Advances in The Management of Breast Cancer

what we have new in 2012?

Mohamed Abdulla M.D.

Prof. of Clinical Oncology

Cairo University

Khartoum 05/07/2012

Disease Epidemiology

• Breast cancer is the most frequently diagnosed cancer and a leading cause of cancer death among females in the world1

– Accounts for 23% (1.38 million) of the total cancer cases1

– Accounts for 14% (458,400) of cancer deaths1

• 1 in 8 women in Western developed countries will be afflicted with breast cancer in her life time2

• Approximately 5% of all breast cancer is classified as metastatic at time of diagnosis2

– 5-year survival rate of 23.3% – significantly lower than localized and regional breast cancer (98.3% and 83.5%, respectively)2

• Most important risk factors – female gender and increasing age3

• Prognostic factors for newly diagnosed advance breast cancer (BC)– Grade 3 disease, increasing age, hormone receptor-negative disease, and no breast

conserving surgery or mastectomy4

1Jemal A, et al. CA Cancer J Clin. 2011;61:69-90; 2American Cancer Society. Breast Cancer Facts & Figures 2009-2010. www.cancer.org; 3National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. V2.2011. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Assessed September 4, 2011; 4Dawood S, et al. J Clin Oncol. 2008;26(30):4891-4898.

Stages of Breast Cancer

Stage Primary Tumor Nodes Metastases

Stage 1A ≤ 20 mm None None

Stage 1B ≤ 20 mm Nodal Micrometastases(>0.2 mm <2.0 mm)

None

Stage IIA ≤ 20 mm> 20 mm ≤ 50 mm

N1None

NoneNone

Stage IIB > 20 mm ≤ 50 mm > 50 mm

N1None

None

Stage IIIA ≤ 50 mm> 50 mm

N2N1 or N2

None

Stage IIIB Extension to chest wall and/or skin

N0 - N2 None

Stage IIIC Any size N3 None

Stage IV Any size Any involvement DetectableN0 = no regional lymph node metastasisN1 = 1-3 axillary lymph nodes involved and/or internal mammary nodes with metastases detected by biopsyN2 = 4-9 axillary lymph nodes involved or clinically detected internal mammary nodes in the absence of axillary nodal involvementN3 = ≤ 10 axillary lymph nodes involved, or infraclavicular lymph nodes, or clinically detected mammary lymph nodes with axillary involvement, or > 3 axillary nodes with internal mammary nodes detected by biopsy, or in ipsilateral supraclavicular lymph nodes

American Joint Committee on Cancer 7th Edition. Breast Cancer Staging.

Female Breast Cancer Survival Ratesby Stage of Disease

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10

% s

urv

iva

l

Years after diagnosis

1National Cancer Database Analytic https://cromwell.facs.org/BMarks/BMCmp/ver10/Docs/#sxs_2008, Assessed September 12, 2011Graph: West Midlands Cancer Intelligence Unit, 2009. http://info.cancerresearchuk.org/cancerstats/types/breast/survival/#stage. Assessed September 12, 2011.

10-year relative survival

Stage IV (3.7%)

Stage III (8.7%)

Stage II (24.4%)

Stage I (37.7%)

*Additionally, 20.3% of patients in the US are diagnosed as stage 0 and 5.2% are unknown1

Stage (% at dx)*

Should All Patients with Newly Diagnosed Breast Cancer Receive Adjuvant Chemotherapy?

NewlyDiagnosed

Patients

LNs +ve

LNs -ve

NewlyDiagnosed

Patients

NewlyDiagnosed

Patients

LNs +ve

NewlyDiagnosed

PatientsSubsequent Risk of Relapse

Is not Sufficiently Low

•Size.

•Grade.

•ER & PR.

•Her 2 Status.

•Ki 67 Score

Prognosis

Prognostic Calculators

Bonadonna et al. N Engl J Med. 1976;294:405-10

Harris et al. J Clin Oncol. 2007;25:5287-312

HR +

HER2 +

Triple Negative

Current Clinical Subtypes in Breast Cancer

10% to 15%2

25% to 30%1 60% to 70%3

1Slamon DJ, et al. New Eng J Med. 2001; 344:783-792; 2Dawood S, et al. J Clin Oncol. 2009;27:220-226; 3 Bedard PL, et al. Breast Cancer Res Treat. 2008;108:307–317.

