pertuzumab.
1. NCCN version 3.2014

Regimens for HER2(-) Disease


(all category 1)

Preffered regimens:

Dose dense AC followed by paclitaxel every 2 weeks


Dose dense AC followed by weekly paclitaxel
TC (Docetaxel and Cyclophosphamide), etc

Other regimens:
Dose dense AC (doxorubicin/cyclophosphamide) every 2 weeks
FAC (fluorouracil/doxorubicin/cyclophosphamide) or FEC
(cyclophosphamide/epirubicin/fluorouracil) every 3 weeks
CMF (cyclophosphamide/ methotrexate/fluorouracil)
AC followed by docetaxel every 3 weeks
AC followed by weekly paclitaxel
EC (epirubicin/cyclophosphamide) every 3 weeks
FAC/FEC followed by weekly docetaxel or paclitaxel
TAC (docetaxel/doxorubicin/cyclophosphamide) , etc
NCCN Guidelines Version 3.2014

Regimens for HER2(+) Disease


(all category 1)

Preferred Regimen:
AC followed by T + trastuzumab pertuzumab
(doxorubicin/cyclophosphamide followed by paclitaxel plus
trastuzumab, various schedule)
TCH (docetaxel, carboplatin, trastuzumab) pertuzumab
Etc

Other Regimens:

AC followed by docetaxel + trastuzumab pertuzumab


FEC followed by docetaxel + trastuzumab pertuzumab
FEC followed by paclitaxel + trastuzumab pertuzumab
Pertuzumab + trastuzumab + docetaxel followed by FEC
Pertuzumab + trastuzumab + paclitaxel followed by FEC
Etc
NCCN Guidelines Version 3.2014

Highlights of the St Gallen International


Expert Consensus 2013
For patients with triple-negative disease, optimal

chemotherapy regimens have not been defined, but


there is evidence supports the benefit of bevacizumab,
platinums, capecitabine, or gemcitabine
No standard duration of adjuvant chemotherapy has yet

been identified for patients with endocrine nonresponsive disease


The selection of regimen for neoadjuvant chemotherapy

generally follows guidelines similar to those applying to


the conventional adjuvant setting.

Goldhirsch A, et al. Annals of Oncology 2013;24: 22062223

Targeted Terapi
Endocrine Therapy (ET):

Indication: all patients with ER / PR positive.

For premenopausal women with hormone receptor positive BC, the

standard endocrine therapy is tamoxifen.1


In women with ER (+) BC, 5 years of adjuvant tamoxifen reduces the

annual risks of recurrence and BC mortality by 39 and 31%,


respectively.2
The ATLAS trial reported superiority for 10 years compared with 5

years of adjuvant tamoxifen.1

Should not simultaneously prescribed with RT to minimize risk of


pulmonary fibrosis (Radiother Oncol 2002,Br J Cancer 2004).

Should not simultaneously prescribed with chemotherapy as it reduce its


effect and significantly increase the incidence of thromboembolism.

1. Goldhirsch A, et al. Annals of Oncology 2013;24: 22062223


2. Ring A, et al. British Journal of Cancer 2011;105: 189193

Highlights of the ESO-ESMO 2nd international


consensus guidelines 2014
Endocrine therapy:
For premenopausal women, ovarian

suppression/ablation combined with additional ET is the


first choice (LoE: IA).
The additional endocrine agent should be tamoxifen

unless tamoxifen resistance is proved (LoE: IB)


An aromatase inhibitor is also a viable option, but

absolutely mandates the use of ovarian


suppression/ablation (LoE: IB)
Endocrine treatment after CT (maintenance ET) to

maintain benefit is a reasonable option (LoE: IC)


Cardoso F, et al. Annals of Oncology 2014;00: 1-18

Targeted Terapi
Anti HER2 (+)
Indicated for adjuvant treatment of HER2 positive BC
Conclusions from BCIRG 006 trial:1
Trastuzumab provides a similar and significant advantage for both

DFS and OS when used with either anthracycline-based (ACTH) or


non-anthracycline (TCH) chemotherapy; this advantage is seen in both
low- and high-risk patients
The acute and chronic toxicity profiles of TCH are better compared
with those seen with the ACTH regimen
Trastuzumab-induced cardiac dysfunction might be a particular
concern in older patients

Conclusions from N9831 trial:


DFS is significantly improved with the addition of 52 wks of

trastuzumab to AC T (5-yr DFS: 72% vs 80%)


There is a statistically significant 33% reduction in the risk of an
event with the sequential addition of trastuzumab following AC T
1. Slamon D, et al. SABCS 2009. Abstract 62
2. Perez EA, et al. SABCS 2009. Abstract 80.

Highlights of the ESO-ESMO 2nd international


consensus guidelines 2014
Anti HER2 positive for MBC:
HER2 positive MBC: Anti-HER-2 therapy should be offered early to

all patients with HER-2+ MBC, except in the presence of


contraindications (LoE: IA).
For patients with ER+/HER-2+ MBC for whom ET was chosen over

CT, anti-HER-2 therapy + ET should be considered with the


initiation of ET since anti-HER-2 therapy (either trastuzumab or
lapatinib) in combination with ET has shown substantial PFS benefit
compared with ET alone. The addition of anti-HER-2 therapy in this
setting has not led to a survival benefit (LoE: IA).
The optimal duration of anti-HER-2 therapy for MBC (i.e. when to

stop these agents) is currently unknown.


