confer longer survival of High-Grade Serous. Ovarian Cancer patients. Non carrier. BRCA1 BRCA2. Double. BRCA1/2. VUS. HGSC. 375. 70. 36. 5. 17. LGSC.
Association between BRCA mutation and survival in the Epithelial Ovarian Cancer COEUR cohort Cécile Le Page1, Kurosh Rahimi1,15, Martin Köbel2, Patricia Tonin3 , Brad H. Nelson, Marcus Bernardini4; Dimcho R. Bachvarov4, John Bartlett5, Walter H. Gotlieb8, Jessica N. McAlpine9, Blake Gilks9,12,14, Alain Piché10, Mark Nachtigal11, Peter H. Watson12, Barbara C. Vanderhyden12, David G. Huntsman9,12,14 , Diane M. 1,15 1,15 Provencher , Anne-Marie Mes-Masson Centre de Recherche du CHUM, Montreal, QC; 2 University of Calgary, Calgary, AB; 3 McGill University, Montreal; 4 UHN, Toronto, ON; 5 Ontario Institute Cancer Research, Toronto,ON; 8 Lady Davis Institute, Montreal, QC; 9 Vancouver General Hospital, 10 CHUS, Sherbrooke, QC; 11 University of Manitoba, MB; 12 BC Cancer Agency, BC; 13 OHRI, Ottawa, ON; 14University of British Columbia, Vancouver, BC, 15 University of Montreal, Montreal, QC 1
BRCA carriers in the COEUR cohort
COEUR project To improve clinical management of ovarian cancer patients, the goals of the COEUR program are to: Ø Develop a unique platform of Canadian banked biospecimens annotated with clinical data. Ø Validate biomarkers that can be used in the stratification of ovarian cancer patients. Ø Integrate molecular studies to build a unique nomogram of molecular signatures
Specimens
Clinical data
Central site
COEUR repository 2000 cases
Ovarian Cancer
Pathological and clinical characteristics of CŒUR patients tested for germline BRCA mutations
Impact of germline BRCA mutation on CŒUR HGSC patient prognosis
Rate of survival in HGSC
Histopathology distribution Non Double BRCA1 BRCA2 VUS carrier BRCA1/2 375 70 36 5 17
HGSC LGSC EC MC CCC
31
3
1
0
0
46
1
0
0
1
6
0
0
0
0
27
1
0
0
0
VUS: variant of unknown significance, HGSC: high grade serous, EC: endometrioid, MC: mucinous, CCC: clear cell
Non carrier
Survival rate 5-yrs survival Long term survival (>10yrs) Response to treatment*
Double BRCA1 BRCA2 VUS BRCA1/2
32%
43%
54%
20%
44%
44%
56%
69%
20%
31%
11%
20%
28%
NA
NA
65%
87%
73%
NA
75%
Restricted to HGSC patients with platinum-based treatment *Response as defined by absence of progression within 6 months of end of first-line treatment in patient with residual disease after surgery. NA: not applicable , low numbers of patients
BRCA INCIDENCE IN HGSC
BRCA2 Double BRCA1/2 1% 7% BRCA1 14%
Conclusion
Disease specific survival
VUS 3%
Prognosis of BRCA carriers with low stage HGSC is not better than non-carriers
Non carrier 75%
Disease stage distribution
Häggström, Mikael (2014)
5 histotypes: 5 diseases 13%
High Grade Serous Endometrioid
5%
5% 15%
62%
Low-Grade serous Clear Cells Mucinous
Survival per histotype
Stage 1 Stage 2 Stage 3 Stage 4
Non carrier 17 47 272 38
Double BRCA BRCA1 BRCA2 BRCA1/2 VUS 9 1 0 2 12 7 0 3 45 19 4 11 2 8 1 1
Chemotherapy treatment of HGSC Chemo Non Double BRCA BRCA1 BRCA2 Treatment carrier BRCA1/2 VUS None 6 0 0 0 1 carbo+ taxol 300 62 28 3 16 Cisplat+ 27 5 5 1 0 taxol Platinum alone Platinum+ other Non platinum
10
1
1
1
0
19
0
0
0
0
9
1
1
0
0
BRCA1 and BRCA2 mutation carriers are largely restricted to the High-Grade Serous Ovarian Cancer subtype BRCA1, and particularly BRCA2, mutations confer longer survival of High-Grade Serous Ovarian Cancer patients BRCA2 may not confer better response to platinum-based chemotherapy Double BRCA1/BRCA2 mutation carriers may have a worse outcome than single BRCA mutation carriers, although this needs to be confirmed in a larger cohort Since our finding confirm that BRCA1 and BRCA2 mutations are associated with favorable outcome, but also show that double mutations are not, germline and somatic mutation status should be integrated into clinical trial design for high-grade serous carcinomas
Participating Biobanks • • • • • • • • • • •
Prognosis of single BRCA carriers is better than noncarriers with advanced HGSC (p
