1. Understanding and Treating Triple-Negative Breast Cancer Elshami M. Elamin, MD Medical Oncologist Central Care Cancer Center www.cccancer.com Wichita, KS - USA

2. Molecular Subtypes of Breast Cancer 1. Luminal A: ER+ and or PR+ Her2 -ve 2. Luminal B: ER+ and or PR + Her2+ 3. Her2: Her2+ ER-ve PR-ve 4. Basal-like: ER-ve PR-ve Her2-ve, cytokeratin 5/6+, and or Her1+ 5. Normal-like: negative for all markers

3. Basal-like tumors Mostly ER/HER2–negative Marked increases in mitotic count, geographic necrosis Pushing borders of invasion Stromal lymphocytic response

4. BRCA1, BRAC2 Mutation Carrier BRCA1: Chromosome 17 57% risk of breast, 40% ov ca Bil breast ca ER-PR –ve Higher G Basal-like BRCA 2: Chromosome 13 49% risk of breast, 18% ov ca Pancreatic, prost, bile/GB, stomach ER/PR +ve BRCA 1-2: 2/3 - 3/5 of familial breast ca 50-87% risk of invasive breast ca 15- 65% risk of invasive epith ovarian ca

5. Epidemiology In 2008, it is estimated that over 1 million women worldwide will be diagnosed with breast cancer, of which 172,695 will be classified as “triple-negative.

6. TNBC ER/PR/Her2-neu negative It is characterized by: unique molecular profile majority carry the “basal-like” molecular profile on gene expression arrays majority of BRCA1-associated breast cancers are TN and basal-like majority of BRCA1-associated breast cancers are TN and basal-like the extent to which the BRCA1 pathway contributes to the behavior of sporadic basal-like breast cancers is an area of active research aggressive behavior younger age higher mean tumor size higher-G higher rate of node positivity distinct patterns of metastasis Early relapse Predilection for visceral metastasis, including brain lack of targeted therapies

7. TNBC Increasing evidence suggests that the risk factor profile differs between this subtype and the more common luminal subtypes.

8. TNBC Although sensitive to chemotherapy, early relapse is common Targeted agents, (EGFR, VEGF, PARP) inhibitors, are currently in clinical trials and hold promise in the treatment of this aggressive disease

9. Relationship between TNBC, BRCA and Basal-like phenotype Triple-negative is a term based on clinical assays for ER, PR, and HER2 Basal-like is a molecular phenotype initially defined using cDNA microarrays characterized by low expression of ER, PR, and HER2 Not all TNBC are basal-like Majority of BRCA1-associated breast cancers are triple-negative and express a high proportion of basal-like cytokeratins

10. Current Treatment for Metastatic TNBC No FDA-approved treatment option specifically for metastatic TNBC Limited treatment options for metastatic TNBC –Most patients already treated with adjuvant anthracycline, taxane, and cyclophosphamide –PFS ≤ 4 mos with chemotherapy for metastatic disease Rationale for gemcitabine/ carboplatin in MBC –Synergistic antitumor activity between gemcitabine and carboplatin –Active combination in MBC, with response rates from 21% to 53% Rationale for PARP inhibitor– based therapy in TNBC –PARP1 is upregulated in majority of triple-negative human breast cancers 1. Kassam F, et al. Clin Breast Cancer. 2009;9:29-33. 2. Li HC, et al. Oncology (Williston Park). 2004;18(14 suppl 12):17-22. 3. Loesch D, et al. Clin Breast Cancer. 2008;8:178-188.

11. Anthracycline/Taxane–Based Chemotherapy Two neoadjuvant studies: proportionally higher sensitivity to anthracycline- or anthracycline/taxane–based chemo for basal-like/ER- negative breast cancers compared to luminal/ER-positive subtypes Despite initial chemosensitivity, DFS (P =.04) and OS (P =.02) remained poorest among those with basal-like and HER2-positive tumors compared to luminal tumors Pts with a pCR had excellent outcomes regardless of subtype Pts with a pCR had excellent outcomes regardless of subtype the poorer outcome among triple-negative patients was attributed to a higher rate of recurrence among patients with residual disease

12. Platinum Tumors with BRCA1 dysfunction harboring deficient double-stranded DNA break repair mechanisms are sensitive to agents that cause DNA damage, such as platinum agents* *Garber J, Richardson A, Harris L, et al: Neo-adjuvant cisplatin (CDDP) in triple-negative breast cancer (BC) (abstract 3074). Breast Cancer Res Treat 100(suppl 1), 2006. *Sirohi B, Arnedos M, Popat S, et al: Platinum-based chemotherapy in triple-negative breast cancer. Ann Oncol June 20, 2008 (epub ahead of print). *Yi S, Uhm J, Cho E, et al: Clinical outcomes of metastatic breast cancer patients with triple-negative phenotype who received platinum- containing chemotherapy (abstract 1008). J Clin Oncol 26(15S):43s, 2008.

13. Targeted Strategies EGFR expression is seen in approximately 60% of TNBC phase II trial (cetuximab + carbo): 18% RR, 27% overall clinical benefit rate 18% RR, 27% overall clinical benefit rate CPT11/carbo +/- cetuximab 49% vs 30% RR

14. THANKS