Ovarian Cancer BRCA carriers in the COEUR

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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