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Abstract
Background Ovarian cancer is the fifth most common cause of cancer death for women in the UK. Up to 18% of cases can be attributed to germline mutations in BRCA1 and BRCA2genes. Identifying patients who carry a BRCA mutation provides important information about potential response to treatment and eligibility for therapies such as poly ADP ribose polymerase (PARP) inhibitors. Implementation of systematic genetic testing of patients with ovarian cancer via oncology clinics (mainstreamed genetic testing, MGT) is increasing.
Methods and results This service evaluation reports on the first year of MGT at a tertiary oncology centre in London, UK. In total, 122 patients with high-grade non-mucinous ovarian cancer underwent BRCA germline testing via MGT. Eighteen patients (14.8%) were found to carry a deleterious BRCA1/BRCA2 mutation. Four BRCA carriers did not meet previous criteria for genetic testing and would have been missed. Six BRCA carriers accessed PARP inhibitors post-MGT. Only 22% of patients with a variant of unknown significance (VUS) were referred to clinical genetics services.
Conclusions MGT appears to be a feasible way of providing BRCA testing to patients with ovarian cancer. Greater clarity of how oncologists use VUS results is needed, as well as further research on psychosocial implications of MGT for patients with ovarian cancer, which may include somatic testing in the future.
- ovarian cancer
- genetic testing
- mainstreaming
- BRCA
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Introduction
One in 70 women will develop ovarian cancer over their lifetime, leading to over 4000 deaths per year in the UK.1 There is an inherited component to ovarian cancer; between 5.8% and 24.8% of cases can be attributed to germline mutations in BRCA1 and BRCA2 genes.2 Until recently, BRCA genetic testing has been provided by clinical genetics services. Patients with ovarian cancer could access testing if they had a significant family history of breast and/or ovarian cancer or Ashkenazi Jewish ancestry. Consequently, genetic testing was only offered to a minority of patients; however, up to 44% of BRCA mutation carriers do not have a significant family history.3 Furthermore, barriers to referral and uptake of genetic counselling for both clinicians and patients have been reported.4–7 A review of current ovarian cancer and BRCA genetic testing guidelines found only 5 from 15 guidelines recommend testing regardless of family history, Ashkenazi Jewish ancestry or cancer histology.2
Identifying patients with ovarian cancer with a BRCA mutation is increasingly important for treatment decisions, in particular for accessing poly ADP ribose polymerase (PARP) inhibitors (such as olaparib, rucaparib and niraparibi), targeted therapies for relapsed, BRCA-mutated ovarian cancer. Recent changes to the UK National Institute for Health and Care Excellence (NICE) guidelines mean that women with high-grade epithelial ovarian cancer (EOC) but without a family history should be able to access BRCA genetic testing.8 Integrating BRCA testing into oncology clinics, referred to as ‘mainstreamed’ genetic testing (MGT), is key to providing testing to more women. Systematic genetic testing for all women with high-grade non-mucinous EOC is increasing, either via oncology (MGT) or clinical genetics services. However, there is a lack of consensus as to how BRCA testing should be provided to patients with ovarian cancer,9 and this will lead to inequities in accessing testing in this group.
At University College London Hospital (UCLH), a tertiary referral centre in North London, MGT was introduced within the gynaecological oncology department in February 2015 with funding for BRCA germline testing provided by the UCLH Charity for an initial period of 12 months.
The objective of this evaluation was to examine clinical outcomes from the first year of MGT, which could be used to inform development of this service.
Methods
This service evaluation was approved by the UCLH Applied Health Research in Cancer Governance Group.
All women with a diagnosis of high-grade non-mucinous EOC currently under the care of UCLH were eligible for BRCA testing with no age or family history restrictions. Testing was provided by medical/clinical oncologists who completed an online training course via the Marsden Mainstreamed Genetic Testing in Cancer Programme.10 Timing of testing was guided by clinician and patient preference. Testing was discussed at the patient’s oncology appointment alongside other treatment decisions. Women who agreed to BRCA testing received their results from their oncologist. Where a BRCA mutation or variant of unknown significance (VUS) was identified, patients were referred to their local clinical genetics service. Referrals were also recommended for women without a mutation but with a relevant family history.
Clinical files were reviewed for all patients who had MGT, including genetic reports. If histopathology was unclear from medical records, these were reviewed with an expert gynaecological oncology pathologist. Two local clinical genetics services were contacted to review referral patterns, family history data and referral of at-risk relatives for predictive testing.
Results
Patient characteristics
Between February 2015 and April 2016, 122 eligible patients had BRCA testing via MGT. Most (100/122, 82%) had high-grade serous ovarian cancer and were diagnosed with stage III or IV disease (95/122, 78%). The median age at diagnosis was 62 years (range 28–88); 68 women (56%) were younger than 60 years at diagnosis.
BRCA mutation carriers
Eighteen women with a BRCA mutation were identified from MGT: 10 BRCA1 and 8 BRCA2 mutations. Ashkenazi Jewish/Polish founder mutations comprised 11% of pathogenic mutations (2/18). Nine VUS were identified.
