Guidance
Rationale and impact
- Organisation of services
- Information and support
- Assessing the risk of having a pathogenic variant
- Criteria for genetic testing
- Gene panel testing
- Assessing the risk of developing ovarian cancer
- Primary preventive medicines
- Risk-reducing surgery
- Pathology protocol for handling specimens from risk-reducing surgery
- Hormone replacement therapy after risk-reducing surgery
Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice or services.
Organisation of services
Recommendations 1.1.1 to 1.1.9
Why the committee made the recommendations
There was limited evidence, with a small number of studies and uncertainties about the effect size and the way the studies were conducted, so the committee based the recommendations on the evidence and their knowledge and experience.
Commissioners and service providers in all settings (primary care, genetics services, gynaecology oncology and familial ovarian cancer multidisciplinary services)
The committee discussed their experience of variations in how people are referred from healthcare professionals, for example, whether people are referred first to specialist gynaecological services or directly to genetic specialist services. They decided to recommend direct referral to make services more efficient, together with ways of making the referral process smoother (including clearer referral criteria).
The committee discussed their experience of why people who may be at risk of having a pathogenic variant associated with ovarian cancer do not access services. They agreed that people from under-represented or underserved groups may know that the guideline applies to them but may need more support to access services. This could include people who are physically disabled, people with neurodevelopmental conditions or a learning disability, people from Black, Asian and ethnic minority backgrounds, and people who are LGBTQ+. In addition, people may not realise that they may be at risk of having a pathogenic variant associated with ovarian cancer because they cannot develop ovarian cancer, for example, men, trans women and non-binary people born with male reproductive organs. The committee agreed that these groups need encouragement to discuss referral to genetics services. The committee further noted that healthcare professionals are not always aware of the potential barriers, and agreed that training and information would help raise awareness.
The committee also noted that there is an overall lack of awareness, which is a barrier to identification of people at risk. They decided, based on their experience, that it should be within the remit of commissioners and service providers to raise awareness both among healthcare professionals and the general public. A lack of knowledge about who may be eligible (for example, people from at‑risk populations) could lead to a delay in assessment and identification of people at risk, and this has potentially serious consequences, such as the risk of developing ovarian cancer. Including this information in continuing education programmes and having public awareness initiatives could be ways to help raise awareness.
Primary care services
The committee discussed that primary care has limited capacity to seek out potential index cases. However, if a family history is known (including family history from a population with increased risk), a person is known to be from an at‑risk population or a person has ovarian cancer, GPs can refer people directly to genetics services. The committee also noted that information and support should be provided in primary care to enable people to make informed decisions.
Genetics services
In the committee's experience, there is little variation in the responsibilities of genetics services because their services are specified by NHS England commissioning guidance for medical genetics services. The committee agreed to list the main responsibilities so that people know what to expect when they are being referred.
The committee discussed whether rarer types of ovarian cancer would be the responsibility of genetics services or gynaecology oncology services. It was agreed that the care of these types of genetic conditions (see the non-epithelial ovarian cancers listed in recommendation 1.4.6) is very specialised and that therefore genetic counselling and genetic testing should be within the remit of genetics services.
Gynaecology oncology multidisciplinary team
Based on the evidence about mainstream genetic testing and counselling, which showed services run more efficiently and faster, the committee agreed that mainstream genetic counselling and genetic testing of anyone with a histopathological diagnosis of epithelial ovarian cancer should be carried out by their gynaecology oncology multidisciplinary team.
Familial ovarian cancer multidisciplinary team
Having a pathogenic variant or being above a threshold for testing leads to many decisions having to be made during the person's life, for example, in relation to fertility and risk-reducing surgery. The committee acknowledged that services run more effectively when roles and responsibilities are defined so that staff and people using the services know what to expect. They noted that the person's care would need to be coordinated because different services may become relevant to them at different points in their life (including, for example, providing information and support, and carrying out reviews). The committee decided that a multidisciplinary approach would be beneficial and that this should continue throughout the person's life. They clarified that the person would usually see the appropriate person relevant to their circumstances and would not usually see the entire team.
Based on their experience, the committee specified the expertise that is essential for the familial ovarian cancer multidisciplinary team (core expertise that is always required) and the other services that the multidisciplinary team would need access to, such as menopause services.
How the recommendations might affect services
The committee discussed that some of these services already exist but that there is variation in practice in how referral between them takes place and how they are set up.
The committee noted that broader eligibility criteria for genetic testing may result in more pressure on existing services, such as primary care. However, people are generally responsible for the completion of their family history questionnaires and specialist service referrals can be completed quickly online, which may help to mitigate some of the pressure on primary care services.
Not all trusts have dedicated familial ovarian cancer multidisciplinary teams, and there is variation in practice. The committee noted that similar teams already exist for breast cancer, and have improved outcomes. Although the recommendations may incur initial set‑up costs, these will be offset by improved outcomes. The recommendations will also standardise service organisation. The committee also noted that, although access to specialists is essential and the overall care is coordinated by them, specialists do not need to be located in a single clinic, potentially mitigating the resource impact on services.
