Aviad Zick. Role of BRCA status in treatment planning
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1) BRCA status is important for treatment planning in breast cancer patients. Those with BRCA1/2 mutations have increased risk of contralateral breast cancer and benefit more from risk-reducing bilateral mastectomies. 2) Patients with BRCA mutations, especially BRCA1, have better responses to platinum-based chemotherapy compared to non-carriers. Platinum drugs may be a better option for these patients. 3) Testing for a wide panel of hereditary cancer genes is now possible using new sequencing technologies, which may help guide more personalized treatment decisions.
Aviad Zick. Role of BRCA status in treatment planning
- 1. Role of BRCA status in treatment planning Aviad Zick, M.D, Ph.D Sharett Institute of Oncology Hadassah Medical Center E-mail – aviadz@hadassah.org.il Phone – 050-4048024
- 2. Subjects - Homologues recombination repair - Hereditary breast ovarian cancer syndrome - Risk-reduction measures - Choice of chemotherapy - Future prospectives
- 3. Homologues recombination repair Buisson et al, Nature structural and molecular biology, 2010
- 4. Hereditary breast cancer In Ashkenazi and Iraqi Jews breast cancer patients 7-9% are BRCA carriersFoulkes, NEJM, 2008
- 5. Francken et al, The Breast 2013
- 6. Robson & Offit, NEJM, 2007
- 7. Rennert et al, NEJM, 2007
- 8. Risk reduction mastectomy Prospective, multicenter cohort study of 2482 women with BRCA1 or BRCA2 mutations ascertained between 1974 and 2008. The study was conducted at 22 clinical and research genetics centers in Europe and North America to assess the relationship of risk-reducing mastectomy or salpingo-oophorectomy with cancer outcomes. The women were followed up until the end of 2009.
- 9. Domchek et al, JAMA, 2010
- 10. 390 women with a family history of stage I or II breast cancer who were carriers of BRCA1 and BRCA2 mutations and initially treated with unilateral or bilateral mastectomy. 181 patients had mastectomy of the contralateral breast. Patients were followed for up to 20 years from diagnosis.
- 11. Metcalfe et al, BMJ, 2014
- 12. Chemotherapy Patients were 379 women with stage I breast cancer for whom a BRCA1 mutation had been identified, in herself or in a close family member. Patients were followed for up to 15 years from the initial diagnosis of breast cancer. Narod et al, BCRT, 2013 Non-carriersBRCA1 - carriers
- 13. Which Chemotherapy? A total of 317 women who underwent BRCA genetic testing and were treated with neoadjuvant systemic chemotherapy for breast cancer between 1997 and 2009 were included in the study. Arun et al, JCO, 2011
- 14. Bryski et al, JCO, 2010 From a registry of 6,903 patients, we identified 102 women who carried a BRCA1 founder mutation and who had been treated for breast cancer with neoadjuvant chemotherapy.
- 15. Germline panel Ion PGM™ Sequencer Up to 8 samples per run Custom germline panel - Number of bases – 107,871 Number of genes – Exons of 22 (Overall Coverage) ATM (95.9%), BARD1 (100%), BRCA1 (99.8%), BRCA2 (95.3%), BRIP1 (95.8%), CDH1 (100%), CDKN2A (100%), CHEK2 (91.4%), MLH1 (100%), MRE11A (96.2%), MSH2 (98.6%), MSH6 (99.2%), MUTYH (100%), NBN (99.9%), NLRP2 (100%), PALB2 (98.6%), PMS1 (89.5%), PMS2 (79.8%), PTEN (98.6%), RAD50 (93.9%), RAD51C (95.2%), STK11 (100%), TP53 (96.6%)
- 16. Patient population: 22 patients from the onco- genetic clinic in Hadassah Medical Center that have signed an informed consent "Anonymous examination of a representative sample of breast and ovary patients, for the presence of mutations in BRCA1 and BRCA2 from blood and pathological parameters” that harbor mutations in the BRCA1, BRCA2, MLH1 and PMS2 genes. Validation
- 17. Results DetectedRepeatsMutation √X4BRCA1 185delAG √X1BRCA1 3053T-G √X1BRCA1 3832C>T (P1238L) √X2BRCA1 5382insC √X1BRCA1 E1373X √X1BRCA1 A1708E NoX1BRCA1 Ex 18-20 dup √X1BRCA2 969 C>T √X1BRCA2 6024dupG √X3BRCA2 6174delT √X1BRCA2 8675delAG √X1BRCA2 IVS2+1 G>A NoX1BRCA2 Del Ex 12-13 √X1MLH1 655 A>G/N √X1PMS2 943 C>T √X1PMS2 2192 T>G
- 18. Conclusion The number needed to screen for carriers of BRCA is low in breast cancer patients. Current data is based on retrospective cohorts and not on randomized clinical trials. BRCA mutational statues is predictive of bilateral mastectomy for breast cancer recurrence and death from breast cancer. BRCA mutational statues is predictive of chemotherapy for death from breast cancer.
- 19. Future perspective • Clinical trials addressing the role of different agents in early stage disease – Olaparib, Cisplatin. • The role of multigene testing results.
- 20. Thank you