Disease Free Survival and Overall Survival Rates Based on Clinical Subtype

Disease Free Survival Overall Survival

Onitilo AA, et al. Clinical Medicine & Research. 2009; 7(1/2):4-13

Should All Patients with Newly Diagnosed Breast Cancer Receive Adjuvant Chemotherapy?

Surrogate Definitions of Intrinsic Subtypes

Subtype1 Characteristics1 Prognosis2,3,4

Luminal A ER+ and/or PR+HER2-Low Ki67

Better prognosisHigh survivalLower recurrence

Luminal B ER+ and/or PR+HER2+ or HER2- with high Ki67

Poorer prognosis than Luminal AHigh survival

HER2 ER- and PR-HER2+

Poor prognosisEarly and frequent recurrence

Basal-like* Triple negativeER- and PR-HER2-

Poor prognosisAggressive

1Goldhirsch A, et al. Ann Oncol. 2011;22(8): 1736-1747; 2Carey LA, et al. JAMA. 2006;295(21):2492-2502; 3Calza S, et al. Breast Cancer Res. 266;8(4):R34; 4Dawood S, et al. Breast Cancer Res Treat. 2011; 126:185-192.

*Approximately 80% overlap between ‘triple negative’ and intrinsic ‘basal-like’ subtype but ‘triple negative’ also includes some special histological types such as (typical) medullary and adenoid cystic carcinoma with low risks of distant recurrence. Staining for basal keratins although shown to aid selection of true basal-like tumors, is considered insufficiently reproducible for general use

Time to Distant Metastasis and Survival Rates Based on Molecular Subtype

Sørlie T, et al. PNAS. 2003;100(14):8418-8423.

Time to Distant Metastasis Overall Survival

Luminal ALuminal BBasalHER2+Censored

p<0.01

N = 97

0

0.2

0.4

0.6

0.8

1.0

Pro

bab

ility

0 24 48 72 96 120

Time to distant metastases (months)

144 168 192

p<0.01

N = 72

0

0.2

0.4

0.6

0.8

1.0

Pro

bab

ility

0 24 48 72 96

Overall survival(months)

Should All Patients with Newly Diagnosed Breast Cancer Receive Adjuvant Chemotherapy?

Should All Patients with Newly Diagnosed Breast Cancer Receive Adjuvant Chemotherapy?

Treatment of HR+ Advanced Breast Cancer

Targeted Therapy in Advanced HR+ BC

• The focus of oncology research to specifically inhibit tumor growth without the damaging side effects of cytotoxic chemotherapy

• Endocrine therapy works by depriving the tumor of estrogen1

– Selective estrogen receptor modulators • Blocks the effects of estrogen by binding to ER to block estrogen binding• Includes tamoxifen (Novaldex®), toremifene (Fareston®)

– Selective estrogen receptor down-regulator• Blocks the effects of estrogen by reducing the number of ER available• Includes fulvestrant (Faslodex®)

– Aromatase inhibitors• Inhibits conversion of androgens into estrogen to deprive tumor of estrogen• Includes anastrozole (Arimidex®), letrozole (Femara®), exemestane

(Aromasin®)

• Recently approved therapies in advanced BC include molecularly-targeted agents– HER: Trastuzumab (Herceptin®)2,3, – VEGF: Bevacizumab (Avastin®)4,– EGFR/HER: Lapatinib (Tykerb®)5

1Bilynskyj BT. Exp Oncol 2010; 32(3): 190–194; 2Slamon DJ, et al. N Engl J Med 2001;344:783–792; 3Vogel CL, et al. J Clin Oncol 2002; 20:719–726; 4Miller K, et al. N Engl J Med 2007; 357:2666–2676; 5Geyer CE, et al. N Engl J Med 2006;356:2733–2743.

HR+ Breast Cancer

• Approximately 75% of invasive breast cancers (BC) depend on estrogen receptor (ER) and/or progesterone receptor (PgR) signaling1,2

• ER signaling leads to:

– cell proliferation rate

– time available for DNA repair

– risk of mutation

• Hormone receptor positive (HR+) BCs are slightly slower growing than HR- cancers1

• Increased HR expression correlates with improved response to hormonal tx1

– Multiple mechanisms within the HR pathway allow development of resistance to antiestrogen treatment3

1Cleator SJ, et al. Clin Breast Cancer 2009;Suppl 1:S6–S17; 2Milani M, et al. Clin Med Ther 2009;1:141–156; 3Arpino G, et al. Endocr Rev. 2008 Apr;29(2):217-33.