Information and support
Information and support about familial ovarian cancer in all settings
Recommendations 1.2.1 to 1.2.6 and table 1
Why the committee made the recommendations
The committee based their recommendations on qualitative evidence.
There was evidence that although people want information tailored to their individual situation, preferences and needs, this does not always happen. In addition, people want information at the most appropriate time, as well as several opportunities for discussions. There was also evidence that information about risks can be difficult to digest for people and varies according to each person's circumstances. There was evidence highlighting that people can feel overwhelmed by the volume and complexity of information and feel that it is not always sufficiently individualised. There was also evidence about the importance of involving families. The committee agreed the importance of providing sufficient information on an ongoing basis, tailored to the person's needs, so that people can make informed choices.
The evidence showed that rather than receiving all information at once, which can be overwhelming, people appreciate having opportunities to review their decisions at key stages in the pathway. The committee noted that people would need to know how they can access services to make these discussions possible, and recommended providing opportunities to address this.
There was evidence that the considerable psychological impact is not always sufficiently addressed, so the committee recommended that healthcare professionals ask people about their emotional health and wellbeing at each appointment. This means that onward referral to genetic counselling or psychological services can be arranged if needed, for example, in situations where there is anxiety around testing or severe emotional distress.
There was evidence that many people believe that genetic risk only affects women and people born with female reproductive organs. The committee agreed that this perpetuates a lack of clarity around the risk for men, trans women and non-binary people born with male reproductive organs, and discussed the need to raise awareness about the risks.
Based on their knowledge and experience, and the equality impact assessment for this guideline, the committee highlighted that some groups may need additional support to access services, for example, by having online rather than in‑person appointments.
To emphasise the need for standard information in all settings and the content of this information, the committee highlighted key information that should be given to people.
How the recommendations might affect practice
The committee agreed that it is current practice to provide information and support but noted that there is variation in when, what and how often it is provided. The recommendations should lead to greater consistency. Although this may take up additional time, it will allow people to better understand their risk and make informed choices. For example, appropriate information and support at the right time may mean a person choosing to have risk-reducing surgery, which will substantially reduce their cancer risk and associated healthcare costs. Also, existing processes to provide similar information and support to those at risk of familial breast cancer should help lessen the resource impact.
Information and support about risk assessment and genetic testing in genetics services
Recommendations 1.2.7 to 1.2.11 and table 2
Why the committee made the recommendations
The committee based the recommendations on the evidence and their knowledge and experience. They discussed that informed choices can only be made if good information is provided, and agreed that information and support is needed when people come to genetics services, so summarised the information that should be provided as a minimum.
Evidence showed that, compared with usual care, genetic counselling is associated with a higher uptake of the options being considered and higher scores on a knowledge questionnaire about ovarian cancer risk (it could be inferred that better knowledge would lead to a higher-quality decision). The committee acknowledged that genetic counselling would not be needed by everyone but recommended it for people who meet the referral criteria for genetic testing.
Evidence comparing telephone with face-to-face genetic counselling showed no differences in outcomes apart from a higher uptake of options with face-to-face counselling. Economic evidence also showed telephone counselling to be a cost-effective option. The committee noted that the evidence was from 2014 and that online genetic counselling has become a lot more common since the COVID‑19 pandemic. They agreed that online or face-to-face counselling should be offered. They also noted that certain factors may influence which option is most preferable. For example, face-to-face counselling may be more appropriate if an interpreter is needed, whereas online counselling may be more appropriate if family members in a different geographical location are attending the session.
The committee considered clinical and economic evidence that compared a group session in which a video was shown before individual genetic counselling sessions, with individual sessions alone. The committee noted that there were not many clinical differences but that there were cost savings associated with group sessions. The committee agreed that a group session before the individual session could be an option. Despite the potential cost savings, the committee did not want to be prescriptive about this because circumstances can vary widely (for example, level of risk, level of distress or other factors such as communication or language difficulties), which may mean that an individual session may be preferable for some people.
Using a decision aid alongside genetic counselling showed benefits compared with genetic counselling alone for some outcomes such as higher satisfaction with the support received and better decision quality. Adding a decision aid was also associated with a higher number of people taking up the option that was considered (which related to ovarian cancer screening). However, the evidence was not clear about the components used in the decision aid so the committee's recommendation reflected the uncertainty about whether a decision aid made up of different components would be equivalently effective. The committee noted general principles related to decision aids in the NICE guideline on shared decision making.
To emphasise the need for standard information about risk assessment and genetic testing in genetics services and the content of this information, the committee highlighted key information that should be given to people.
There was no evidence for any particular type of psychological intervention to support decision making so the committee therefore made a recommendation for research on the effectiveness of psychological interventions. However, the committee noted that making decisions related to cancer risk can be stressful and can cause some people considerable distress because it may impact their families' lives as well as their own, so psychological support could be beneficial.
How the recommendations might affect practice
Genetic counselling is current practice. However, the broader eligibility criteria for genetic testing may lead to an increased demand for these services, resulting in additional pressure on existing genetics services. Some of this pressure may be reduced by people choosing remote counselling or having group counselling sessions before individual genetic counselling.
