HEREDITARY BREAST OVARIAN CANCER SYNDROME: THE AUSTRALIAN - PowerPoint PPT Presentation

HEREDITARY BREAST OVARIAN CANCER SYNDROME: THE AUSTRALIAN EXPERIENCE Gillian Mitchell BC Cancer Agency Vancouver

Disclosures • AstraZeneca • Advisory Board, honoraria • AbbVie • Coordinating Chief Investigator • No off-label drug use will be discussed

BRCA mutation status could be an important diagnostic tool • The association between germline BRCA1/2 mutations and ovarian cancer is well established • At the time this study was conceived it was widely reported that BRCA1/2 mutations account for 5-10% of epithelial ovarian tumours • Identification of mutation carriers has important preventative implications for un-affected family members • Significant activity of PARPi in ovarian cancer patients has introduced the idea of BRCA1/2 mutation testing early in a patient’s disease trajectory • A better understanding of which patients should be offered genetic testing and how a mutation could influence both conventional and novel treatment choices is needed.

We used the AOCS to determine BRCA mutation frequency in 1,001 women with ovarian cancer • The Australian Ovarian Cancer Study (AOCS) is a population based case-control study • The AOCS recruited 1,764 women diagnosed with ovarian, peritoneal or fallopian tube cancers • To be eligible for our study, women had to be diagnosed with an invasive tumour of non-mucinous histology

We used the AOCS to determine the mutation frequency in 1,001 ovarian cancer patients • 109 cases had some indication of referral to a Familial Cancer Centre • Testing results were available for 58, and we were able to satisfactorily determine a germline status for 52 • The remaining cases were considered eligible for testing through our investigation

We used the AOCS to determine the mutation frequency in 1,001 ovarian cancer patients • Testing was performed at the Peter MacCallum Cancer Centre • Full genomic sequencing of both BRCA1 and BRCA2, including all coding regions and flanking intronic sequences • MLPA for large genomic rearrangements and deletions • 949 cases sequenced • 850/956 cases received BRCA1 MLPA • 848/956 cases received BRCA2 MLPA

The clinical characteristics of the final genotyped cohort did not differ significantly from the remaining eligible cases

A high frequency of germline BRCA1/2 mutations identified in the AOCS • 141 pathogenic mutations in 141 women for an overall frequency of 14.1% (95% CI: 11.9-16.3%) • 9 mutations, or 7% overall, were identified using MLPA • Over half the mutations identified were in BRCA1 (88/141: 62.4%) • A large proportion of the BRCA2 mutations were identified in the ovarian cancer cluster region (21/53; 39.6%) • Fourteen mutations occurred multiple times within the cohort • 10% of mutations (15/141) were Ashkenazi Jewish/Eastern European founder mutations

44% percent of the mutation carriers had no indication of a potentially significant family history • Family cancer history was available for 94.2% of the cohort, recorded at time of study entry • a first degree relative diagnosed with breast cancer at an age younger than 60 year • a first degree relative diagnosed with ovarian cancer at any age • a combination of two of more first degree relatives with breast or ovarian cancer • a male first degree relative diagnosed with breast cancer at any age • 19.4% of the cases were assessed as having a PSFH; 38% were carriers • 44% (62/141) of the mutation carriers did not report a strong family history of breast and/or ovarian cancer • Having a mother with breast and/or ovarian cancer was a strong predictor of BRCA mutation status (54% of women whose mothers were diagnosed with breast cancer <50 years were carriers) • 18.9% of the women diagnosed under the age of 60 were mutation carriers

BRCA1/2 germline mutations are likely to be associated with serous tumours only • 16.6% of women diagnosed with serous tumours were found to carry a pathogenic mutation • We found no association between mutation status and molecular subtype (Tothill et al, 2008) of high-grade serous tumours. • Lesser frequency of mutations identified amongst women diagnosed with endometrioid (8.4%; 10/119) or clear cell tumours (6.3%; 4/63) • 8/10 endometrioid tumours reclassified as serous (immunohistopathology) • 3./4 clear cell tumours reclassified as serous with focal clear cell differentiation (immunohistopathology and gene expression data

All women diagnosed with an invasive, non-mucinous ovarian tumour should be offered BRCA genetic testing • Age, family history, a breast cancer diagnosis and histotype are all indicators of a pathogenic BRCA1/2 mutation • Family history is not a reliable indicator of mutation status, and can no longer be recommended as the primary criteria • The overall frequency (14.1%) is high enough to suggest that genetic testing should be offered to all women Walsh et al PNAS 2011 18032-18037 None BRCA1 BRCA2 "other"

COULD WE SHOW THAT MUTATION STATUS ALSO HAS AN IMPORTANT PROGNOSTIC AND CLINICAL ROLE TO PLAY IN OVARIAN CANCER MANAGEMENT?

