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Debu Tripathy, MD Professor of Medicine University of Southern California

Challenges in Breast Cancer Management : Navigating the Heterogeneity of Triple-Negative Breast Cancer without getting lost in the details. Debu Tripathy, MD Professor of Medicine University of Southern California Norris Comprehensive Cancer Center.

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Debu Tripathy, MD Professor of Medicine University of Southern California

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  1. Challenges in Breast Cancer Management:Navigating the Heterogeneity of Triple-Negative Breast Cancerwithout getting lost in the details Debu Tripathy, MD Professor of Medicine University of Southern California Norris Comprehensive Cancer Center

  2. Triple Negative is typically A-E“Basal” also may include F-H HER- PR - High grade ER- HighKi-67 p53Mut CK14 p63

  3. Basal-like Breast Cancer • Unique subtype seen in gene array analyses accounting for 10-15% of all breast cancer; 85% of BRCA-/- breast cancer • ER-, PgR-, and HER2- • High grade • Scant DCIS component • Other characteristics • Mutations in p53 tumor suppressor gene • EGFR + (approximately 50%) • C-kit + • CK 5/6, 14, 17 + (basal cytokeratins) • High Ki-67 • High degree of genomic instability

  4. Gene Expression Profiling Reveals Distinct Clusters HER2+ subtype 1. 15-20% of tumors 2. prognostic/predictive 2. proliferation 3. two types (ER -/+) Basal subtype 1. 10-15% of tumors 2. ER/PR/HER2-negative 3. very proliferative 4. EGFR, c-kit, c-myc + 5. includes BRCA1 mutations Luminal A and B (ER+) 1. continuum 2. prognostic/predictive 3. ER-GATA3-HNF3a-XBP1 4. proliferation (mutant p53) 5. cyclin D1 and BCL2 + Ki-67, STK6, Survivin, Cyclin B1 and MYBL2 Sorlie T et al. PNAS 2003

  5. BRCA1-Tumors Are Basal-like Sorlie T, PNAS, 2003

  6. p <0.0001 p <0.001 Sorlie T et al. PNAS 2003

  7. What Should We Actually Be Doing for TNBC in 2014 ?? • All Patients • Genetic counseling/testing for age <60 or positive family history • Use standard evidence-based chemotherapy • Early Stage • Increase estimation of recurrence risk and benefit from chemo • No role (yet) for adding or extending therapy for higher risk or residual disease after NAC • Advanced Stage • Consider platinums earlier on (beware they may exclude from clinical trials) • Clinical trials (PARP, PI3K, Stem cell inhibitors)

  8. TNBC isHeterogeneous Prat A, et al, MolecOncol 2010 Prat A, et al, The Oncologist, 2013

  9. Heterogeneity of Triple Negative Breast Cancer Otto Metzger-FilhoO et al., 2012

  10. TN Cancers and Chromosomal Anomalies Stephens PJ et al. Nature 2009

  11. BRCA1-Deficient Cells May Be Hypersensitive to Cisplatin Cisplatin Doxorubicin Paclitaxel Tassone et al BJC 2003

  12. TNBC Responses to Platinum Agents Baselga J et al. ESMO 2010; O’Shaughnessy J et al. SABCS 2007; Carey L, et al ASCO 2008; Isakoff J, et al. ASCO 2011; Byrski T et al. JCO 2010; Gronwald, J, et al. ASCO 2009; Silver DP, et al. JCO 2010, Alba E, et al. BCRT 2012

  13. Efficacy of Ixabepilone/Capecitabine in TN Metastatic Breast Cancer Resistant to Anthracyclines and Taxanes Rugo et al. SABCS 2007, Abstract 6069

  14. Eribulin vs. Capecitabine OS HR by Subsets Kaufman P, et al. SABCS 2012, Abstr S6-6

  15. E2100: Paclitaxel ± Bevacizumab as First-line Therapy in MBC (HER2-) Pac.+ Bev. 11.8 months Paclitaxel 5.9 months 100 HR = 0.60 (0.51-0.70) Log Rank Test p<0.001 Progression-free Survival (%) Paclitaxel plus bevacizumab 80 Subgroups: PFS HR 60 ER-/PR- ER+/PR- 40 ER+/PR+ Overall Month 20 Paclitaxel 0 0 12 24 36 48 6 18 30 42 54 Miller K et al. N Engl J Med. 2007

  16. Randomized Trials of Bevacizumab in TNBC O’Shaughnessy J et al, ASCO 2011; Brufsky A, et al. BCRT 2012

  17. EGFR is Expressed in 30-50% of TNBCRandomized Trials Testing Cetuximab in TNBC Carey L, et al JCO 2012; O’Shaughnessy J et al. SABCS 2007; Baselga J et al. JCO 2013

  18. Single Strand Breaks Nucleotide excision repair Base excision repair PARP1 Double Strand Breaks Non-homologous end-joining Homologous recombination BRCA1/BRCA2 Fanconi anemia pathway Endonuclease-mediated repair Mechanisms of DNA Repair Environmental factors (UV, radiation, chemicals) DNA DAMAGE Normal physiology (DNA replication, ROS) Cell Death Chemotherapy (alkylating agents, antimetabolites) Radiotherapy MAJOR DNA REPAIR PATHWAYS Replication Lesions • Base excision repair • PARP1 x x DNA Adducts/Base Damage • Alkyltransferases • Nucleotide excision repair • Base excision repair • PARP1 Helleday et al. Nature Reviews. 2008

