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