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

Subjects - Homologues recombination repair

- Hereditary breast ovarian cancer syndrome - Risk-reduction measures - Choice of chemotherapy - Future prospectives

Homologues recombination repair

Buisson et al, Nature structural and molecular biology, 2010

Hereditary breast cancer

In Ashkenazi and Iraqi Jews breast cancer patients 7-9% are BRCA carriers Foulkes, NEJM, 2008

Francken et al, The Breast 2013

Robson & Offit, NEJM, 2007

Rennert et al, NEJM, 2007

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.

Domchek et al, JAMA, 2010

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.

Metcalfe et al, BMJ, 2014

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-carriers BRCA1 - carriers

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

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.

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%)

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

Results Detected Repeats Mutation √ X4 BRCA1 185delAG √ X1 BRCA1 3053T-G √ X1 BRCA1 3832C>T (P1238L) √ X2 BRCA1 5382insC √ X1 BRCA1 E1373X √ X1 BRCA1 A1708E No X1 BRCA1 Ex 18-20 dup √ X1 BRCA2 969 C>T √ X1 BRCA2 6024dupG √ X3 BRCA2 6174delT √ X1 BRCA2 8675delAG √ X1 BRCA2 IVS2+1 G>A No X1 BRCA2 Del Ex 12-13 √ X1 MLH1 655 A>G/N √ X1 PMS2 943 C>T √ X1 PMS2 2192 T>G

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.

Future perspective

•  Clinical trials addressing the role of different agents in early stage disease – Olaparib, Cisplatin.

•  The role of multigene testing results.

Thank you