  19. A Phase II trial of the Oral PARP Inhibitor Olaparibin BRCA Deficient Advanced Breast Cancer • Mostly low grade toxicities • Grade III/IV toxicities (400 mg cohort) • Fatigue 15% • Nausea 19% • Vomiting 11% • 30% dose interruptions or reductions BRCA 1 BRCA 2 Tutt A et al. Lancet 2010

  20. Phase II Veliparib (ABT-888) + Temozolamide in TNBC Veliparib (ABT-888) + Chemotherapy Combinations * = BRCA carriers • Phase I dose escalation. Mixed tumor types. • 7/35 partial responses • 6/13 BRCA1/2+ * % change • Response rate = 7% • - ONLY in BRCA1/2+ (RR 38%) * * * * * Phase I Veliparib + oral Cyclophosphamide IsakoffS, et al, ASCO 2011 BRCA carriers: Median PFS = 5.5 Mo Noncarriers: PFS = 1.8 Mo p-value = 0.0042 Kummar, et al, Clin Cancer Res 2012

  21. HRD Score Distribution – A New Measure of “BRCAness”Neoadjuvant gemcitabine, carboplatin and iniparib HRD score ≥ 10 in 16/19 BRCA1/2 mutants No difference in mean HRD scores in BRCA1/2 mutant vs. intact responders BRCA1/2 mutant responders BRCA1/2 intact responders Non-responders HRD score Telli ML, et al. SABCS 2012

  22. The PI3K/Akt/mTOR pathway and Breast Cancer HER2/HER3 PI3K Ras Raf PIP3 PTEN PDK1 Akt TORC2 MEK Tuberin Erk Rheb Rsk TORC1 S6K 4EBP1 S6

  23. Phase I Trial of mTOR Inhibitor BKM120 TNBC • Bendell JC, et al. JCO 2012

  24. TBCRC 011: Bicalutamide in AR+ TNBC Consented for AR testing (n=452) • Bicalutamide 50 mg daily • No Responses • Clinical Benefit Rate • = 5/26 evaluable • (19%) • (95% CI 7-39%) Ineligible for testing (n=28) Screened for AR expression (n=424) AR(-) (n=373) AR(+) (n=51) 12% Ineligible for therapy (n=8) Eligible for therapy; trial closed to accrual (n=15) On study (n=28) Ineligible post therapy (n=2) Eligible on study (n=26) Also in testing: enzalutamide, abiraterone Gucalp A, et al. Clin Cancer Res 2013

  25. Tigatuzumab (Anti-DR5) for TNBC Death Receptor DR5 on 2LMP TNBC Cells In Phase II trial with nab-paclitaxel for advanced TNBC Buchsbaum DJ , et al. Clin Cancer Res 2003

  26. Triple-Negative Breast Cancers: Potential Therapeutic Targets IGF-1R EGFR Tyrosine Kinase C-KIT tyrosine kinase Dasatinib Sunitinib Src inhibitors Cetuximab PI3K, Akt, MEK inhibitors MAP Kinase Pathway Akt Pathway HDAC, DNMT inhibitors Wnt, NOTCH inhibitors Transcriptional Control PARP inhibitors; Trabectedin Cell Cycle Anti-Angiogenesis DNA Repair pathways Bevacizumab Modified from: CleatorS et al. Lancet Oncol 2006 Cell Death

  27. Targeting Heterogeneity of TNBC Multiple potential targets? • Basal-like 1 and 2 – DNA damage response genes, growth factor paths (EGFR) • Immunomodulatory - ? Immune approaches • Mesenchymal and mesenchymal / stem cell – PI3K/mTOR pathway • LAR – androgen receptor signaling Lehmann BD, et al, JCI 2011

  28. Triple Negative Breast Cancer is Heterogeneous and Includes a “HER2-like” Subset  Prat et al, MolecOncol 2010

  29. Reverse Phase Protein Array Reveals HER2 signaling in TNBC (I-SPY1) Wulfkuhleet JD al, Clin Cancer Res 2012

  30. HER2 Somatic Mutations in 25 Patients • 8 publications, total of 1499 patients (estimated incidence of 1.7%) • 20% of mutations at AA 309 or 310 • 80% of mutations from 755-781 Bose R, et al. Nature Discovery, 2013

  31. Bose R, et al. Nature Discovery, 2013

  32. Bose R, et al. Nature Discovery, 2013

  33. HER2 Mutations Differentially Activate HER2 Signaling Bose R, et al. Nature Discovery, 2013

  34. Colony formation of HER2 Mutants inhibited by HER1/2 Kinase Inhibitor Neratinib Multi-center Phase II Trial with NeratinibInitiated Bose R, et al. Cancer Discovery 2013

  35. TNBC: Where are We Going? • Risk-based stratification for additional chemotherapy or radiotherapy • Testing of post (neo) adjuvant of platinum agents and PARP inhibitors • Sequencing and target-drive therapy (eg. PI3K inhibitors, JAK2 inhibitors) • Use of gene profiling to identify and treat variants • Androgen blockade for AR expressors • HER2 TKIs for HER2 mutations • Stem cell pathways inhibitor for Notch/Wntupregulation

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