Staining of ER+ BC nuclei by immunohistochemistry (IHC)

A. Strong nuclear staining indicating widespread expression of HR (Allred score = 8)

B. Weak nuclear staining indicating low–moderate expression of HR (Allred score = 4)

Molecular Biology of ER+ Breast Cancer

ERα Subtype

• Expressed in human breast cancer

• Clinically useful predictive marker for breast cancer

• Target of treatment regimens in ER+ breast cancer patients

Arpino G. Endocr. Rev. 2008 29:217-233. Image: Bardin A, et al. Endocrine-Related Cancer 2004; 11:537-551.

ERβ Subtype

• Expressed in human breast cancer

• Its normal function and role in cancer have not yet been clearly defined

• ERβ may be able to antagonize ERα

•levels may be associated with resistance to tamoxifen (TAM)

Normal Cells

ERβERα

OH

HO

HO

OH

ERαERβ

Growthinhibition

Proliferation

Balance?

Tumor Cells

ERβERαOH

HOHO

OH

ER

Baselga J. Oncologist 2011;16:12-19.

Targets of Endocrine Therapy in Hormone Receptor-Positive Breast Cancer

PP P

P

PP

HER2-1

P

PI3-KSOS

RASRAF

Akt P

mTOR

MEK

MAPK

IGFR-1

Plasmamembrane

ER

Cytoplasm

Nucleus

Estrogen

ERE

CBP

ER target gene transcription

p160

BasalTranscription

machineryER

CBP = CREB binding protein, ER = estrogen receptor, ERE = estrogen-responsive element, HER2 = human epidermal growth factor receptor 2, MAPK = mitogen-activated protein kinase, MEK = mitogen-activated protein kinase/extracellular signal–related kinase kinase, mTOR = mammalian target of rapamycin, PI3K = phosphoinositide-3 kinase, SOS = son of sevenless

P

PP

PPP

Definitions of Resistance in ER+ Advanced BC

• With initial endocrine treatment in advanced disease, 30% have objective CR or PR and another 20% have prolonged SD

• Despite the benefits of 5 years of adjuvant tamoxifen3,4

– >50% of women experience BC recurrence

– >2/3 die from their disease after the initial 5 yrs after surgery

• AIs have increased the benefit of adjuvant endocrine treatment5

– risk of recurrence by 19% (LET v TAM)

– chance of distant metastases by 27% (LET v TAM)

1Bachelot T, et al. Breast Cancer Res Treat. 2010;100(suppl 1)SABCS 2010:Abstract S1-6; 2Osborne CK, et al. Ann Rev Med. 2011;62:233-247. 3Lancet. 1992;339:1–15, 71–8; 4Lancet.1998;351:1451–67; 5NEJM. 2005; 353: 2747-2757

Primary Resistance1 Secondary Resistance1

Adjuvant Relapse during adjuvant therapy

Metastatic Progression <6 mo of treatmentResponse to treatment with relapse ≥6 mo

Phase III: Everolimus + Exemestane in ABC

EVE 10 mg PO daily+

EXE 25 mg PO daily (n=485)

Placebo PO daily+

EXE 25 mg PO daily (n=239)

R

Key endpoints• Primary: PFS (local and central review)• Secondary: OS, ORR, time to ECOG PS deterioration, safety, change in QOL

2:1

Until disease progression or unacceptable toxicity

N = 724

• Postmenopausal ER+

• Unresectable locally advanced or MBC

• Recurrence or progression after letrozole or anastrozole

Stratification• Sensitivity to prior hormone therapy and

visceral metastases

Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.

Summary

• Endocrine therapy is an integral component of therapy for ER+ BC, but emergence of resistant disease is challenging

• There are multiple pathways of endocrine resistance in BC, both through de novo and acquired mechanisms

• Despite extensive research, many questions remain on the roles of the ER, growth factor receptors, and intracellular signaling in endocrine-therapy resistance

• There is a large unmet need for the treatment of endocrine therapy-resistant HR+ BC

• Everolimus may represent a paradigm shift in the management of HR+ ABC

Thank You