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
• f 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

• r 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

• 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

We used the AOCS to determine the mutation frequency in 1,001 ovarian cancer patients

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
• f 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

• varian tumour should be offered BRCA genetic testing
• Age, family history, a breast cancer diagnosis and histotype are all indicators
• f 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

None BRCA1 BRCA2 "other"

Walsh et al PNAS 2011 18032-18037

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

status is an important prognostic indicator, along with tumour FIGO stage and de-bulking status after primary surgery

p=0.011 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 mutation positive cases compared to mutation negative cases

• We also compared the responses
• f second and third line platinum

and non-platinum based treatments

• Responses to second and third line

treatments were assessed using the modified RECIST (CA125) criteria

1 10 100 1000 10000 Jun-03 Oct-03 Jan-04 Apr-04 Aug-04 Nov-04 Feb-05 May-05 Sep-05 Dec-05 Mar-06 Upper Limit of Normal Ca125 Level Surgery Carboplatin Paclitaxel Liposomal Doxorubicin Gemcitabine Etoposide Methotrexate Cyclophosphamide Relapse Secondary Surgery Death

Date Ca125 Level (U/ml)

Mutation carriers were more likely to have >6 months PFS after primary platinum treatment

• 918 patients were eligible for this

analysis

• 834 received a primary-platinum

based chemotherapy regimen (90.8%)

• Mutation carriers were more likely

to have >6months progression free survival (p<0.0001)

(n=134)

> 6 month PFS (85.1%) < 6 month PFS (14.9%)

(n=700)

> 6 month PFS (68.4%) < 6 month PFS (31.6%) BRCA1/2 mutation positive BRCA1/2 wild type

Amongst patients with > 6 months PFS …

(n=134) (n=700)

BRCA1/2 mutation positive BRCA1/2 wild type

(n=48)

64.6% 29.2% 6.3% > 6 month PFS (85.1%) > 6 month PFS (68.4%) 58.6% 21.6% 19.8%

(n=222)

Platin re-treatment Non-Platin re-treatment 52.9% 35.3% 11.8%

(n=17) (n=46)

21.7% 63.0% 15.2%

… mutation carriers are more responsive to both platin and non-platin treatments

(n=134) (n=700)

BRCA1/2 mutation positive BRCA1/2 wild type

(n=48)

64.6% 29.2% 6.3% > 6 month PFS (85.1%) > 6 month PFS (68.4%) 58.6% 21.6% 19.8%

(n=222)

Platin re-treatment Non-Platin re-treatment 52.9% 35.3% 11.8%

(n=17) (n=46)

21.7% 63.0% 15.2%

p= 0.07 p= 0.05

(n=134) (n=700)

BRCA1/2 mutation positive BRCA1/2 wild type

(n=48)

64.6% 29.2% 6.3% > 6 month PFS (85.1%) > 6 month PFS (68.4%) 58.6% 21.6% 19.8%

(n=222)

Platin re-treatment Non-Platin re-treatment 52.9% 35.3% 11.8%

(n=17) (n=46)

21.7% 63.0% 15.2%

p= 0.07 p= 0.07

Patients with < 6months PFS are considered to be “platinum resistant” …

< 6 month PFS (14.9%)

(n=700)

< 6 month PFS (31.6%) BRCA1/2 mutation positive BRCA1/2 wild type

(n=134)

Platin re-treatment Non-Platin re-treatment

(n=10)

80% 10% 10% 42.8% 57.2%

(n=7) (n=39)

43.6% 43.6% 12.8%

(n=112)

16.1% 73.3% 10.7%

< 6 month PFS (14.9%)

(n=700)

< 6 month PFS (31.6%) BRCA1/2 mutation positive BRCA1/2 wild type

(n=134)

Platin re-treatment Non-Platin re-treatment

(n=10)

80% 10% 10% 42.8% 57.2%

(n=7) (n=39)

43.6% 43.6% 12.8%

(n=112)

