The Ovary
Vol. 22 No 1 | Autumn 2020
Feature
Ovarian cancer risk and how to manage it
Chloe Ayres
MBBS, FRANZCOG, CGO


This article is 4 years old and may no longer reflect current clinical practice.

Epithelial ovarian cancer (EOC) is a highly lethal malignancy and the most common cause of gynaecological cancer death. In Australia in 2019, there were an estimated 1510 new diagnoses and 1046 deaths from EOC, representing the sixth leading cause of cancer-related death in women.1

Most cases are diagnosed at an advanced stage and have a poor prognosis, with a 46% chance of surviving five years.1 EOC is a heterogenous disease composed of multiple histologic subtypes with unique genomic features.2 The most common histotype is high-grade serous carcinoma (Box 1). The disease has a major heritable component, which provides opportunities to identify women at increased risk and to reduce risk.3

In Australia, the lifetime risk of EOC is 1.2% by the age of 80 years.4 Family history is an important risk factor, with an approximate three-fold increase in relative risk to all first-degree relatives. For a woman with a first-degree relative with EOC and no known genetic susceptibility, the lifetime risk of EOC is 2–3%5 and guidelines do not recommend risk-reducing surgery.5 Women with two first-degree relatives with EOC have a lifetime ovarian cancer risk of 8%, provided that a BRCA1 or BRCA2 mutation has been excluded in a relevant family member.6 In families with a strong history of both breast and ovarian cancer, and no known genetic susceptibility, the ovarian cancer risk may be as high as for BRCA mutation carriers. Discussion with a clinician with relevant expertise is essential when making decisions about the role, if any, of risk-reducing surgery for an individual woman.

Box 1. Epithelial ovarian cancer histotypes.

Epithelial ovarian cancer histotypes

There are several different EOC histotypes that behave and respond differently to treatment:

  1. High-grade serous carcinoma account for the majority of EOC (70%). These are the most chemo-sensitive histology. Heritable BRCA1/2 mutations are found in approximately 17% of women with a high-grade serous EOC unselected for family history7
  2. Endometrioid (10%) high-grade endometrioid ovarian carcinomas may be associated with germline BRCA1/2 mutations
  3. Clear cell (10%) may be associated with germline BRCA1/2 mutations
  4. Low-grade serous (<5%) are not associated with BRCA1/2
  5. Mucinous carcinomas (<5%) are not associated with BRCA1/2

 

Most women diagnosed with EOC do not have a family history of ovarian cancer. One third of women with EOC with a BRCA1/2 mutation will have no known family history of breast or ovarian cancer.8 9 10 Ashkenazi Jewish populations have a high BRCA1/2 mutation carrier rate (1 in 40 compared to approximately 1 in 400 in the general population) and 30% of Ashkenazi Jewish women with EOC will have a BRCA1/2 mutation.11 12

The most common inherited mutations in EOC include:

  • BRCA1 and BRCA2, which are inherited in an autosomal dominant pattern. EOC typically occurs at an earlier age and with greater frequency among BRCA1 carriers than among BRCA2 carriers.
  • DNA mismatch repair (MMR) genes associated with Lynch syndrome are also inherited in an autosomal dominant pattern. There is an increased susceptibility to ovarian cancer, although less than 1% of patients with EOC have germline mutations in MMR genes.13 Ovarian endometroid and clear cell histotypes predominate in Lynch patients. Patients will generally only be eligible for germline mutation testing, however, if there is loss of MMR expression on immunohistochemical staining of their tumour.
  • Pathogenic mutations in RAD51C, RAD51D and BRIP1 confer an elevated lifetime risk of ovarian cancer and are now offered in conjunction with BRCA testing as part of next generation sequencing multigene ovarian cancer panels.
  • Mutations in the PALB2 gene (partner and localiser of BRCA2) have recently been shown to be associated with a moderate increase in lifetime risk (5% to age 80 years) of EOC.14
  • Other emerging genes in which mutations that may be associated with increased EOC risk include ATM, NBN and BARD1, but until there are more data they should not be routinely tested.

