ovarian cancer genetics and risk reducing surgery · •14% had brca mutation •17% of patients...
TRANSCRIPT
Ovarian Cancer Genetics and Risk Reducing Surgery
A/Professor Paul A. Cohen FRANZCOG MD GP Education Project
Breast and Ovarian Cancer: Identifying, and managing, high risk patients
Tuesday 12 February 2019, 6.30 – 8.30 pm
Bendat Parent and Community Centre
Disclosures
• None
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Take Home Messages
• Ovarian cancer lifetime population risk is 1.2% or 1 in 84
• High risk of ovarian cancer defined as lifetime risk >5%
• Bilateral risk-reducing salpingo-oophorectomy is currently THE ONLY EFFECTIVE WAY to reduce the risk of ovarian cancer
• Decisions about RRSO should be individualised based on empiric residual lifetime risk, comorbidities, anxiety, personal preference of the woman
• Discussion with a clinician with relevant expertise is advised when making decisions about the role for RRSO (if any)
• Ask about Family History - you could save lives
• Currently NO role for surveillance in high risk women: DO NOT use serum CA125 or pelvic ultrasound – you may cause harm
• ≈ 1 in 5 women diagnosed with non-mucinous epithelial ovarian cancer will have a hereditary gene mutation so all these women should be offered genetic testing
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Ovarian Cancer Anatomy
The human ovary
Ovarian Cancer Subtypes
• Ovarian Cancer Histopathological Subtypes:
• 90% Epithelial – high grade serous (70%), endometrioid (12%), clear cell (10%), mucinous (3-4%), low grade serous (<5%)
• 5% Stromal tumours – most are adult granulosa cell tumours
• 5% Germ cell tumours – dysgerminoma, yolk sac tumour, immature teratoma
• The term ‘epithelial ovarian cancer’ includes primary fallopian tube and peritoneal carcinomas
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Ovarian Cancer Anatomy
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Fig. 1
Gynecologic Oncology 2019 152, 426-433DOI: (10.1016/j.ygyno.2018.11.033)
Copyright © 2018 Elsevier Inc.
Ovarian cancer pathogenesis
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Ovarian cancer pathogenesis
Fig. 3
Copyright © 2018 Elsevier Inc
Gynecologic Oncology 2019 152, 426-433DOI: (10.1016/j.ygyno.2018.11.033)
Ovarian cancer pathogenesis
Fig. 4
Gynecologic Oncology 2019 152, 426-433DOI: (10.1016/j.ygyno.2018.11.033)
Copyright © 2018 Elsevier Inc.
Ovarian cancer pathogenesis
Ovarian cancer pathogenesis
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Ovarian cancer pathogenesis
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Ovarian cancer screening
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Ovarian cancer screening
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Ovarian cancer screening in high risk women
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Ovarian Cancer Genetics
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Somatic vs. Germline
Ovarian Cancer Genetics
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Ovarian Cancer Somatic Mutations
• TGCA analysed 489 high-grade serous ovarian cancers (HGSOC)
• Somatic mutations • P53 ubiquitous (96% of tumours) • BRCA1, BRCA2, RB1, NF1, CDK12 (lower prevalence)
• 113 focal DNA copy number aberrations (gains or losses)
• Promoter methylation events in 168 genes
• 4 subtypes of HGSOC based on transcriptional differences
• Clear cell, endometrioid, mucinous and low grade serous ovarian cancers each characterised by completely different somatic mutations
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Ovarian Cancer Germline Mutations
• Germline mutations in 9 genes in epithelial ovarian cancer:
• BRCA1
• BRCA2
• RAD51C
• RAD51D
• BRIP1
• MLH1
• MSH2
• MSH6
• PMS2
• Other hereditary cancer syndromes:
• DICER1 Syndrome – Sertoli-Leydig cell tumours (stromal)
• Peutz-Jeghers Syndrome STK11 – sex cord stromal tumours with annular tubules (SCTAT) - benign or malignant
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Mismatch Repair Genes - Lynch Syndrome
Lifetime Risk of Ovarian Cancer By Gene Fault*
BRCA1 BRCA2 BRIP1 RAD51C RAD51D
MLH1 MSH2 MSH6 PMS2 General Popn to age 85
44% 17% ≅5% 11% 15% Low - 1.2%
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*Residual lifetime risk is dependent on age at consultation
BRCA1 carrier cancer risk in the next 12 months
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Age
General
population risk of ovarian cancer in next
year
BRCA1 carrier risk of ovarian cancer in next
year
BRCA2 carrier risk of ovarian cancer in next
year
20s 1 in 23,000 1 in 500* 1 in 1000*
30s 1 in 20,000 1 in 500 1 in 700
40s 1 in 7,000 1 in 100 1 in 500
50s 1 in 4,000 1 in 60 1 in 150
60s 1 in 3,000 1 in 60 1 in 90
* Estimate based on limited information
Long-term risks for BRCA1 carrier age 40
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Long-term risks from 40 yrs (BRCA1)
0%
20%
40%
60%
80%
100%
20 30 40 50 60 70
Age (yrs)
breastovarypopl'n (br&ov)
Long-term risks for BRCA2 carrier age 40
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Long-term risks from 40 yrs (BRCA2)
0%
20%
40%
60%
80%
100%
20 30 40 50 60 70Age (yrs)
breastovarypopl'n (br&ov)
Important Caution
• “We strongly recommend that individuals discuss these risks and their options with a health professional experienced in these matters”
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Ovarian Cancer Genetics
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Mutations in high grade serous tubo-ovarian cancers
Ovarian Cancer Genetics
• Plasma from 1001 patients
• 14% had BRCA mutation
• 17% of patients with HGSOC had germline BRCA mutation