The provision of group counselling varies in practice and there may be some implementation costs for services that do not already provide this. However, providing group counselling would result in shorter individual counselling sessions, thereby helping to alleviate some of the pressure on genetics services and potentially leading to cost savings over time. Remote counselling may be more efficient and it may, for example, enable more appointments to take place.
Patient decision aids (or aids that help the healthcare professional make decisions) are already used in some services but there is variation in practice. The recommendation would make decision aids more available in practice. Healthcare professionals already provide a range of approaches to support decision making so adapting this to the relevant decision context would not change current practice.
It is already current practice to refer someone who is distressed or has difficulties in reaching a decision, for psychological support. The recommendation may potentially increase referrals, but addressing such problems early on could result in significant benefits to patients and cost savings to the NHS. For example, a lack of psychological support may prevent engagement with care, or delay genetic testing or risk-reducing surgery uptake.
The committee highlighted the limited availability of specialised psychological services in some regions, specifically those designed to deal with psychological issues arising due to genetic testing and risk management. They noted that all services should have referral pathways to psychological services so that people in psychological distress can receive the support they need. The committee also recognised that genetic counselling could help address certain psychological concerns and that some people may need only 1 consultation with a psychologist, thus mitigating the potential impact on psychological services.
Information and support in specialist services if a person has a pathogenic variant or a strong family history of ovarian cancer
Recommendation 1.2.12 and table 3
Why the committee made the recommendation
The committee based the recommendation on qualitative evidence and evidence about other specialist assessment or risk management services or strategies.
The evidence showed that people want information at the most appropriate time, as well as several opportunities for discussions. An important time for this would be when the person knows that they have a pathogenic variant or a strong family history of ovarian cancer. The committee agreed the importance of providing sufficient information on an ongoing basis. They recommended that in specialist services, people should receive general as well as more specific information depending on their circumstances. There was evidence that women are concerned about reproductive options and how having a pathogenic variant affects this. The committee therefore also agreed that people should have information about reproductive choices and risk-reduction options.
To emphasise the need for standard information in specialist services if a person has a pathogenic variant and the content of this information, the committee highlighted key information that should be given to people.
How the recommendation might affect practice
The committee agreed that it is current practice to provide information and support, but noted that there is variation in when, what and how often it is provided. The recommendation should lead to greater consistency. Although this may take up additional time, it will allow people to better understand their risk and make informed choices. This will improve people's satisfaction with services and may reduce their risk of developing ovarian cancer and associated healthcare costs.
Assessing the risk of having a pathogenic variant
Recommendations 1.3.1 to 1.3.3
Why the committee made the recommendations
The committee based the recommendations on evidence as well as their knowledge and experience. The available evidence only focused on tools that identify people at risk of carrying a BRCA1 or BRCA2 pathogenic variant.
The committee agreed that healthcare professionals need a set of simple criteria to know when a person should be referred for genetic counselling and genetic testing. They agreed that all people should be referred to genetics services who meet the criteria for genetic testing to identify people at risk of having a pathogenic variant. They emphasised that this would not only include people coming forward for testing but also family members of people with a pathogenic variant who would be referred for cascade testing. People who are unaffected by ovarian cancer but have a first- or second-degree relative with a diagnosis of ovarian cancer may also have concerns about having a genetic risk, so can also be referred. The committee clarified that this would apply to any first-degree relative of someone with ovarian cancer. They clarified that for people with second-degree relatives with ovarian cancer, this applies to the maternal and paternal sides, even if the intervening relative is not affected (which would be in line with the thresholds in table 4). Other criteria relate to people from at‑risk populations and those with a diagnosis of ovarian cancer (who may already be under the care of gynaecology oncology services responsible for genetic counselling and genetic testing).
The committee noted that genetic tests are now commercially available (known as direct-to-consumer testing), and discussed what would happen if a person accesses NHS services and presents with a positive genetic test result. They agreed that not all direct-to-consumer laboratories produce accurate test results or prepare people for their test results. Therefore, positive test results for a pathogenic variant for which NHS testing is offered will need to be discussed with an NHS genetics service to decide if referral is needed. This is consistent with the joint guidance by the Royal College of GPs and the British Society for Genetic Medicine.
There was evidence that there are a number of tools with good performance statistics (sensitivity, specificity and area under the curve) to identify BRCA1 and BRCA2 variants. The committee provided examples of tools (those with the largest evidence base) but did not want to be too prescriptive because other tools had good accuracy (with less evidence) and further calculation methods could be developed. The committee noted that some clinical circumstances and the particular family history would impact the tool that is used. They also discussed that sometimes people describe family histories which they believe to be ovarian cancer even if it was another type of gynaecological cancer, and this contributes to potentially inappropriate referral for genetic testing. They therefore recommended that family histories should be verified (for example, via the Cancer Registry or other medical documents).
Given the uncertainties about variants other than BRCA1 and BRCA2 and to address the gap in the evidence, the committee also made a recommendation for research on optimal tools to assess mutation carrier probability for a wider range of ovarian cancer susceptibility genes, not limited to BRCA1 and BRCA2.