EOC risk is age dependent. The prevalence of BRCA1/2 mutations in women with ovarian cancer is highest for women in their 40s and 50s.7 The median age of ovarian cancer diagnosis for BRCA1 mutation carriers is 54 years (43.5–62.5) and in BRCA2 mutation carriers is 59.5 years (53.3¬–64.7).15 In one study, the incidence of ovarian cancer in BRCA1/2 carriers in the 30 and younger age group was 0%, and in the 31–40 age group was 1.8% and 0.3% in BRCA1 and BRCA2 carriers respectively.16 There appears to be an increase in ovarian cancer incidence with age up to 61 to 70 years for both BRCA1 (29.4 incidence per 1000) and BRCA2 carriers (10.3 incidence per 1000).17 18 19 Based on a small number of studies, the prevalence of BRCA1/2 mutations in women with ovarian cancer aged 70 years or over at diagnosis is less than 10%.20 21 22 23 24

Risk prediction tools such as Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA), BRCAPro and the Manchester scoring system predict the probability of a BRCA1/2 mutation based on family and personal history, and breast cancer histopathology.25 26 27

Some also estimate cancer risks, regardless of gene status. Sufficient information to guide genetic risk assessment is usually provided by age, histology and family history for women with ovarian cancer.

Table 1. Lifetime risk of ovarian cancer by gene mutation

Cancer BRCA1 mutation carrier BRCA2 mutation

carrier

 

MMR deficient RAD51C

RAD51D

BRIP1

PALB2

General female population by age 85 years
Ovarian/fallopian tube 44% to age 80 years 17% to age 80 years MLH1 – 11%

MSH2 – 15%

MSH6 – low

PMS2 – no increased risk

5–10% 1.2%
Primary peritoneal carcinoma post RRBSO

 

<2% <1% <1%
Recommend RRBSO 35–40 years 40–45 years 40 years 45–50 years

 

Screening in high-risk women

For asymptomatic women at high risk for EOC, transvaginal ultrasound and serum CA125 levels lack sufficient sensitivity and specificity. In the second phase of the UK Familial Ovarian Cancer Screening Study, of more than 4000 high-risk women undergoing four-monthly serum CA125 testing using the Risk of Ovarian Cancer Algorithm (ROCA) there was evidence of a stage shift (a higher proportion of EOC was diagnosed at earlier stages during screening compared to the period after screening had ceased).28 The authors concluded that ROCA-based screening is an option for women at high risk of EOC who defer or decline RRBSO. However, whether this strategy would decrease mortality in screened high-risk women is unknown and current Australian guidelines recommend against the use of pelvic ultrasound and CA125 in this population.29

Risk-reducing bilateral salpingo-oophorectomy

Risk-reducing bilateral salpingo-oophorectomy (RRBSO) is the only evidence-based strategy to reduce EOC mortality in high-risk women. Decisions about RRBSO should be individualised based on the residual lifetime risk, current health status, cancer anxiety and personal preference. The decision to undergo prophylactic surgery is highly personal and challenging for many women. Confronting personal cancer risk can be confusing and frustrating and undergoing these procedures can have profound effects on a woman’s body and quality of life. Historically the prevalence of the use of cancer risk-reducing strategies among Australian BRCA1 and BRCA2 mutation carriers has been low. Prospective follow up of female carriers of BRCA1/BRCA2 mutations who had no personal history of cancer and were enrolled in a multiple-case breast cancer family cohort study (kConFab) found that 125 of 325 (38%) BRCA1 and BRCA2 mutation carriers underwent RRBSO during 2447 person-years of follow-up (median follow up nine years).30 A psychosocial study conducted in the same patient cohort showed that factors predicting uptake of RRBSO included being parous (OR 3.3, p = 0.015); knowing one’s mutation positive status (OR 2.9, p < 0.001) and having a mother and/or sister who died from ovarian cancer (OR 2.5, p = 0.013).31

