ovarian cancer genetics and risk reducing surgery · •14% had brca mutation •17% of patients...

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

http://www.elsevier.com/termsandconditions


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Fig. 3

Copyright © 2018 Elsevier Inc




Fig. 4


Copyright © 2018 Elsevier Inc.





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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


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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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Mutations in high grade serous tubo-ovarian cancers


• 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


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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’

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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• 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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• 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

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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• 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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https://www.womencentre.com.au/sarah-osullivan.html



https://kemh.health.wa.gov.au/For-health-professionals/GP-referrals








• 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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https://www.eviq.org.au

https://canceraustralia.gov.au/publications-and-resources/position-statements/surveillance-women-high-or-potentially-high-risk-ovarian-cancer























ovarian cancer genetics and risk reducing surgery · •14% had brca mutation •17% of patients...

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