How the recommendations might affect practice and services
The committee noted that once criteria are met, it is current practice to arrange a referral to genetics services. The criteria have changed (see the rationale and impact sections for section 1.4) and therefore some of the referral criteria have changed in line with these. The committee noted that referring people for genetic counselling and genetic testing if they have a first-degree relative with ovarian cancer is current practice. However, referring people with a second-degree relative who has ovarian cancer if they do not have an affected intervening relative is not current practice (particularly on the maternal side), but is in line with the thresholds in table 4. This change would be associated with a resource impact, however, this will lead to more people being identified and taking up risk management.
Direct-to-consumer testing is becoming more popular. The recommendation will standardise practice and possibly reduce the burden on services having to manage unreliable test results. The committee agreed that there are significant NHS costs in confirming or refuting direct-to-consumer testing results and these are not warranted unless there are clinical indications for testing. By liaising with NHS genetics services, it can be ensured that only people at increased risk are referred. This is consistent with the joint guidance by the Royal College of GPs and the British Society for Genetic Medicine and should be current practice for most services.
Some tools are already being used but there is variation in practice. Where they are currently not used, introducing them will not incur a substantial cost and will lead to better identification and risk management.
Criteria for genetic testing
Family history of ovarian cancer
Recommendations 1.4.1 to 1.4.4 and table 4
Why the committee made the recommendations
The committee based the thresholds for genetic testing on results from an economic model that had been specifically conducted, which showed variation in the cost effectiveness of panel genetic testing, where the thresholds differed according to gender and age.
The committee discussed that cascade testing of family members of people with a pathogenic variant is already current practice. This helps to identify people who also have the same pathogenic variant so that risks can be managed to help prevent cancer. The committee also noted that it is important to make recommendations for people in situations where it is impossible or not clinically appropriate to test the relative who has ovarian or breast cancer (or the tissue), or where people have a distant relative with a known pathogenic variant but a closer relative cannot be tested.
The committee discussed genetic testing for people with a personal or family history suggestive of a clinically defined syndrome associated with an increased risk of ovarian cancer. They did not make any recommendations because people would be tested or cascade tested if they or a family member had any of the syndromes specified in the protocol. They also decided not to make a research recommendation for this topic because these syndromes are very rare, so research would be unlikely or unfeasible.
How the recommendations might affect practice
Testing when a person has less than a 10% of having a pathogenic variant is not current practice and the recommendations will make testing available to more people. This may require service providers to make healthcare professionals and the public aware of this change, and to make arrangements for implementation. This could also increase the demand for support services such as psychological and menopause services. However, this will lead to more people being identified and taking up risk management, and is a cost-effective approach. Recommendations related to cascade testing are current practice.
At-risk populations
Why the committee made the recommendation
The committee considered clinical as well as economic evidence. The clinical evidence summarised the prevalence of pathogenic variants associated with ovarian cancer.
The evidence showed that the prevalence of BRCA1 and BRCA2 is higher in people from Ashkenazi Jewish families (between 1.2% and 2.2%). The evidence also showed a higher prevalence of BRCA1 in Greenlander people (between 1.1% and 11.64%).
Although the prevalence is lower in people from Sephardi Jewish populations compared with Ashkenazi Jewish populations, there was economic evidence that testing of Ashkenazi and Sephardi Jewish people is cost effective even if only 1 grandparent is from the population. Based on this evidence, the committee used 'at least 1 grandparent' as the definition for being from the specified population.
The committee agreed that the economic evidence supports genetic counselling and genetic testing for people from the at‑risk populations specified, even if the family background is the only criterion for genetic testing. However, they noted that this would not be done through a centrally coordinated national screening programme, but that awareness should be raised about the higher risk of having a founder pathogenic variant so that people could come forward for testing. Healthcare professionals should then recognise that the risk in these populations is higher and offer people referral to genetics services.
How the recommendation might affect practice
The committee discussed that more people from at‑risk populations may come forward for genetic counselling and genetic testing, which will have resource implications. However, they noted that this would not be full panel testing but only testing for the founder genetic variant, which would be less costly.
The committee noted that the recommendation may initially be difficult to implement if more people access genetics services, which are already overstretched. The committee agreed that the impact will reduce after the first wave because numbers would become naturally smaller. However, the recommendation could also increase the demand on existing support services, including psychological and menopause services. Raising awareness and increasing access to genetic counselling and genetic testing among at‑risk populations will, however, identify more people who will participate in risk management, which is a cost-effective approach.
The committee noted that there is an NHS programme offering BRCA testing to those with Jewish ancestry (the NHS Jewish BRCA testing programme) as well as a published programme model (A collaborative genetic carrier screening model for the British Ashkenazi Jewish community), and agreed that linking up with these projects may make implementation easier because some of the pathways into the services would already be established.