Patient consultation with experts in cancer genetics and gynaecologic oncology is recommended to assist women in their decision-making regarding RRBSO. Implications of loss of fertility, surgical menopause, the safety of menopausal hormone therapy (MHT), the risk of diagnosing an occult tubal cancer (up to 6% of women undergoing risk reducing surgery), and the residual lifetime risk of primary peritoneal carcinoma (1–2% risk) need to be discussed. If risk-reducing bilateral salpingo-oophorectomy (RRBSO) is undertaken prior to menopause, MHT should be considered to minimise potential cardiovascular complications, bone loss and sexual dysfunction associated with surgical menopause, until the age of natural menopause (50 years). The use of MHT is generally considered safe32 as long as there is no personal history of breast cancer or medical contraindications to MHT, and does not appear to negate the benefits of salpingo-oophorectomy in BRCA1 and BRCA2 carriers.33 The reader is referred to an excellent patient resource published in English, Arabic and Chinese by the Royal Women’s Hospital in Melbourne entitled ‘Considering surgery to reduce the risk of ovarian cancer’ available to download at: www.thewomens.org.au/health-professionals/clinical-resources/events-and-resources#a_downloads. Pink Hope, an Australian not-for-profit organisation established for the education and prevention of hereditary breast and ovarian cancer is another excellent resource for high-risk individuals: pinkhope.org.au

The combined oral contraceptive pill (COCP) has been found to reduce ovarian cancer risk in BRCA1 mutation carriers. Although the COCP can reduce ovarian cancer risk, it is significantly less effective than RRBSO and is not recommended for cancer prevention.34 There are no data on Implanon or Mirena in BRCA1 mutation carriers with regard to ovarian cancer risk; however, a recent population study with substantial numbers of users, showed a small increased risk of breast cancer in Mirena users, but no increased risk in users of progesterone implants. 35 We await the results of the prospective STICs and STONes study of Aspirin versus placebo for chemoprevention in high-risk women with BRCA mutations and women wishing to delay RRBSO (ClinicalTrials.gov Identifier: NCT03480776 and Australia and New Zealand Clinical Trials Registry no. ACTRN12619000520134).

In women at high risk, RRBSO remains the standard of care36 and confers up to a 98% reduction in ovarian and fallopian tube cancer risk. Favourable effects of salpingo-oophorectomy include significantly reduced cancer-related worry in approximately 80% of BRCA1 and BRCA2 carriers and 95% satisfaction with their decision to undergo surgery.

Box 2. Referral guidelines for ovarian cancer risk assessment and consideration of genetic testing
(adapted from eviQ Referral guidelines for ovarian cancer risk assessment and consideration of genetic testing 2019 V.3).37

All of the people who fall into the categories below warrant a referral to a family cancer clinic for assessment.

Ovarian Cancer

  • Untested adult blood relative of a person with an identified mutation in an ovarian cancer predisposition gene (e.g. BRCA1/2)

Tumour Pathology

Characteristics that warrant referral irrespective of other factors:

  • Invasive grade 2/3 non-mucinous, epithelial ovarian, fallopian tube or primary peritoneal adenocarcinoma (regardless of age)
  • Ovarian cancer that is MMR-deficient

For those with a personal history of cancer

Individual characteristics that warrant referral irrespective of other factors:

  • Invasive non-mucinous epithelial ovarian, fallopian tube or primary peritoneal cancer (regardless of age and grade) AND a close relative* with breast or ovarian cancer
  • Invasive epithelial ovarian cancer (regardless of age, grade and subtype) including mucinous AND one of the following:
    • a personal history of a second Lynch syndrome-associated cancer#
    • a close relative with colorectal or endometrial cancer under the age of 50 years
    • two or more close relatives with a Lynch syndrome-associated cancer#
  • An individual with ovarian cancer in whom tumour testing has identified a somatic BRCA1 or BRCA2 mutation

For those with a family history of cancer

Characteristics sufficient to warrant referral irrespective of other factors:

  • Close relative* with invasive epithelial ovarian, fallopian tube or primary peritoneal cancer AND an additional close relative* with one of the following:
    • epithelial ovarian, fallopian tube or primary peritoneal cancer
    • breast cancer or colorectal cancer under the age of 50 years
    • endometrial cancer under the age of 50 years
  • Three or more close relatives with a Lynch syndrome-associated cancer#

*close relative = 1st or 2nd degree
#Lynch syndrome-associated cancer includes adenocarcinoma of the colorectum, endometrium, small intestine, stomach, ovary or pancreas, urothelial carcinoma of the ureter or renal pelvis, cholangiocarcinoma, brain tumour, sebaceous gland tumour

 

RRBSO had previously been thought to reduce the risk of breast cancer in BRCA1 mutation carriers.38 This has recently been challenged by a prospective study showing no protective effect of RRBSO on breast cancer risk in women with a BRCA1 mutation.39 This study found that RRBSO reduces breast cancer risk in BRCA2 mutation carriers, but the effect of oophorectomy was only significant for breast cancer in BRCA2 mutation carriers diagnosed prior to age 50 years (age-adjusted HR = 0.18, 95% CI = 0.05 to 0.63, P = 007).

