Diagnosis and Treatment of Breast Cancer: A Core Lecture Rita Mehta, MD Health Science Clinical Professor Div. of Hem/Oncology School of Medicine Medical Director of Breast Cancer Center October 2014

What Will We Learn Epidemiology of Breast Cancer Stages of Breast Cancer Morphologic Sub-types of Breast cancer IHC Sub-types of Breast Cancer Treatment of metastatic Breast Cancer Pre/Postoperative treatments of Breast Cancer 2

Epidemiology of breast cancer Female/male ratio 100:1 More than 200,000 women will be Dxd in US in 2013 >40,000 will die of breast cancer in 2013 2nd leading cause of cancer deaths in women

Breast cancer death rate is declining

Staging of Breast Cancer I II III III-IBC

Stage Four Breast Cancer Distant Metastasis

Types of Breast Cancer Ductal (2/3 of all breast cancers) Lobular (1/3 of all breast cancers)

Systemic Chemotherapy Anthracyclines (Doxorubicin) Alkylators (Cyclophosphamide) Antimetabolites (Methotrexate) Taxanes (Paclitaxel, docetaxel) And Platinums Optimal Chemotherapy Scheduling (dose-dense or metronomic (weekly) paclitaxel. Bisphosphonates? A meta-analysis shows benefit restricted to postmenopausal women

Targeted Treatment Era Of Targeted Treatment began 100 years ago with oopherectomy, and then the target was found. 2000: Trastuzumab followed the discovery of the target HER2

Estrogen, Estrogen Receptor and Anti-estrogens: Aromatase Inhibitors (AIs): Anastrozole Selective Estrogen Receptor Modulators (SERMs): Tamoxifen Selective Estrogen Receptor Downregulators (SERDs): Fulvestrant AI and SERD: Anastrozole and Fulvestrant Courtesy NCI 10

HER2 Over-Expression (IHC3+ or FISH+) and Anti-HER2 in Breast Cancer Monoclonal Antibodies: Trastuzumab and Pertuzumab Tyrosine Kinase Inhibitor: Lapatinib Neratinib 11

Four Subtypes of Breast Cancer HR-negative and HER2-negative (Triple Negative) HR-negative and HER2-positive (HER2-enriched) HR-positive and HER2-negative (HR-positive) HR-positive and HER2-positive (Triple positive)

Chemotherapy and Targeted Rx Ado Trastuzumab: Emtansine (chemotherapy molecule) attached via a linker molecule to Trastuzumab (monoclonal antibody).

Kaplan–Meier Estimates of Progression-free Survival, According to Whether Patients Were Randomly Assigned to Receive Chemotherapy plus Trastuzumab or Chemotherapy Alone (Panel A), and Whether Chemotherapy Consisted of Either a Combination of an Anthracycline and Cyclophosphamide (Panel B) or Paclitaxel (Panel C). It also improved OS! Slamon DJ et al. N Engl J Med 2001;344:783-792.

CLEOPATRA: The Study Overview Pertuzumab, an anti-HER2 antibody, recognizes a different epitope of HER2 than does trastuzumab and behaves differently. In patients with metastatic breast cancer, the combination of the two antibodies plus docetaxel (NCCN allows paclitaxel substitution) significantly increased progression-free and Overall Survival.

CLEOPATRA: Progression-free Survival, as Assessed at an Independent Review Facility. It also improved OS! Baselga J et al. N Engl J Med 2012;366:109-119

Original Article Combination Anastrozole and Fulvestrant in Metastatic Breast Cancer Rita S. Mehta, M.D., William E. Barlow, Ph.D., Kathy S. Albain, M.D., Ted A. Vandenberg, M.D., Shaker R. Dakhil, M.D., Nagendra R. Tirumali, M.D., Danika L. Lew, M.A., Daniel F. Hayes, M.D., Julie R. Gralow, M.D., Robert B. Livingston, M.D., and Gabriel N. Hortobagyi, M.D. N Engl J Med Volume 367(5):435-444 August 2, 2012 17

S0226: Schema Arm 1 R Anastrozole A N D O M I Z E Arm 2 Anastrozole San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 6-10, 2011 S0226: Schema R A N D O M I Z E Arm 1 Anastrozole Arm 2 Anastrozole Fulvestrant This presentation is the intellectual property of the author/presenter. Contact them at rsmehta@uci.edu for permission to reprint and/or distribute.