People with ovarian cancer
Why the committee made the recommendation
The committee discussed the evidence that in people with ovarian cancer, the overall prevalence of BRCA1 and BRCA2 pathogenic variants is around 17%. When grouped by histological type of ovarian cancer, the highest prevalence of BRCA1 and BRCA2 pathogenic variants is around 22% in those with high-grade serous cancers. One study reported a prevalence of around 18% for pathogenic variants of BRCA1, BRCA2, RAD51C, RAD51D or BRIP1. There was also economic evidence that testing for pathogenic variants in people with ovarian cancer is cost effective. The committee agreed that this supports testing people with ovarian cancer to establish whether they carry a pathogenic variant. If a pathogenic variant is identified, it will help not only manage the person's ongoing care, but will also mean that family members can be tested for the pathogenic variant. Based on their expertise, the committee also recommended that people with other ovarian cancer histotypes associated with pathogenic variants should also be tested.
How the recommendation might affect practice and services
According to current criteria, only people with non-mucinous epithelial ovarian cancer are referred for genetic testing. However, the committee also noted that testing of mucinous epithelial ovarian cancer is already common practice in many services. They further discussed that mucinous ovarian cancer is associated with Lynch syndrome, which is within the remit of this guideline and should therefore be included. However, in services where people with mucinous epithelial ovarian cancer are not currently being tested, it would represent a small change in practice due to the small number of people with mucinous ovarian cancer. There may also be more people diagnosed with rarer non-epithelial ovarian cancers accessing genetic counselling and genetic testing. However, these cancers are very rare and this recommendation is not expected to result in additional pressure on services.
Gene panel testing
Recommendations 1.5.1 and 1.5.2
Why the committee made the recommendations
Overall, the evidence showed that genes associated with an increased risk in ovarian cancer were consistent with the genes recommended by the UK national genomic test directory. Therefore, the committee agreed that BRCA1, BRCA2, MLH1, MSH2, MSH6, RAD51C, RAD51D, BRIP1 and PALB2 should be the genes tested for in panel testing. They noted that the national genomic test directory has different gene panels for different conditions that may increase the risk of ovarian cancer, such as Lynch syndrome, or a family history of breast as well as ovarian cancer. Because such panels would contain different pathogenic variants to test for, the committee recommended which gene panel to use in relation to each person's family or personal history.
How the recommendations might affect practice and services
The committee noted that it is already standard practice to use the gene panels recommended by the UK national genomic test directory. However, the committee noted that the criteria for a gene test are quite different to those in this guideline and that this would lead to more people becoming eligible for gene testing. The committee agreed that although this would have a cost impact, it would improve outcomes because more people would be identified as having a pathogenic variant, and risk-reducing strategies as well as cascade testing can be planned.
Assessing the risk of developing ovarian cancer
Recommendations 1.6.1 to 1.6.5
Why the committee made the recommendations
There was only evidence identified for 1 tool to assess the absolute risk of ovarian cancer (CanRisk), so the committee used this evidence as well as their experience and knowledge. They noted that the methods for assessing both probability of having a pathogenic variant and the risk of developing ovarian cancer are related, and stressed the need to take into account the recommendations in the section on assessing the risk of having a pathogenic variant (because someone with a high risk of having a pathogenic variant would therefore also have a higher likelihood of developing ovarian cancer).
The committee discussed the different services that may be involved in assessing someone's risk of developing ovarian cancer. Once an increased risk is established (as outlined in the section on criteria for genetic testing) and the person is under the care of genetics services or a familial ovarian cancer multidisciplinary team, the service or team should offer to assess their risk of developing ovarian cancer. If it has already been established that the person has a pathogenic variant, the familial ovarian cancer multidisciplinary team would be responsible for the assessment.
The committee agreed that the evidence showed a reasonable level of accuracy for the CanRisk tool. It was also the only tool identified and they acknowledged that it would provide some framework for an assessment, so decided to give this as an example of a tool to use. They acknowledged that CanRisk is used to assess the risk of developing breast and ovarian cancer, and that more specific tools to assess the risk of developing ovarian cancer may be developed.
To use tools such as CanRisk, it is important to have as much information as possible. However, with limited information, the person should be asked whether they know of any other potential risk factors that may increase their risk of ovarian cancer. Based on their experience, the committee discussed the factors that may not be accurately assessed by tools, so highlighted some of these for clinicians to take into account when assessing risk.
The committee agreed that communicating risk and numerical data can be a challenge, particularly in light of uncertainties around estimates. They also thought it would be helpful to present this information in a variety of ways to make it more understandable. The committee referred to the NICE guideline on shared decision making. They also referred to the NICE guideline on familial breast cancer for risk factors that increase both breast and ovarian cancer.
The committee also made a recommendation for research about tools or models to assess the absolute risk of developing ovarian cancer, to encourage further tools to be developed.
Primary preventive medicines
Recommendations 1.7.1 to 1.7.4
Why the committee made the recommendations
Aspirin
The evidence on aspirin did not show a protective effect in terms of ovarian cancer incidence, so the committee did not recommend it for the sole purpose of reducing ovarian cancer risk. However, they noted that there is existing NICE guidance on the use of aspirin to reduce the risk of colorectal cancer in people with Lynch syndrome. Because people with Lynch syndrome are included in the scope of this guideline, the committee felt it was important to link to the NICE guideline on colorectal cancer to ensure that they are aware of this recommendation.
