Dr arun Triple Negative Breast cancer Presentation
- 1. Treatment Approaches for Metastatic “Triple Negative” Breast cancer Where are we now and Where are we going? Dr. Arun Shahi MD Medical Oncology (Final Part) NICRH
- 5. Within these, there are other ways to further sub-divide breast cancers
- 6. Breast Cancer is many diseases!
- 8. “Triple Negative” Breast Cancer (TNBC) • Represents about 15% of all breast cancer • More likely to present in younger women and in women of African ancestry • May be associated with an inherited mutation in BRCA1 – National guidelines recommend consideration of genetic testing in women younger than age 60 with TNBC, regardless of family history – But--most patients with triple negative breast cancer do not carry a hereditary BRCA1 mutation
- 9. Hormonal therapy Hormonal therapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Herceptin + perjeta + chemotherapy TDM1 Lapatinib + Capecitabine Herceptin + chemotherapy Herceptin + chemotherapy Hormone receptor positive Triple-negative HER2-Positive *Note, these are just examples. Each patient is different and treatment is tailored accordingly. How Do We Treat Metastatic Breast Cancer?
- 10. Chemotherapy for Metastatic TNBC Many active and tolerable chemotherapy choices
- 11. • Order of chemotherapy does not appear to influence survival • Choose chemotherapy based on: – Activity level seen in clinical trials – Amount of active cancer/need for rapid response – Prior treatments – Route of administration (oral versus IV) – Side effect profile – BRCA 1/2 status – Other health problems • Blood counts, neuropathy, diabetes, heart problems, liver function Choice of Chemotherapy in Metastatic TNBC
- 12. Drug Route Hair loss Diarrhea Neuropathy Hand foot redness Effecton blood counts Paclitaxel (Taxol) IV weekly 2 or 3 wks in a row Then off1 wk Yes No Yes No + Capecitabine (Xeloda) Oral twice daily 2 wks in a row Then off 1 wk No Yes No Yes + Eribulin (Halaven) IV weekly 2 wks in a row Then off 1 wk Sometimes No Yes No ++ Choice of Chemotherapy in Metastatic TNBC One example •What chemotherapies have been given previously? How long ago? •Able to take and absorb orally? •How is the liver function? •How important is avoidance of hair loss? •Any baseline neuropathy and how severe?
- 13. Is all TNBC the same? ER-negative, PR-negative HER2-negative
- 14. Heterogeneity of TNBC TNBC is not just one disease— Different subtypes likely have different “Achilles’ heels” VEGF PTEN loss BRCA1- EGFR Basal-like AR Immune infiltrate
- 15. Challenges • Only 30% of TNBC patients achieve pathological complete response(pCR) after undergoing neoadjuvant chemotherapy. • Approx 70% of metastatic TNBC patients will not survive the first 5 year after diagnosis. • African-American women are2-3 times more likely to be diagnosed with TNBC and experience poorer clinical outcomes than Asian-European- American women. • Vast interpatient and intratumor heterogeneity.
- 16. Where is the treatment now going?
- 17. Many Approaches Under Evaluation for TNBC in Clinical Trials Pathway/Drug type Drugs in development DNA repair PARP inhibitors (olaparib, rucaparib, veliparib), platinum agents (cisplatin, carboplatin) PI3K/Akt/mTOR PI3K inhibitors (buparlisib, taselisib, GDC0941, AZD8186, many others); Akt inhibitors (GDC0068, others), mTOR inhibitors (everolimus, others) Androgen (testosterone) signaling Anti-androgens (bicalutamide, enzalutamide) Immune CTLA4 blockade (ipilumumab), PD1/PD-L1 blockade (nivolumab, pembrolizumab, atezolizumab), Antibody-drug conjugates IMMU-132, SGN-LIV1A, PF06647263, CDX-011 Cell cycle Dinaciclib, seleciclib Chk1 GDC0575 Bromodomain TEN-101, GSK525762 Heat shock (stress) Ganetespib, others Angiogenesis Ramucirumab, cedirinib
- 19. Environmental Insults Cause DNA Damage Cross-linking agents Cross-links DNA Damage leads to mutations that can contribute to development of cancer
- 20. Platinum Agents and Breast Cancer • Include the drugs cisplatin and carboplatin • DNA cross-linking agents—so there is reason to believe they may be especially effective in patients with BRCA ½ mutations and/or with triple negative breast cancer • These drugs are active in breast cancer in general….but the questions is: How does platinum chemotherapy compare with other chemotherapy drugs?
