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Ovarian cancer: genetic risk

"While I’m here, we bought cancer test kits because it’s best to know early, isn’t it? My wife had the ‘all-clear’, but my result says that I have a gene which can cause ovarian cancer. I know I haven’t got ovaries, but what if I have passed this to our daughter? She is not sure whether to order a kit herself now: they’re expensive and she wants me to ask if they are reliable."

Patients who receive direct-to-consumer results after undergoing testing by commercial organisations may increasingly approach us for advice.

Ovarian cancer is difficult to diagnose at an early stage and we do not have an effective screening programme (this is discussed in detail in our article on Ovarian cancer). Reducing the risk of ovarian cancer death by risk-reduction surgery is an alternative for some at higher genetic risk of the disease. So, how can these people be identified?

NICE published guidance about familial ovarian cancer risk in March 2024, summarised here, with additional information drawn from an associated BMJ Practice Guidelines article (NICE 2024 NG241, BMJ 2024;385:q807).

Further information on the genetic risks of other specific cancers is included in our articles Breast cancer: genetic risk and Lynch syndrome: an overview of cancer risks.

This article was updated in August 2024.

The NICE guidance recommends establishing familial ovarian cancer multidisciplinary teams in each hospital trust.

Multidisciplinary input is needed because having a genetic risk of ovarian cancer is associated with an increased risk of other cancers, including breast and bowel, but also pancreatic, prostate and primary peritoneal malignancies.
The main pathogenic genetic variants conferring increased risk of ovarian cancer are BRCA1 and BRCA2, but there are others (including mismatch repair gene variants found in Lynch syndrome, and RAD51C, RAD51D, BRIP1 and PALB2).
These are of potential significance to biological males as well as females, both for the individual and, through their ‘carrier’ status, for their genetic relatives.

What is the role of primary care?

NICE outlines two roles for us:

Appropriate referral to genetics services.
Provision of high-quality information to patients.

In the scenario at the beginning of this article, testing has already been conducted by an organisation outside the NHS. NICE says that if direct-to-consumer tests report the presence of a gene that can be tested for in an NHS setting, we should liaise with genetics services to discuss whether an NHS referral is needed. In practice, at Red Whale, we think that a pragmatic approach would be to take a family history and refer if they meet the criteria. If not, we would probably seek advice from genetics about the specific abnormality reported.

Referral to genetics services

So, who does NICE say we should be referring for genetics assessment and possible testing?

Those who:

Referral criteria	Comment
Have a diagnosis of ovarian cancer and have not already had genetic testing.	This should be offered in secondary care at diagnosis, but may have initially been declined or not have been normal practice at the time. We may be approached by these patients.
Have a first-degree relative (parent/sibling/child) with a diagnosis of ovarian cancer, OR Have a second-degree relative (grandparent/grandchild/aunt/ uncle/niece/nephew/half-brother or half-sister, even if there are unaffected intervening blood relatives) with a diagnosis of ovarian cancer.	This is something that should now be advised/initiated in secondary care at index case diagnosis, but it has not been done in the past. You may see people with relatives diagnosed and treated outside the NHS.
Are from an at-risk population: Ashkenazi or Sephardi Jewish descent (at least one grandparent). Greenlanders.	There is an NHS programme to offer those of Jewish descent saliva BRCA testing by post (link in useful resources, below).
Are identified through ‘cascade’ testing. This is where an index case has been identified as having a specific pathogenic genetic variant, and family members are systematically tested to follow the presence of the gene through closer and then more-distant relatives.	We may be involved if this has been started outside the NHS or in a different area, or if follow-up has been disrupted.

At-risk populations

In its evidence review, NICE outlined which groups at higher risk would be eligible for genetic testing. This was based on evidence of population risk alongside cost-effectiveness.

The populations included are:

Ashkenazi or Sephardi Jewish descent (at least one grandparent).
Greenlanders.

NICE felt there was insufficient evidence at the time of writing the guideline for genetic testing in other populations.

Provision of high-quality information

We can help our patients at the time of referral by sharing useful facts about how genetic assessments take place and the type of information they might be asked for. Information should be available in a format suitable for that person.