Combined oral contraceptives
The committee agreed, based on their knowledge and experience, that combined oral contraceptives can be associated with a lower risk of ovarian cancer, but long-term use is associated with an increase in breast cancer. They therefore decided to only recommend oral contraceptives as a preventive medicine in particular circumstances: when the reduction in ovarian cancer risk (based on for example age, family history) may outweigh an increased breast cancer risk; and after taking into account whether the timing of risk-reducing surgery is appropriate or not (for example, it may not be appropriate because of age and planned pregnancy).
In the committee's experience, people are not always fully informed about the potential risks (increased risk of developing breast cancer) and benefits (reduced risk of developing ovarian cancer) of combined oral contraceptives, which is necessary for informed decision making. They therefore recommended that this should be discussed so that people can make an informed choice.
Given that evidence was only identified for 2 types of medicines, the committee decided to make a recommendation for research about the effectiveness of primary preventive medicines for reducing the incidence of ovarian cancer.
Risk-reducing surgery
Factors to take into account when considering risk-reducing surgery
Recommendations 1.8.1 to 1.8.5
Why the committee made the recommendations
The committee discussed general factors that need to be taken into account or discussed with the person when considering risk-reducing surgery. Risk-reducing surgery means that the person would become unable to become pregnant because their ovaries and fallopian tubes would be removed. The committee agreed that risk-reducing surgery should not be offered to people planning to conceive naturally because the incidence of ovarian cancer in people younger than 35 is relatively small. Based on the evidence, they also specified the criteria for offering risk-reducing surgery. The criteria relate to people who have a total lifetime risk of ovarian cancer of 5% or over because they have either a pathogenic variant or a strong family history. The committee noted that it is important to attempt to verify the family history if possible (by exploring testing with the person or their family, or via the Cancer Registry or other medical documents).
The committee discussed the importance of supporting people to make informed decisions, and agreed the information and support that people should receive.
The committee agreed that decisions around risk-reducing surgery can cause anxiety and stress. They discussed that the psychological impact of surgery should be taken into account in discussions with the person, and that psychological support before surgery may be needed.
The committee also discussed information and support to aid decision making, particularly around menopause and managing symptoms for premenopausal people considering bilateral salpingo-oophorectomy.
The committee noted, based on their knowledge and experience, that decisions about risk-reducing surgery for people who are carriers of bi‑allelic pathogenic variants in mismatch repair genes (for example, homozygous PMS2) are complex. However, they are also very rare so the committee agreed that a referral to a specialist multidisciplinary team would be needed for discussions about potential risk-reducing surgery.
Types of risk-reducing surgery and timing in relation to the person's specific pathogenic variant
Recommendations 1.8.6 to 1.8.11 and table 5
Why the committee made the recommendations
The committee agreed that decisions related to risk-reducing surgery for ovarian cancer should take into account the NICE guideline on familial breast cancer because some of the genes associated with ovarian cancer would also increase the risk of breast cancer, so considerations around risk-reducing mastectomy should be made in line with the NICE familial breast cancer guideline.
The committee discussed the evidence that bilateral salpingo-oophorectomy improves overall survival. They noted that most of the evidence came from studies with carriers of the BRCA1 or BRCA2 variants. Based on the evidence, they recommended bilateral salpingo-oophorectomy for people at increased risk of ovarian cancer with BRCA1 and BRCA2, and also RAD51C, RAD51D, BRIP1 or PALB2, which are also associated with an increased risk of ovarian cancer.
The MLH1, MSH2 or MSH6 pathogenic variants are associated with Lynch syndrome, which is associated with an increased risk of endometrial as well as ovarian cancer. Although there was no evidence identified related to different types of surgery within this specific group, the committee decided that total hysterectomy as well as bilateral salpingo-oophorectomy should be recommended to prevent both of these types of cancers. They noted that PMS2 is also associated with Lynch syndrome (and is therefore on the associated gene panel). PMS2 increases the risk of endometrial cancer alone rather than endometrial as well as ovarian cancer. They therefore did not add it to the table of risk-reducing surgery for people at risk of ovarian cancer.
The committee made separate recommendations related to the PMS2 pathogenic variant because of its link to Lynch syndrome. People with this pathogenic variant have an increased risk of endometrial cancer alone, but could have an increased risk of ovarian cancer if there is also a family history of ovarian cancer. They therefore considered it to be safe to only recommend total hysterectomy for people with a heterogenous PMS2 pathogenic variant unless there is also a family history of ovarian cancer when additional bilateral salpingo-oophorectomy could be considered.
The committee used their knowledge and experience to agree the minimum ages for risk-reducing surgery, and discussed that there could be exceptional circumstances when risk-reducing surgery could be considered earlier, based on an individualised assessment.
The committee acknowledged that an argument could be made for having salpingectomy first and then delayed oophorectomy, which would avoid a surgical menopause. They noted that some of the evidence related to this showed promise. However, the evidence had very short follow‑up and therefore, the important outcomes such as overall survival and ovarian cancer incidence could not be measured.
The committee noted that MLH1, MSH2, MSH6 and PMS2 increase the risk of endometrial cancer, and therefore a hysterectomy is indicated only for carriers of these pathogenic variants. The committee recommended against hysterectomy for carriers of other pathogenic variants unless there would be other reasons for this to be done.