16.1% 73.3% 10.7%

… yet there is still a trend for patients to have better response rate to a platin treatment

p= 0.001 p= 0.07

There is still a trend for BRCA1/2 mutation carriers to be more responsive

< 6 month PFS (14.9%)

(n=700)

< 6 month PFS (31.6%) BRCA1/2 mutation positive BRCA1/2 wild type

(n=134)

Platin re-treatment Non-Platin re-treatment

(n=10)

80% 10% 10% 42.8% 57.2%

(n=7) (n=39)

43.6% 43.6% 12.8%

(n=112)

16.1% 73.3% 10.7%

p= 0.10 p= 0.16

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%)

Mutation status may alter treatment approach

• Improved survival in mutation positive women is likely to be a function of an

increased sensitivity to therapeutics leading to multiple clinical responses

• Importantly, our data suggests that the <6 month PFS is not an accurate

measure of platinum insensitivity

• BRCA1/2 mutation positive women tend to be more sensitive to both

platinum and non-platinum treatments – implications for clinical trials

• Bulky residual disease can negate the sensitivity in BRCA1/2 mutation

carriers

Do BRCA mutation carriers really have better

• verall survival?

But…..

• Combined 10-year OS
• 30% (95% CI 28%–31%) for

non-carriers

• 25% (95% CI, 22%–28%) for

BRCA1

• 35% (95% CI, 30%–41%) for

BRCA2 carriers.

• The HR for BRCA1 was 0.53

at time zero and increased

• ver time becoming greater

than one at4.8 years.

• The HR for BRCA2 was 0.42

at time zero and increased

• ver time (predicted to

become greater than 1 at 10.5 years).

• unpublished survival

time data

• 2,242 patients from two

case–control studies

• extended survival time

data for 4,314 patients from previously reported studies.

Conclusions

• Germline BRCA1/2 mutations

are associated with better short- term survival

• this advantage decreases over

time and in BRCA1 carriers is eventually reversed.

• Important implications
• for therapy of both primary and

relapsed disease

• for analysis of long-term survival in

clinical trials of new agents, particularly those that are effective in BRCA1/2 mutation carriers.

• Knowledge of mutation status

essential for interpretation of clinical trials

Where next – ovarian cancer?

• Germline mutation screening in women with non-serous ovarian

cancer

• PARP inhibitor therapy in ovarian cancer
• Mechanisms of resistance in ovarian cancer
• AOCS
• Rapid autopsy study
• Xenografts

Where next – breast cancer?

• Germline mutation screening in HBOC families without BRCA

mutations

• 2000 families and 2000 Breastscreen controls
• Large gene panel
• 18 genes commonly included in commercial gene panels
• Common genomic variant profiles in HBOC families

Acknowledgements …

Kathryn Alsop David Bowtell Anna deFazio Penny Webb Sian Fereday

Georgia Chenevix-Trench Adele Green Dorota Gertig Nadia Traficante

Jillian Hung

Laura Galletta Joy Hendley Leanne Bowes Debra Giles Andreaa Waltmann Sarah Ftouni

The AOCS Study Group

The Jack Brockhoff Familial Cancer Centre

Mary-Anne Young Trina Reeve

PMCC Pathology Department

Stephen Fox Cliff Meldrum Alex Dobrovic

Nidhi Bhatt Victoria Beshay Stephen Macaskill Heidi Williams Erin McKay Ravikiran Vedururu Trent Bosma Hazel Phillimore Su ping Chang Stephen Wong Megan Rehfisch Wasanthi De Silva Timmy Chan Tai Nguyen Heather Hondow Thomas Mikeska

Supported by The Westmead Institute for Cancer Research

Catherine Emmanuel

King Edward Memorial Hospital

Colin Stewart

US DoD 2008-2011 The Peter MacCallum Cancer Foundation

Bowtell Lab, PMCC

Joshy George

Prince of Wales Hospital

Michael Friedlander

Massachusetts General Hospital

Michael Birrer