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: 2206–2223

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

Histological & Molecular subtypes of BC

TNM Staging System for Breast Cancer

1. NCCN Guidelines version 3.2014

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

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

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: 189–193

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

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

2. Goldhirsch A, et al. Annals of Oncology 2013;24: 2206–2223 EBCTCG : The Early Breast Cancer Trialists’ Collaborative Group

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: 2206–2223

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 non-

responsive 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: 2206–2223

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: 2206–2223

2. Ring A, et al. British Journal of Cancer 2011;105: 189–193

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®)

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

receptors

Overexpressed HER2 (10-100x)

up to ~ 2,000,000 HER2 receptors

Excessive cellular division

HER2 Overexpression in Breast

Cancer

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.

HER2 is overexpressed in

~ 25% of breast cancers

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

* 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):vi7–vi23; 2. Cardoso F, et al. Ann Oncol 2012; 23 (Suppl 7):vi11–vi19; 3. Breast Cancer Guidelines V1.2014; www.nccn.org; 4. Goldhirsch A, et al. Ann Oncol 2013; 24:2206–2223.

Neoadjuvantadjuvant therapy for HER2-positive eBC

Neoadjuvant Adjuvant Duration

ESMO1,2

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

• Tumours ≥1 cm

• Use of trastuzumab should be discussed with patients with small node-negative breast cancers

1 year of trastuzumab

NCCN3

• Patients who are HER2-positive and receiving pre-operative chemotherapy should also receive trastuzumab

• Category 1 recommendation: patients with tumours ≥1 cm

• Category 2A recommendation: patients with node-negative tumours 0.6‒1.0 cm

• Node-negative pT1a or pT1b tumours: use of trastuzumab based on individual benefit:risk

1 year of trastuzumab

St. Gallen4

• Trastuzumab should be incorporated into neoadjuvant therapy in patients with HER2 positive disease

• Tumours ≥1 cm

• Node-negative tumours 0.51.0 cm (pT1b)

• Excludes: Node-negative tumours 0.10.5 cm (pT1a)

1 year of trastuzumab

1 year of trastuzumab recommended across international treatment guidelines

H0648g and M77001: addition of trastuzumab to chemotherapy

as first-line therapy increases OS

OS, overall survival; RR, relative risk of death. 1. Slamon DJ, et al. N Engl J Med 2001; 344:783–792; 2. Marty M, et al. J Clin Oncol 2005; 23:4265–4274.

.

Surv

ival pro

ba

bili

ty

Time (months)

22.7 31.2

p=0.0325

Trastuzumab + docetaxel (n=92)

Docetaxel (n=94)

0

0.2

0.4

0.6

0.8

1.0

0 5 10 15 20 25 30 35 50 40 45

M770012 H0648g1

Trastuzumab + chemotherapy (n=235)

Chemotherapy (n=234)

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

p=0.046

20.3

0

20

40

60

80

100

5 15 25 35 45 0

25.1

Surv

ival pro

ba

bili

ty

Addition of trastuzumab to chemotherapy as a first-line therapy

for HER2-positive mBC significantly increases OS : extends life

Time (months)

TTP :11,7 mo (16 cycles)

HER2-targeted therapies are recommended in the

treatment guidelines (ESMO1, NCCN2, AGO3)

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/

Second-line First-line

• Trastuzumab + docetaxel*2,3

• Trastuzumab + paclitaxel*2,3

• Anti-HER2 therapy (trastuzumab or lapatinib) + chemotherapy1,2

• AI + trastuzumab or lapatinib1,2

• Trastuzumab1–3

• Trastuzumab emtansine (T-DM1) 2,3

• Lapatinib + capecitabine1–3

• Trastuzumab + capecitabine2

• Trastuzumab ± chemotherapy1–3

• Trastuzumab + lapatinib1–3

• Trastuzumab + taxane/second-line chemotherapy / ± cytotoxic agents3

• AI + anti-HER2 therapy3

• Trastuzumab1–3

Third-line

• Trastuzumab and/or lapatinib combinations1,3

Treatment of HER2-positive mBC according to lines of therapy

* Please note: Published International guidelines may not be in line with current national guidelines and approved labels

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, IFEMA’s

Convention Center,

Madrid, 26-30 Sept 2014