- 21. TNT Trial Metastatic TNBC Or BRCA ½ associated breast cancer Platinum chemotherapy Taxane chemotherapy
- 22. Tutt et al, SABCS 2014
- 23. PARP(poly ADP ribose polymerase) Inhibitors •Tumors of BRCA 1/2+ patients lose 2 important ways to repair DNA when treated with a PARP inhibitor •Multiple trials testing PARP vs chemo in BRCA 1/2 carriers •Trials combining PARP with other drugs in BRCA 1/2 non-carriers
- 24. Phase 3 Trials Ongoing Inherited BRCA 1 or BRCA2 mutation Up to 2 previous types of chemotherapy for MBC PARP inhibitor Choice of standard chemotherapy -Capecitabine -Vinorelbine -Eribulin -Gemcitabine (allowed in BRAVO and EMBRACA) Olaparib – OLYMPIAD – NCT02000622 Completed accrual, awaiting results Niraparib – BRAVO – NCT01905592 Accruing BMN673 – EMBRACA – NCT01945775 Accruing
- 27. Targeting AR in the Clinic • Bicalutamide – 21% had stable disease > 6 months • Enzalutamide – 20% of patients had stable disease > 6 months – “PredictAR” gene signature sorted patients to those with average disease control 2 months vs 10 months – Phase III study (ENDEAR) to be launched will compare Taxol vs enza vs combination of Taxol + enza for predictAR+ve patients Gucalp et al, CCR 2013; Traina et al, ASCO 2015
- 29. Immune Checkpoint antibodies • PD-1 – PD-L1 interaction is an immune checkpoint. • PD-1 or PD-L1 antibodies re-activate the T cells in order to attack the cancer cells • PD-1 antibodies: Opdivo (nivolumab), Keytruda (pembrolizumab) • PD-L1 antibody: Tecentriq (atezolizumab) • Drugs approved for melanoma, lung cancer, renal cell cancer, bladder cancer
- 30. • Merkel cell skin cancer • Avelumab, March, 2017 • Hodgkins lymphoma • Pembrolizumab, March, 2017
- 32. Antibody Drug Conjugates 1. Antibody that recognizes a marker on tumor cells that is not/less present on normal cells 2. Linker that is stable in circulation but releases the drug in target cells 3. Potent drug designed to attack the cancer cell when internalized and released
- 33. Antibody Drug Conjugates in Development for TNBC • IMMU-132 – Target: Trop2 – Phase 1/2 trial completed, phase III trial planned • CDX-011 – Target: TPNMB – Phase 2 completed, phase 3 trial ongoing • SGN-LIV1A – Target: LIV-1 – Ph1 in breast ca ongoing • PF-06647263 – Target: EFNA4 – Phase 1 in breast cancer ongoing
- 34. So, What are we expecting? 1) Improved drug efficacy and patient response. 2) Reduced relapse/ recurrence rates 3) Reduced morbidity & Mortality 4) Reduced racial disparity in clinical outcomes.
- 35. Need of the Hour 1) Identify & validate actionable, clinically-facile, cost-effective biomarkers. 2) Discover effective targeted treatments
- 36. How Can We Make Progress?
- 38. Take Home Message • TNBC is unique compared to other types of breast cancer • Not all TNBC is the same • Chemotherapy works for TNBC, and there are a number of standard options • No single best target has been identified so far; however, TNBC is an area of very active research; many exciting new agents and approaches in the pipeline Future progress depends on..... Making every woman count!
- 41. Treatments for TNBC Treated with a combination of therapies such as surgery, radiation therapy, and chemotherapy. Researchers still developing their understanding of triple-negative breast cancer, they may vary in their treatment recommendations Research on New Treatment for Triple-Negative Breast Cancer: 1) PARP (poly ADP-ribose polymerase) inhibitors: Olaparib, Iniparib 2) VEGF (vascular endothelial growth factor) inhibitors: Avastin(bevacizumab) 3) EGFR (epidermal growth factor receptor)-targeted therapies: cetuximab