• 44% of those with BRCA mutation had no reported family history of breast or ovarian cancer
• Patients with BRCA mutations had improved survival
• BRCA mutation carriers more frequently responded to chemotherapy at relapse
ALL WOMEN WITH NON MUCINOUS EPITHELIAL OVARIAN CANCERS SHOULD BE OFFERED GENETIC TESTING FOR BRCA1/2 GENE FAULTS
Ovarian Cancer Genetics
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Blue = BRCA1 mutation Grey = BRCA2 mutation Gold = BRCA1/2 combined Black = No BRCA mutation (wild type)
Alsop et al JCO 2012
PARP Inhibitors
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‘Synthetic Lethality’
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When to refer to a a family cancer clinic: Personal history of cancer
• If your patient has been diagnosed with a high-grade epithelial non-mucinous tubo-ovarian/peritoneal cancer (regardless of age)
• If your patient has been diagnosed with one of the following rare ovarian tumours: sex cord tumour with annular tubules, Sertoli-Leydig Cell tumour, small cell carcinoma hypercalcaemic type, ovarian fibroma, ovarian leiomyoma
• If your patient has been diagnosed with any type of ovarian cancer (regardless of age) where there is at least one relative with colorectal cancer and endometrial cancer <50 years of age
• If your patient has been diagnosed with any type of ovarian cancer (regardless of age) and has also had a personal history of a second Lynch Syndrome associated cancer
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When to refer to a family cancer clinic: Personal history of cancer
• If your patient has been diagnosed with any type of ovarian cancer (regardless of age) where there is a family history of one or more first or second degree relatives with colorectal cancer and endometrial cancer where at least one relative was <50 years of age
• If your patient has been diagnosed with any type of ovarian cancer (regardless of age) where there is a family history of two or more first or second degree relatives with colorectal cancer and endometrial cancer diagnosed at any age
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When to refer to a family cancer clinic: Family history of cancer
• A person with a blood relative who is known to carry a
high-risk gene (e.g. BRCA1/2)
• 1st or 2nd degree relative with non-mucinous epithelial tubo-ovarian/peritoneal cancer diagnosed at any age plus one other relative with either breast or ovarian cancer
• 1st or 2nd degree relative with non-mucinous epithelial tubo-ovarian/peritoneal cancer diagnosed at any age and of Ashkenazi Jewish ancestry
• 1st or 2nd degree relative diagnosed with ovarian cancer (any age, grade and histological type) and one or more close relative with colorectal cancer <50 years or endometrial cancer <50 years
• A family history of 3 or more Lynch Syndrome associated cancers regardless of age at diagnosis
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RISK MANAGEMENT
• Risk Reducing Salpingo-oophorectomy (RRSO)
• Age depends on gene fault and the woman’s wishes
• From age 35 and by age 40 for BRCA1
• By age 45 for BRCA2
• Hysterectomy for Lynch Syndrome after family complete or from age 40 or 5 years younger than the youngest affected relative – RRSO considered in selected individuals (MSH6 and PMS2 may not need RRSO)
• HRT is recommended until age of natural menopause and is safe in unaffected BRCA carriers
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RISK MANAGEMENT
• Surveillance
• Pelvic ultrasound and serum CA125 have poor sensitivity and specificity for ovarian cancer, do not reliably detect ovarian cancer at an early stage, and do not affect outcomes
• This is true for women in the general population and for high-risk women
• Effective risk management relies on RRSO
• Risk reducing medication
• Although there is evidence that the oral contraceptive pill can reduce ovarian cancer risk it is significantly less effective than RRSO and is not recommended for cancer prevention
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Aspirin for ovarian cancer chemoprevention
STICs and STONes
• Hypothesis: daily aspirin for at least 6 months compared to placebo will reduce STICs and STONes
• Aim: To compare the frequency of STICs and/or STONes, in the fallopian tube, at the time of RRSO, in BRCA1/2 mutation carriers randomised to daily aspirin vs placebo for > 6 months but < 2 years
• Eligibility criteria:
• Documented pathogenic germline BRCA1 or BRCA2 mutation
• Intact ovaries and tubes
• RRSO planned within 6 months to 2 years
Risk reducing salpingectomy in women at high risk
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Risk reducing salpingectomy in women at high risk
• Currently 5 trials ongoing to assess risk reducing early salpingectomy and delayed oophorectomy (RRESDO)
• Primary outcomes:
• Sexual function/Quality of life in 3 trials
• Proportion of women undergoing DO after RRES in 1 trial
• Number of ovarian cancers before DO (safety) in 1 trial
• Largest study is PROTECTOR – 1000 patients in the UK but follow up 3 years with national registry thereafter
• “Fimbriectomie” French study of 123 participants, completed recruitment and 15 year follow up, will assess safety
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Risk reducing salpingectomy in women at high risk
• RRSO is the gold-standard for prevention of ovarian cancer in women at high risk
• EviQ guidelines: “The effectiveness and safety of risk-reducing bilateral salpingectomy followed by delayed bilateral oophorectomy has not been established, and is not recommended for ovarian cancer risk management.”
