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Understanding and Treating Triple-Negative Breast Cancer

Understanding and Treating Triple-Negative Breast Cancer. Elshami M. Elamin, MD Medical Oncologist Central Care Cancer Center www.cccancer.com Wichita, KS - USA. Molecular Subtypes of Breast Cancer. Luminal A: ER+ and or PR+ Her2 -ve Luminal B: ER+ and or PR + Her2+

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Understanding and Treating Triple-Negative Breast Cancer

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  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 • Luminal A: ER+ and or PR+ Her2 -ve • Luminal B: ER+ and or PR + Her2+ • Her2: Her2+ ER-ve PR-ve • Basal-like: ER-ve PR-ve Her2-ve, cytokeratin 5/6+, and or Her1+ • 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 • 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 • 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 • CPT11/carbo +/- cetuximab • 49% vs 30% RR

  14. THANKS

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