In the case of progression on trastuzumab, the combination of

trastuzumab + lapatinib is also a reasonable treatment option (LoE:


IB)
Cardoso F, et al. Annals of Oncology 2014;00: 1-18

Anti HER2 (Herceptin)

HER2 Overexpression in Breast


Cancer
HER2 is overexpressed in
~ 25% of breast cancers

Normal (1x)
~ 25,000-50,000 HER2
receptors

Overexpressed
HER2 (10-100x)
up to ~ 2,000,000
HER2 receptors

Pegram MD, et al. Cancer Treat Res. 2000;103:57-75.


Ross JS, et al. Am J Clin Pathol. 1999;112(suppl 1):S53-S71.
Slamon DJ, et al. Science. 1987;235:177-182.

Excessive cellular division

HER2 Overexpression Shortens


Survival
HER2 oncogene
amplification

HER2 oncoprotein
overexpression

Shortened survival
Median Survival From First Diagnosis
HER2 overexpressing
3 yrs
HER2 normal
6-7 yrs
Slamon DJ, et al. Science. 1987;235:177-182. Slamon DJ,
et al. Science. 1989;244:707-712.

Treatment recommendations* for use of trastuzumab


in HER2-positive eBC
1 year of trastuzumab recommended across international treatment guidelines
Neoadjuvantadjuvant therapy for HER2-positive eBC
Neoadjuvant

Adjuvant
Tumours 1 cm

ESMO1,2

Trastuzumab should be
added to neoadjuvant
chemotherapy in patients
with HER2-positive
tumours

Category 1 recommendation: patients with


tumours 1 cm

NCCN3

Patients who are


HER2-positive and
receiving
pre-operative
chemotherapy
should also receive
trastuzumab
Trastuzumab should be
incorporated into
neoadjuvant therapy in
patients with HER2
positive disease

Tumours 1 cm

St. Gallen4

Use of trastuzumab should be discussed with


patients with small node-negative breast
cancers

Category 2A recommendation: patients with


node-negative tumours 0.61.0 cm
Node-negative pT1a or pT1b tumours: use of
trastuzumab based on individual benefit:risk
Node-negative tumours
0.51.0 cm (pT1b)

Duration
1 year of
trastuzumab

1 year of
trastuzumab

1 year of
trastuzumab

Excludes: Node-negative tumours 0.10.5 cm


(pT1a)

* Please note that international guidelines may not be in line with current national guidelines.

1. Senkus E, et al. Ann Oncol 2013; 24 (Suppl 6):vi7vi23;


2. Cardoso F, et al. Ann Oncol 2012; 23 (Suppl 7):vi11vi19;
3. Breast Cancer Guidelines V1.2014; www.nccn.org;
4. Goldhirsch A, et al. Ann Oncol 2013; 24:22062223.

H0648g and M77001: addition of trastuzumab to chemotherapy


as first-line therapy increases OS
Addition of trastuzumab to chemotherapy as a first-line therapy
for HER2-positive mBC significantly increases OS :

M770012

H0648g1
Trastuzumab + chemotherapy (n=235)
Chemotherapy (n=234)

80

RR=0.80 (95% CI=0.64,1.00)


p=0.046

60
40
20

Trastuzumab + docetaxel (n=92)


Docetaxel (n=94)

1.0

Survival probability

Survival probability

100

0.8
p=0.0325

0.6
0.4
0.2

25.1

20.3

extends life

22.7

31.2

0
0

15

25

35

Time (months)

45

10 15 20 25 30 35 40 45

50

Time (months)

TTP :11,7 mo (16 cycles)


OS, overall survival; RR, relative risk of death.
1. Slamon DJ, et al. N Engl J Med 2001; 344:783792;
2. Marty M, et al. J Clin Oncol 2005; 23:42654274.

HER2-targeted therapies are recommended in the


treatment guidelines (ESMO1, NCCN2, AGO3)
Treatment of HER2-positive mBC according to lines of therapy
First-line
Trastuzumab +
docetaxel*2,3
Trastuzumab +
paclitaxel*2,3
Anti-HER2 therapy
(trastuzumab or lapatinib)
+ chemotherapy1,2
AI + trastuzumab or
lapatinib1,2
Trastuzumab13

Second-line
Trastuzumab emtansine
(T-DM1) 2,3
Lapatinib + capecitabine13
Trastuzumab +
capecitabine2
Trastuzumab
chemotherapy13
Trastuzumab + lapatinib13
Trastuzumab +
taxane/second-line
chemotherapy / cytotoxic
agents3
AI + anti-HER2 therapy3
Trastuzumab13

Third-line
Trastuzumab and/or
lapatinib combinations1,3

* Please note: Published International guidelines may not be in line with current national guidelines and approved labels
AI, aromatase inhibitor
1. Cardoso et al. Ann Oncol 2012; 23:vii11-vii19;
2. http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf (v1_2014)
3. http://www.ago-online.de/de/start/

Summary
Management of BC involves more than one approach.

Treatment option include surgical option, adjuvant radiation,


systemic therapy, and targeted therapy. Surgical option is the
mainstay of treatment in EBC.

Shorter courses of whole breast adjuvant therapy (40 Gy in


15 or 42,5 Gy in 16 fractions) has advantages of convenience
and cost over the previous standard.

Adjuvant chemotherapy for BC has significans efficacy

compared with no chemotherapy.


HER-2 is prognostic and predictive factor for breast cancer in
woman
Trastuzumab for 1 year (18 cycles) is the standard of care in

HER2-positive BC, based on long-term follow-up data from


large clinical trials demonstrating DFS and OS benefits

Thank You

ESMO Congress, IFEMAs


Convention Center,
Madrid, 26-30 Sept 2014