• In the absence of long-term prospective outcome data bilateral salpingectomy and delayed oophorectomy should only be offered within a clinical-trial/research study
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Current genetic testing landscape in Australia
2001-2013 2014-2016
Not- Tested 12276 1980
Tested 924 1320
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
% G
en
eti
c T
esti
ng
Rate
s
Estimated rates of BRCA1/2 testing in HGNMOC based on 2 Australian studies
Alsop et al 2012, Cohen et al 2016
Current genetic testing landscape in Australia
2001-2013 2014-2016
Not- Tested 12276 1980
Tested 924 1320
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
% G
en
eti
c T
esti
ng
Rate
s
Estimated rates of BRCA1/2 testing in HGNMOC based on 2 Australian studies
Alsop et al 2012, Cohen et al 2016
Prospective Testing
*The problem….. Estimated figures genetic testing of HGNMOC in Australia 2001-2016
Total Untested
Tested
4500
Not
tested
12000
Alive 5280
Deceased 6720
Based on Alsop et al 2013 and Cohen 2016 + taking in to account cohort studies
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Aim: To retrospectively identify BRCA1/2 mutation carriers affected by ovarian cancer and return results to their next of kin to facilitate cascade testing
TRACEBACK
TRACEBACK
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Phone 1800 955 011
Take Home Messages
• Ovarian cancer population risk is 1.2%
• High risk of ovarian cancer defined as lifetime risk >5%
• Bilateral risk-reducing salpingo-oophorectomy is currently THE ONLY RECOMMENDED WAY to reduce the risk of ovarian cancer
• Decisions about RRSO should be individualised based on empiric residual lifetime risk, comorbidities, anxiety, personal preference of the woman
• Discussion with a clinician with relevant expertise is advised when making decisions about the role for RRSO (if any)
• Ask about Family History - you could save lives
• Currently NO role for surveillance in high risk women: DO NOT use serum CA125 or pelvic ultrasound – you may cause harm
• ≈ 1 in 5 women diagnosed with non-mucinous epithelial ovarian cancer will have a hereditary gene mutation so all these women should be offered genetic testing
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Ovarian Cancer Genetics
• Specialist Advice:
• Genetic Services WA
https://ww2.health.wa.gov.au/Articles/F_I/Genetic-Services-of-WA
• Ms. Sarah O’Sullivan, Genetic Counsellor, WOMEN Centre • https://www.womencentre.com.au/sarah-osullivan.html • High Risk Clinic at SJOG Subiaco Hospital
• Dept. of Gynaecological Oncology, King Edward Memorial
Hospital • https://kemh.health.wa.gov.au/For-health-professionals/GP-
referrals
• TRACEBACK (if eligible, can self-refer) phone: 1800 955 011 • https://ovariancancer.net.au/traceback-research-project/
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Ovarian Cancer Genetics
• Useful Resources:
• https://www.eviq.org.au
• https://canceraustralia.gov.au/publications-and-resources/position-statements/surveillance-women-high-or-potentially-high-risk-ovarian-cancer
• Link to a Dropbox folder that includes:
• A copy of this presentation
• Fact sheets for people and families with BRCA gene faults and Lynch, Peutz-Jeghers and DICER1 Syndromes
• PDFs of eviQ Risk Management Guidelines and references
• Any queries please email me at: [email protected]
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