Molecular Classification of Breast Cancer: The Paradigm Shift in the Treatment of Breast Cancer

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1 Molecular Classification of Breast Cancer: The Paradigm Shift in the Treatment of Breast Cancer Rena D. Callahan, MD Assistant Clinical Professor of Medicine Breast Cancer Program Department of Medicine, Division of Hematology-Oncology David Geffen School of Medicine at UCLA No Disclosures 30 Objectives Appreciate the heterogeneity of breast cancer Understand how breast cancer subtypes are defined Understand how subtypes affect treatment choices in adjuvant and metastatic setting Review new therapeutic agents targeted to specific subtypes Future directions in research Treatment Approach to Early Breast Cancer: 10 years ago Local-Regional Treatment Systemic Treatment Surgery (MRM or BCT) Radiation (if BCT or if MRM and > 4+ LN) Tamoxifen (if ER+) Cytotoxic Chemotherapy (>1cm, LN+) Goal: Prevent disease from coming back in breast/surrounding tissues. Some impact on survival. Goal: Kill tumor cells that have already metastasized to distant organs (liver, bones, etc) to improve chance of cure. 1

2 Breast Cancer: New Classification PNAS 2001;98: subtypes of breast tumors defined: Basal-like Her2/neu+ Luminal Subtype A Luminal Subtype B Luminal Subtype C Survival by Subtype LUMINAL A LUMINAL B BASAL HER2+ Sorlie et al PNAS 2003 Intrinsic Subtype Treatment of Breast Cancer by Subtype: Current Markers Proliferation/ Grade Luminal A Usually ER+ Low Ki 67/Low grade Luminal B Usually ER+ High Ki 67/High Grade HER2 enriched Usually HER2+ High Ki 67/High Grade Basal like Usually Triple Negative High Ki 67/High Grade Treatment implications Indolent/Endocrine Therapy/ chemoresistant Endocrine Therapy+ Chemotherapy Aggressive/ Chemotherapy+ Herceptin Aggressive/ Chemotherapy 2

3 Treatment Approach to Early Breast Cancer in Evolution BIOLOGY trumps SIZE Breast cancer: Six women, six paths Breast cancer: Treatment is no longer one-size-fits-all October 1, 2011 Study Reshaping Ways of Treating Breast Cancer September 24, 2012 Targeted Therapy Specifically target tumor cells, sparing normal cells Requires Identification of a target that is driving malignant behavior Ability to assess for the target in the tumor/microenvironment Goal: Less toxic, more effective treatments 3

4 Estrogen/Progesterone Receptor Positive Breast Cancer Antiestrogens: The 1 st Targeted therapies 4

5 Aromatase Inhibitors Aromatase Inhibitors: Approved in the late 1990s Anastrozole (Arimidex) Letrozole (Femara) Exemestane (Aromasin) Appropriate only for post-menopausal women with ER+ and/or PR+ tumors Multiple large randomized phase III clinical trials have been performed, all of which show a 2-6% reduction in the risk of breast ca recurrence compared to tamoxifen Who should receive adjuvant chemotherapy in addition to endocrine therapy? Adjuvant! Online Mammaprint Oncotype Dx Who should receive adjuvant chemotherapy? Oncotype Dx -For ER+HER2- -Stage I/IIA - 21 gene recurrence score - RT-PCR 5

6 Basal Transcription Machinery Recurrences after adjuvant treatment 40% 30% 25% 15% 1 st Line 2 nd Line 3 rd Line 4 th Line Treatment of ER+ metastatic breast cancer: Fulvestrant (SERD) Estrogen receptor antagonist Downregulates and degrades estrogen receptor Approved in the US for metastatic ER+ breast cancer with progression on endocrine therapy IM Injection Mechanisms of Endocrine Resistance MoAb VEGFR TKI TKI P AB P IGF1R P P PI3-K EGFR/HER2 MoAb P P SOS RAS TKI RAF Increased upstream signaling through EGFR and/or IGF-IR and or VEGFR Akt MEK AI SERD T ER E2 CCI RAD p90 RSK MAPK Increased signaling through PI3-K pathway Plasma Membrane Cytoplasm P P P P ER ER p160 CBP ERE ER Target Gene Transcription Nucleus Cell Growth Mechanisms of intrinsic and acquired resistance likely similar From Johnston CCR

7 Treatment of Endocrine Resistant Metastatic Breast Cancer: Everolimus BOLERO-2: Everolimus in Postmenopausal, Hormone Receptor Positive ABC N = 724 Postmenopausal ER+ HER2- breast cancer pts refractory to letrozole or anastrozole Everolimus 10 mg/day + Exemestane 25 mg/day (N = 485) Placebo + Exemestane 25 mg/day (N = 239) Primary PFS Secondary OS ORR Bone Markers Safety PK Stratification: 1. Sensitivity to prior hormonal therapy 2. Presence of visceral disease No cross-over Baselga J, et al. N Engl J Med 2012;366(6):520-9 BOLERO-2 Primary Endpoint: PFS Probability of Event (%) EVEROLIMUS+EXEMESTANE HR = 0.36 (95% CI: ) EVE + EXE: 10.6 Months PBO + EXE: 4.1 Months 20 0 Everolimus + Exemestane (E/N=114 / 485) Placebo + Exemestane (E/N=104 / 239) Baselga J, et al. N Engl J Med 2012;366(6): Time (weeks) Everolimus plus exemestane increased progression-free survival by 64% 7