20% PFS Benefit

19% OS Benefit

Treatment of Early Breast Cancer (Stage I-III) Chemotherapy Chemotherapy Breast cancer Microscopic cancer cells Surgery Cancer free Early response leads to high complete response at surgery. Complete response (pathologic specifically) predicts more than 90% long-term survival for the patient Group-Specific high complete response predicts group-specific survival outcomes

Preoperative Chemotherapy +Trastuzumab Young adult with HER2-pos. primary Resistant IBC (2003) Eureka! Dec 2003:Letter to NSABP: 5/5 pCR: Historical control 2%: “Trastuzumab should be standard Rx” Reply: FDA will not give approval based on pCR! Patient with HER2-positive IBC Relapsed after postoperative chemotherapy (2003) Pre Rx Mid Rx Post Rx pCR pCR Annals of Oncology: Trastuzumab in inflammatory breast cancer; Mehta et al. 2008; pCR: pathologic complete response. The patient is the teacher of a clinician. 22

Preoperative Rx predicted benefit of Postoperative Rx Breaking News Studies 1 & 2: [NSABP 31 (UCI) and NCCTG] NEJM Oct 2005 52% higher chance of remaining cancer free longer in the group of women who received Herceptin* (n=1872) compared with the group that received chemotherapy alone (n=1880) Study 3/4: Slamon et al. NEJM 2012 40% higher chance of remaining cancer free longer in the group of women who received Standard AC and Herceptin * (n=1074) compared with the group that received chemotherapy alone (n=1073)

HER2/HR negative (Triple Negative) breast cancer Preoperative Dose-Dense/Metronomic/Carboplatin predicted benefit of Postoperative Rx HER2/HR negative (Triple Negative) breast cancer A young patient with stage III cancer (FHx negative, BRCA negative) Achieves pathologic complete response following accelerated chemotherapy, and carboplatin. Now a standard preferred first line Rx per NCCN 2013 and PDQ guidelines 2012 20% (non-DD)-70% (DD) patients achieve pathologic complete response Fast forward 2014: Dose dense chemoRx and Carboplatin should be considered in Rx of TN breast cancer (50% pCR) Agrawaal et al. J Clin Oncol December 2007; Mehta RS: J Clin Oncol 2008; 26 (19): 3286-8

HER2-negative, hormone receptor-pos IBC Preoperative (DD AC followed by Metronomic paclitaxel based regimen) Weekly Chemotherapy Mehta RS; HER2 and Response to Paclitaxel in Node-Positive Breast Cancer N ENGL J MED 2008; 358:197-199January 10, 2008; JCO 2009; JNCI 2008 Now a standard preferable first line Rx per NCCN And PDQ guidelines

What are the challenges? Pre Rx Mid Rx Post Rx Up-to 20-50% patients may not achieve subtype-specific complete response. A resistant disease is a resistant disease?

FDA allowed pathologic complete response endpoint for accelerated approval of Pertuzumab 2013. A Decade Long Odyssey 2003-2013 comes to an end.

Treatment of Stage I-III Breast N Cancer Chemotherapy (4-6 months) Pre or Post Surgery (Lumpec-/Mastectomy with LND) +Trastuzumab/Pertuzumab (6-12 months) if HER2+, Pre (or Post) Surgery Radiation Rx: Generally post surgery Hormonal Modulating Agents up to 10 years if HR+: Generally post Surgery

Pearls Survival is 4+ years for HER+ Metastatic BC Test the target (HR and HER2) and treat. Prolonged HER2 suppression is important in HER2-positive MBC(with chemotherapy) but not curative setting. Prolonged Hormonal blockade is important in curative setting, and in MBC (with chemotherapy)? While treatment intent in early BC is curative that in metastatic BC is palliative. Survival is about 2 years for HR- and 4 years for HR+ Metastatic BC Survival is 4+ years for HER+ Metastatic BC

What Did We Learn Epidemiology: >200,000 BC/year incidence, and falling BC death rates Morphologic types of breast cancer: IDC and ILC Stages of breast bancer: Stages I-IV IHC Sub-types of breast bancer: 4 Treatment of metastatic breast cancer: ChemoRx Sequential (or Combination if visceral crisis), Hormonal Rx (Combination or Sequential?) and HER2-Targeted Rx (Combination chemo and HER2 targeted Rx and Maintenance) Preoperative/Postoperative treatment of Breast Cancer: ChemoRx, Hormonal Rx and HER2-Targeted Rx

Thank You Patients who made this presentation possible, and thank you for participating in this mutual learning process !