How the recommendations might affect practice
Risk-reducing surgery is already current practice, but the timing of when it is offered varies. There is currently no specific consideration for the timing related to specific pathogenic variants other than BRCA1 and BRCA2, and the committee noted that the recommendations will standardise this. The recommended ages for risk-reducing surgery correspond with increasing cancer incidence and offer the greatest potential for cancer reduction and associated healthcare cost savings.
The committee noted that broader eligibility criteria for genetic testing will lead to more people opting for risk-reducing surgery. This could put additional pressure on existing services. However, risk-reducing surgeries are generally less complex and require less extensive preoperative and postoperative care compared with ovarian cancer surgery. It would also save costs associated with other cancer treatment as well as save lives. Therefore, in the long term, risk-reducing surgery is likely to result in better outcomes for people and cost savings for services.
Tests before risk-reducing surgery, referral to the gynaecology oncology multidisciplinary team, and what to consider during surgery
Recommendations 1.8.12 to 1.8.17
Tests before risk-reducing surgery
The committee used their knowledge and experience to agree the tests that should be carried out before risk-reducing surgery to minimise the risk of missing asymptomatic ovarian or endometrial cancer.
Referral to the gynaecology oncology multidisciplinary team
There was evidence that risk-reducing surgery is effective and will identify asymptomatic cancer in some people undergoing risk-reducing surgery. Based on this evidence, the committee recommended that if this is identified before or after surgery, a referral should be made to the gynaecology oncology multidisciplinary team so that cancer treatment can be planned.
During risk-reducing surgery
Based on their knowledge and experience, the committee agreed that minimal access surgery is generally preferred over a laparotomy. They noted that some of the evidence included peritoneal washing, but the study included this in both arms of the comparison. It was therefore unclear whether this would be more effective than not using it. However, the committee recommended that peritoneal washings should be taken to prevent missing cancerous cells that may have spread to the peritoneal cavity. Missing cancerous cells, such as serous tubal intraepithelial carcinoma (STIC), would affect staging and ongoing management. In their experience, the committee were aware that up to 5% of incidental cancers could be missed if ultrasound alone is used, and that ultrasound is particularly unreliable in Lynch syndrome. They therefore recommended that any lesions noticed during surgery should be investigated – even if they are found outside the organs that are being removed (such as in the peritoneal cavity) – to increase the likelihood of finding any asymptomatic cancers.
Ovarian cancer surveillance by the familial ovarian cancer multidisciplinary team for people who choose to delay or not have risk-reducing surgery
Recommendations 1.8.18 to 1.8.20
Why the committee made the recommendations
The recommendations are based on limited evidence of the effectiveness of ovarian cancer surveillance as well as how accurately the methods diagnose cancer. Not many studies were identified, and the available studies were limited in the applicability of the populations and the comparisons investigated.
The committee agreed that risk-reducing surgery is always superior to surveillance in relation to preventing cancer and therefore decided not to recommend surveillance because it could encourage people to delay or avoid risk-reducing surgery; the evidence supported this. The committee also discussed the evidence that surveillance is associated with an earlier detection of cancer but also noted a lack of data on an associated survival benefit. However, the committee acknowledged that because people often have children later in life, they may delay or choose to not have risk-reducing surgery. The committee discussed, based on their expertise and the evidence, that the risk of ovarian cancer rises with age and incidence curves vary according to the pathogenic variant, and therefore suggested varying ages for onset of surveillance if surgery was delayed or declined.
They were also concerned about the risk of false-positive surveillance results so recommended the test with the best performance characteristics in relation to false-positive and false-negative rates. If surveillance is carried out, the evidence showed that serial 4‑monthly CA125 longitudinal testing using an algorithm was the most accurate test for this. In the evidence, this was based on the Risk of Ovarian Cancer Algorithm (ROCA) Test, but the committee did not want to rule out using other CA125 longitudinal testing using another algorithm as long as it has demonstrated accuracy. The committee acknowledged that an infrastructure needs to be in place, so recommended that all surveillance activities should come under the remit of the familial ovarian cancer multidisciplinary team who should coordinate, audit and interpret it, using a call and recall mechanism. They recommended that there should be a review at least once a year to discuss the recommendation of having risk-reducing surgery.
The committee agreed that people should be made aware that surveillance is not an alternative to risk-reducing surgery and that risk-reducing surgery is the only way to reduce their risk of developing ovarian cancer. It should also be explained that surveillance would involve 4‑monthly blood tests with an algorithm to analyse results and that there is a possibility that a test result could be false. The committee decided that this information is needed to encourage people not to delay the recommended risk-reducing surgery indefinitely.
The committee also made a recommendation for research to obtain more evidence on the long-term benefits and risks of ovarian cancer surveillance.