BRCA1/2 mutation status is an independent prognostic indicator • In multivariate analyses mutation p=0.011 status is an important prognostic indicator, along with tumour FIGO stage and de-bulking status after primary surgery p=0.013

Optimal debulking remains an important prognostic indicator p<0.001 p<0.001

We looked at responses to standard treatments as a mechanism of improved survival in mutation carriers • We compared the response to primary platinum treatment in 10000 mutation positive cases compared to mutation negative cases Upper Limit of Normal Ca125 Level Surgery 1000 Carboplatin Paclitaxel Liposomal Doxorubicin Ca125 Level (U/ml) Gemcitabine Etoposide • We also compared the responses Methotrexate Cyclophosphamide 100 Relapse of second and third line platinum Secondary Surgery Death and non-platinum based 10 treatments 1 Jun-03 Oct-03 Jan-04 Apr-04 Aug-04 Nov-04 Feb-05 May-05 Sep-05 Dec-05 Mar-06 Date • Responses to second and third line treatments were assessed using the modified RECIST (CA125) criteria

Mutation carriers were more likely to have >6 months PFS after primary platinum treatment • 918 patients were eligible for this BRCA1/2 mutation < 6 month positive analysis PFS (14.9%) • 834 received a primary-platinum based chemotherapy regimen > 6 month (90.8%) PFS (85.1%) (n=134) BRCA1/2 wild type • Mutation carriers were more likely < 6 month PFS (31.6%) to have >6months progression free survival (p<0.0001) > 6 month PFS (68.4%) (n=700)

Amongst patients with > 6 months PFS … BRCA1/2 mutation positive Platin re-treatment Non-Platin re-treatment > 6 month 11.8% PFS (85.1%) 29.2% 35.3% 6.3% 64.6% 52.9% (n=48) (n=17) (n=134) BRCA1/2 wild type > 6 month 15.2% 21.6 % PFS (68.4%) 21.7% 63.0% 19.8% 58.6% (n=700) (n=222) (n=46)

… mutation carriers are more responsive to both platin and non-platin treatments BRCA1/2 mutation positive Platin re-treatment Non-Platin re-treatment > 6 month 11.8% PFS (85.1%) 29.2% 35.3% 6.3% 64.6% 52.9% (n=48) (n=17) (n=134) p= 0.07 p= 0.05 BRCA1/2 wild type > 6 month 15.2% 21.6 % PFS (68.4%) 21.7% 63.0% 19.8% 58.6% (n=700) (n=222) (n=46)

BRCA1/2 mutation positive Platin re-treatment Non-Platin re-treatment p= 0.07 > 6 month 11.8% PFS (85.1%) 29.2% 35.3% 6.3% 64.6% 52.9% (n=48) (n=17) (n=134) BRCA1/2 wild type p= 0.07 > 6 month 15.2% 21.6 % PFS (68.4%) 21.7% 63.0% 19.8% 58.6% (n=700) (n=222) (n=46)

Patients with < 6months PFS are considered to be “platinum resistant” … BRCA1/2 mutation positive Platin re-treatment Non-Platin re-treatment < 6 month 10% PFS (14.9%) 57.2% 10% 42.8% 80% (n=134) (n=10) (n=7) BRCA1/2 wild type < 6 month 12.8% 10.7% PFS (31.6%) 16.1% 43.6% 43.6% 73.3% (n=700) (n=39) (n=112)

… yet there is still a trend for patients to have better response rate to a platin treatment BRCA1/2 mutation positive p= 0.07 Platin re-treatment Non-Platin re-treatment < 6 month 10% PFS (14.9%) 57.2% 10% 42.8% 80% (n=134) (n=10) (n=7) BRCA1/2 wild type p= 0.001 < 6 month 12.8% 10.7% PFS (31.6%) 16.1% 43.6% 43.6% 73.3% (n=700) (n=39) (n=112)

There is still a trend for BRCA1/2 mutation carriers to be more responsive BRCA1/2 mutation positive Platin re-treatment Non-Platin re-treatment < 6 month 10% PFS (14.9%) 57.2% 10% 42.8% 80% (n=134) (n=10) (n=7) p= 0.10 p= 0.16 BRCA1/2 wild type < 6 month 12.8% 10.7% PFS (31.6%) 16.1% 43.6% 43.6% 73.3% (n=700) (n=39) (n=112)

A high frequency of somatic BRCA1/2 mutations in patients without a germline mutation whose tumours have multiple responses to platinum • 30/134 mutation positive women were treated with platinum three times: 20 (66.7%) were continuing to respond at the third line • 98/700 mutation negative women were also treated with platinum three times: 37 (37.8%) were continuing to respond (p=0.03) • Tumour tissue was available for 16/37 germline mutation negative tumours; somatic mutations were identified in 4 (25%)