8 + FDA approval July 20, 2012 HER2 AMPLIFIED Breast Cancer HER2 Overexpression in Breast Cancer Median Survival from First Diagnosis HER-2 overexpressing 3 yrs HER-2 normal 6-7 yrs Normal (1X) ~20,000-50,000 HER2 receptors HER2 is overexpressed in ~25% of breast cancers Pegram et al. Cancer Treat Res. 2000;103:57. Ross and Fletcher. Am J Clin Pathol. 1999;112(suppl 1):S53. Slamon et al. Science. 1987;235:177. Overexpressed HER2 (10-100X) Up to ~2,000,000 HER2 receptors Excessive cellular division 8

9 Burstein NEJM 2005; 353 Trastuzumab (Herceptin) H FDA approved for metastatic (Stage IV) Her2/neu+ breast cancer in 1998 FDA approved for non-metastatic Her2/neu+ breast cancer in 2005 More effective when given with chemotherapy Relatively non-toxic, but increased risk of cardiac toxicity, especially when given with anthracyclines Trastuzumab Resistance Over time, resistance develops to herceptin and chemotherapy Induce responses by changing the chemotherapeutic agent with which herceptin is paired Change of HER2 targeted agent Combine HER2 targeted agents 9

10 Trastuzumab Resistance: Lapatinib (Tykerb) Small molecule Tyrosine Kinase inhibitor Targets intracellular portion of HER2 receptor (and EGFR) On March 13, 2007, FDA approval for use in combination with xeloda for patients who progressed on herceptin Dual Targeting of HER2 Receptor May Have Enhanced Efficacy T Trastuzumab L L L L L L Lapatinib Downstream signaling pathways Cell proliferation Cell survival Trastuzumab Resistance: Pertuzumab Inhibition through direct antibody binding Inhibition through dimerization inhibition I II III IV Tyrosine kinase Dimerization domain Trastuzumab I II III IV Tyrosine kinase Pertuzumab Dimerization domain Trastuzumab does not bind/hinder HER2 dimerization domain Pertuzumab blocks dimerization of HER2 with HER3 Abbreviations: mabs, monoclonal antibodies 1. Reprinted from Baselga J, Swain SM. Nat Rev Cancer 2009;9: ; 2. Fuentes G, et al. Breast Cancer Res. 2011;13:R

11 CLEOPATRA 1 st line Study of Trastuzumab+Pertuzumab+Docetaxel PFS PFS (%) Independent assessment Investigator assessment Pertuzumab + T + D Placebo + T + D Pertuzumab + T + D Placebo + T + D HR = % CI, ; P< HR = % CI, ; P<0.001 Independently assessed Investigator-assessed Months Baselga J et al. N Engl J Med. 2012;366: Obtains FDA approval June 8, 2012 Trastuzumab resistance: TDM-1 HER2 T-DM1 Emtansine release Inhibition of microtubule polymerization Lysosome P P P Internalization Nucleus Adapted from LoRusso PM et al. Clin Cancer Res. 2011;17:

12 SciCom Responsible: Sheila Deymann. For Internal Use Only. EMILIA: Overall Survival % (95% CI, ) Median No. of Months LAP + CAP 25.1 T-DM No. of Events % (95% CI, ) Overall Survival, % 78.4% (95% CI, ) % (95% CI, ) Stratified hazard ratio, (95% CI, ) P <.001 Efficacy stopping boundary, P =.0037 or hazard ratio, No. at risk: Time, mo LAP + CAP T-DM CAP, capecitabine; LAP, lapatinib Reprinted from Verma S, et al. N Engl J Med [Epub ahead of print]; DOI: /NEJMoa Obtains FDA approval Feb 22, 2013 Summary: HER2 DIRECTED AGENTS 12

13 Triple Negative Breast Cancer Triple Negative Breast Cancer Defined by what it doesn t have 15 % of breast cancer High risk of recurrence High grade Younger age African Americans, disproportionate BRCA overlap What is Triple Negative Breast Cancer? TRIPLE NEGATIVE AND BASAL LIKE 75% Not all Triple Negative Breast Cancers are Basal Like 13

14 The Importance of Clinical Trials Clinical trials: Neoadjuvant therapy Neoadjuvant Chemotherapy Why give chemo before surgery? No difference in survival comparing patients who have had chemo before or after surgery Shrink a large tumor, increasing chances that patient can have breast-conserving surgery rather than mastectomy In vivo assessment of antitumor effects Research tool 14

15 Meta-analysis results from the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC) 12 neoadjuvant randomized controlled trials N=12993 All trials included chemotherapy Cortazar, et al. SABCS S Association of pcr on EFS & OS Cortazar, et al. SABCS S1-11 pcr=ypt0/is ypn0 44 Obtains FDA approval for neoadjuvant treatment September 30,

16 pcr rates by tumor subtypes Cortazar, et al. SABCS S Clinical trials: Patient selection by Molecular Features Identify the molecular target Develop a drug that hits the target Enroll patients in a clinical trial, most of whom have the target See whether the drug works See whether the drug works preferentially in those patients that have the target 47 The Future DC Koboldt et al. Nature 000, 1-10 (2012) doi: /nature

17 The Future? FOR DOCTORS Commercially available, pan cancer genomic profiling Uses next generation sequencing Right now: 236 genes Results in 3 weeks May help identify patients for clinical trials FOR PATIENTS mycancergenome.org 49 Conclusions Adjuvant treatment of breast cancer should be based on knowledge of tumor biology Treatment of metastatic breast cancer can be informed by molecular markers Enrollment in clinical trials is essential to developing rational therapeutics where efficacy is increased and toxicity minimized THANK YOU! 17