Advice for all	Extra information that may need discussion
Understanding their risk of ovarian cancer.	Advice about how their risk compares with the general population’s risk. Advice about lifestyle factors which might impact ovarian cancer risk, including family size and timing.
Genetic risk of ovarian cancer is relevant to all, including biological men and trans women.	Even those not at risk of developing ovarian cancer themselves may be at higher risk of other cancers, and can also pass genetic risk on to both male and female descendants.
Some histological types of ovarian cancer are more likely to be familial than other types; genetic testing may therefore not be offered based on the index case histology, if known.	Germline variant genes (those we are born with) are the ones that are significant here. ‘Somatic variants’ (found as a new variant in a specific tumour in an individual) may be analysed further to decide on individualised treatment regimens. This apparent variation in management depending on the gene variant may be confusing to patients, and may be an area where we can provide reassurance.
A genetic risk assessment will include confirming the family history. This will usually mean that the person referred will need to complete forms with as much detail as they are able to provide, before further assessment.	We should bear in mind that some people will need support with completing family history forms. The complexity of getting a clear and accurate history, especially in ‘blended’ families, should not be underestimated.
Advice on medication that could affect ovarian cancer risk may be needed.	Contraception: Although combined oral contraceptives may be protective against ovarian cancer, this must be weighed against the potential increased risk of breast cancer in those already at higher genetic risk. This is dependent on their pathological gene variant. Aspirin: There is no evidence that daily aspirin improves overall outcomes for those at higher-than-background risk of ovarian cancer. HRT: HRT should be commenced in most cases where risk-reduction surgery takes place before normal menopausal age. However, risk of breast cancer in those with some genetic variants will need to be considered and advised on by secondary care.
Safety-netting.	Provide information about ovarian cancer symptoms to look out for, and when to come back. Any subsequent change in family history will alter the risk assessment, and they may need to be re-referred if testing was not considered appropriate this time.
Psychological support.	We should remember the potential psychological impact and level of anxiety these discussions make cause for patients, and start to address these at the time of referral. NICE recommends that psychological services are linked with the familial ovarian cancer team in secondary care, but some people may need support at an earlier stage.

There are sources of support we can direct people to for more information, and links to some of these are in the useful resources below.

What to expect in secondary care

When making the decision to refer for genetic testing, patients may ask what they can expect in secondary care following their assessment.

Cascade testing

Where an individual is found to carry a genetic variant conferring increased risk of a disease, relatives can be offered testing for this variant in a systematic programme of cascade testing. This starts with first-degree relatives who wish to be tested. Where the variant is found to be present, this process ‘cascades’ to more distant relatives in a structured way. This is also recommended for several non-malignant conditions, including cystic fibrosis and familial hypercholesterolaemia.

Surveillance

In this context, surveillance refers to monitoring people who are found to be at high enough genetic risk to be offered risk-reduction surgery, but opt to decline or delay this. Importantly, surveillance is recommended to be short term only, and people should be aware that, even though diagnosis may be made earlier than without surveillance, there is no evidence of reduced ovarian cancer mortality with this approach. Currently, surveillance would involve a CA125 measurement every 4 months.

Risk-reduction surgery

If a >5% lifetime personal risk of ovarian cancer is estimated, or a ‘strong’ family history confirmed, risk-reduction surgery may be offered:

This will be dependent on age and other criteria.
Bilateral salpingo-oophorectomy will usually be advised.
If endometrial risk is also raised (by the presence of Lynch syndrome variant mismatch repair genes), hysterectomy may also be offered.

Ovarian cancer: genetic risk

Assessing genetic risk of ovarian cancer with a view to risk-reduction surgery is now recommended by NICE.

There are implications for family members of those diagnosed with ovarian cancer or deemed to be at high risk. This includes biological males.

In primary care, we will be involved in referrals for genetic risk assessment and provision of support and information to those affected.

The psychological impact of being offered genetic testing can be significant.

Useful resources:
Websites (all resources are hyperlinked for ease of use in Red Whale Knowledge)

Jewish BRCA - the NHS Jewish BRCA Testing Programme

Target Ovarian Cancer - hereditary ovarian cancer

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Ovarian cancer: genetic risk