The decision to perform hysterectomy at the time of RRBSO should be individualised. There are no data to support an increased risk of endometrial cancer in Australian BRCA1 mutation carriers, although there is limited evidence that serous histology may be more common.40 41 Hysterectomy may rationalise subsequent MHT (by permitting oestrogen-only MHT), or the use of Tamoxifen for breast cancer chemoprevention or as adjuvant treatment of breast cancer, but it is not recommended for endometrial cancer prevention.42

Consideration needs to be given to the timing of RRBSO, even in the setting of elevated risk, given the potential harms of premature menopause. The NCCN and other guidelines recommend RRBSO once childbearing is complete: by age 35–40 years for BRCA1 and 40–45 years for BRCA2.43

Prior to RRBSO it is essential that women have been adequately counselled and have had sufficient time to consider surgery and its potential implications. In premenopausal women, referral to a menopause clinic prior to RRBSO is recommended. Informing the pathologist that the patient is at high risk for EOC is critical to ensure that the Serial and Extensive Sectioning of the FIMbrial end of the fallopian tube (SEE-FIM) pathology protocol is followed, otherwise occult carcinomas may be undiagnosed and untreated. Surgery by a gynaecologic oncologist who informed the pathologist that the woman was at high risk for EOC was independently associated with optimal RRBSO pathology in a prospective cohort study of women at high risk of pelvic serous cancer in the Australian kConFab cohort.44In this study, eligible women had RRBSO between 2008 and 2014 and their RRBSO surgical and pathology reports were reviewed. ‘Adequate’ surgery and pathology were defined as complete removal and paraffin embedding of all ovarian and extra-uterine fallopian tube tissue, respectively. Of 164 contemporary RRBSOs performed in 78 centres, 99% had ‘adequate’ surgery and 66% had ‘adequate’ pathology. Surgery performed by a gynaecologic oncologist rather than a general gynaecologist was independently associated with adequate pathology (OR 8.2, 95%CI [3.6–20.4], p < 0.001).

At the time of risk-reducing surgery, the following steps should be performed: a thorough inspection of the abdomen and pelvis to exclude macroscopic malignancy; peritoneal washings for cytology; at least 2 cm of the infundibulopelvic ligament resected to ensure that no residual ovary is left in situ; complete removal of tubes and fimbria; and the ovaries/tubes removed in separate Endo Catch bags in the event that an occult cancer is found. Histological examination should be according to the SEE-FIM protocol.45 46

The question of whether early bilateral salpingectomy alone with delayed bilateral oophorectomy may be an option for premenopausal women who want to delay surgical menopause has arisen following the discovery that most pelvic serous cancers originate in the fimbrial end of the fallopian tube.47 Although this approach is increasingly being used, data regarding its safety and efficacy are lacking and bilateral salpingectomy with delayed oophorectomy should only be performed as part of a clinical trial. Microscopic tubal fimbriae adherent to ovaries were observed in three of 20 macroscopically-normal surgical specimens from high-risk women undergoing RRBSO.48

If confirmed in larger studies, this finding challenges the concept of bilateral salpingectomy alone for risk-reducing surgery because the primary site of carcinogenesis may be left on the ovary and subsequently develop into a high-grade serous carcinoma.

Conclusion

Next-generation sequencing has led to the discovery of genes in addition to BRCA1/2 that are associated with increased EOC risk. However, the level of risk is not uniform, and knowledge of the cancer risks due to particular gene mutations is essential to provide appropriate advice and avoid inappropriate intervention. All women with non-mucinous high-grade EOC should be offered genetic testing. RRBSO is currently the only evidence-based strategy to reduce EOC mortality but may have negative effects on physical and psychosexual wellbeing. Decision making is complex, and patients require adequate time and psychological support to process information and consider their options. Discussion with a clinician with relevant expertise is essential when making decisions about the role, if any, of risk-reducing surgery for an individual woman.

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