How the recommendations might affect practice
Because surveillance would be a change to current practice, the infrastructure for services is not established. Implementing the recommendations may be a challenge and associated with a considerable resource impact. Implementation would take up clinical as well as administrative time, for example, screening invitations, appointments, cost of tests (the ROCA Test is currently not available on the NHS), interpretation of tests and providing the outcomes of tests. Surveillance has been shown to detect ovarian cancer at an earlier stage but it has not been shown to translate into a survival benefit. The committee also noted that most people would be expected to opt for risk-reducing surgery; hence, only very few people would require surveillance, potentially mitigating some of the resource impact.
Pathology protocol for handling specimens from risk-reducing surgery
Recommendations 1.9.1 to 1.9.5
Why the committee made the recommendations
The committee agreed, based on their knowledge and experience, that people undergoing risk-reducing surgery are at increased risk of having an occult precancerous or malignant lesion, so intensive pathological investigation is needed. The committee discussed that pathology protocols for the detection of microscopic lesions found within the fallopian tubes have changed over time. The SEE‑FIM (Sectioning and Extensively Examining the FIMbriated End) protocol entails multiple sagittal sections of fimbriae combined with 2 mm‑thick sections of the remainder. The committee agreed, based on their knowledge and experience, that this type of sectioning is necessary to maximise the detection of precancerous lesions and early cancers.
The committee discussed that immunohistochemistry is a relatively inexpensive, yet informative, investigation that is available in all NHS pathology laboratories. Immunohistochemistry (for p53 and Ki67/MIB1) helps in the identification of serous tubal intraepithelial carcinoma (STIC) and high-grade serous ovarian carcinomas. The committee agreed that investigations of these markers are only necessary if a premalignant or malignant lesion is suspected on morphological examination. They should not be performed in morphologically normal fallopian tubes because immunohistochemistry would not provide any additional information.
The committee agreed that to enable accurate reporting, surgical specimens need to be correctly labelled. It is not possible to determine the laterality of an adnexa once it has been removed from the body. Therefore, at the time of removal, surgeons should ensure adnexal specimens are submitted in 2 separate containers and labelled as originating from either the left or right adnexa. This will enable pathologists to issue accurate reports.
The committee also agreed that peritoneal cytology is needed to correctly stage any precancerous or cancerous lesions and detect occult peritoneal cancers.
The committee noted that people with Lynch syndrome are at increased risk of developing endometrial cancers. In Lynch syndrome, there is a propensity for endometrial cancers to arise within the lower uterine segment. The committee decided that the entire endometrium, including the lower uterine segment, should be submitted for pathological examination to ensure that such cancers and precancerous lesions are identified.
How the recommendations might affect practice
There is already widespread use of the SEE‑FIM protocol by pathologists in dealing with risk-reducing surgery specimens. Where this is not currently used, it will improve detection of occult precancers and cancers and therefore may lead to earlier treatment. Therefore, the recommendations will standardise the use of this pathology protocol.
Hormone replacement therapy after risk-reducing surgery
Recommendations 1.10.1 to 1.10.4
Why the committee made the recommendations
There was little evidence about hormone replacement therapy (HRT) after risk-reducing salpingo-oophorectomy. Studies were small and most had follow‑up that was too short for some of the outcomes investigated, such as cardiovascular events for which the baseline risk is relatively low at a younger age. The committee noted that the evidence showed that HRT is effective in decreasing vasomotor symptoms and agreed that this is in line with the general literature on managing troublesome vasomotor symptoms. There was evidence that HRT is associated with fewer diagnoses of osteoporosis as well as higher bone mineral density. Despite the relatively small evidence base, this was consistent with the committee's experience and knowledge. They recommended that HRT should be offered to prevent loss of bone density and manage symptoms and, based on their knowledge and experience, decided that it should be offered until the average age of menopause (which is usually around 51 years).
The committee agreed that premenopausal women and people with female reproductive organs without a history of breast cancer should be offered HRT after risk-reducing surgery. They agreed that those with a history of certain types of breast cancer may sometimes be prescribed HRT after risk-reducing bilateral salpingo-oophorectomy, but that this should only be offered after advice from their breast cancer team. This is to ensure that HRT would not increase the risk of breast cancer recurrence given other potential risk factors (for example, oestrogen receptor-positive breast cancer).
The committee noted that oestrogen-only HRT is appropriate after a hysterectomy, whereas only combined preparations are appropriate for those with a uterus. The committee were also aware of a Royal College of Obstetricians and Gynaecologists (RCOG) Scientific impact paper on HRT after risk-reducing salpingo-oophorectomy. To be consistent with this paper, they agreed that in most cases, HRT could be started immediately after surgery unless this is not clinically appropriate. They also decided, in line with the RCOG recommendations, that it may be advisable to insert a levonorgestrel intrauterine system at the same time as the surgery, if this was the preferred HRT option. The committee discussed whether or not HRT should be continued after the person reaches the average age of menopause. They agreed that although this is a possibility, it should not automatically happen. If a person wants to take HRT beyond the average age of menopause, there should first be a discussion to assess the person's individual risks and benefits.
The committee were aware that genitourinary symptoms are effectively treated by vaginal oestrogen for people who have not had breast cancer. This is consistent with the conclusions from the NICE guideline on menopause.
Because of the sparsity of evidence, the committee made a recommendation for research on the effectiveness and safety of HRT after risk-reducing surgery.