The prevalence of BRCA mutations in our cohort was 14.8%, which is similar to other studies of large cohorts of women with EOC.3 Two UK sites offering systematic BRCA testing to patients with ovarian cancer reported a prevalence of 7.8% and 15.9% (table 1).9 11
Prevalence of BRCA mutations from systematic genetic testing in the UK
Age, mutation status, disease pathology and stage are shown in table 2. The median age at diagnosis of BRCA mutation carriers was 57 years (range 42–74 years), compared with 66 and 62 years in the VUS and no mutation groups, respectively. There was no significant difference in age between women with a BRCA mutation and those with either a normal result or VUS (P=0.171). BRCA1 mutation carriers were younger at diagnosis than BRCA2 carriers (P=0.012). One BRCA carrier had a carcinosarcoma; 17 had high-grade serous cancer. Most BRCA carriers had stage III or IV disease (17/18, 94%).
Summary of patient characteristics
During this evaluation it was noted two patients who had received normal BRCA germline results from MGT were identified as carrying BRCA somatic mutations as part of clinical trial participation.
Testing process and timing
All BRCA germline testing was performed by the North East Thames Regional Genetics Laboratories. The median time from sample receipt to result was 26 working days (range 14–48 days).
Timing of testing ranged from at diagnosis to up to 104 months postdiagnosis. Approximately half of patients in this cohort had been newly diagnosed within the previous 12 months (56/122, 46%). From this group, 20/56 (36%) women underwent MGT within 1 month of diagnosis. Among 18 women carrying a BRCA mutation, 10 (56%) were newly diagnosed with ovarian cancer in the 12 months prior to genetic testing, 6 of whom were tested within 1 month of diagnosis. Eight carriers (44%) were diagnosed 21–104 months prior to BRCA testing.
Clinical genetics and family history
After MGT, women with a BRCA mutation or VUS should have been referred to their local clinical genetics service by their oncologist. Most patients were referred between 12 and 43 working days after their MGT results were reported. At the time of this evaluation, 22% (4/18) of BRCA mutation carriers had not yet been referred to clinical genetics. Two of these patients were subsequently referred, 98 and 127 working days from date of MGT results. Of nine patients with a BRCA VUS, only two had been referred to clinical genetics.
Family history data documented at the time of genetic counselling were available for 13 BRCA carriers. Nine patients had a family history of breast, ovarian and/or other cancers; four patients had no significant family history and did not meet previous criteria for BRCA genetic testing (ie, Manchester score <15).12 Fifteen relatives of BRCA carriers were referred to clinical genetics services, with 11 undergoing predictive testing.
Patient management in BRCA carriers
Of the 18 BRCA mutation carriers, there was no change to treatment for 67% (11/18); seven patients completed first-line chemotherapy, with three of these patients on maintenance bevacizumab, and four completed or were undergoing second-line chemotherapy. One patient was deceased 8 months after MGT. Thirty-three per cent (6/18) of patients were subsequently able to access PARP inhibitors. Four patients commenced olaparib, one patient accessed rucaparib via a compassionate use programme, and one patient was participating in an olaparib clinical trial. Family history data were available for five patients in this group, and of these three did not meet previous criteria for BRCA genetic testing.
Discussion
The MGT service at UCLH provided BRCA germline testing to 122 patients with ovarian cancer and identified 18 women with BRCA mutations (prevalence 14.8%). The variation in mutation rates between the three UK sites with published BRCA testing data may be due to several factors. The lower rate in East Anglia (of 7.8%) could result from testing only newly diagnosed patients, and ethnicity; no Ashkenazi/Polish founder mutations were found in their cohort. The higher prevalence (15.9%) at the Royal Marsden may be due to a younger cohort; an age cut-off of <65 years was used for the first 9 of 16 months of MGT. The higher prevalence at both UCLH and the Royal Marsden may be due to retrospective testing of patients several years from their initial diagnosis. This may indicate enrichment based on treatment response, that is, increased prevalence of BRCA mutations in platinum-sensitive disease.
Currently there is no consensus as to the best time to offer BRCA testing to women with ovarian cancer, although many clinicians choose to do this early in the treatment pathway. At UCLH, germline testing of all patients more than 12 months after diagnosis identified 44% of BRCA carriers. MGT should be offered to patients regardless of time elapsed since diagnosis as results may inform clinical decisions and identification of at-risk relatives for patients identified as mutation carriers; first-degree blood relatives have a 50% risk of carrying the same mutation.
Patient management was reviewed for the 18 women identified as BRCA mutation carriers. Six patients were able to access a PARP inhibitor therapy or trial; most patients had received MGT results between 6 and 14 months earlier. For 11 patients, there was no change to treatment. The lack of immediate impact on clinical management is largely due to timing, as olaparib is available only for platinum-sensitive relapsed ovarian cancer after three or more lines of treatment and the niraparib managed access programme was not yet available at the time of this evaluation. Clarifying BRCA mutation status while patients are still on first-line or second-line chemotherapy would identify those who are eligible for PARP inhibitor therapies or trials in the future.
Knowledge of BRCA status provides important cancer risk information for families. Patients found to carry a BRCA mutation or VUS should be referred to clinical genetics services to discuss the implications of their results, including communicating results to relatives. In this service evaluation, although most women with a BRCA mutation were referred immediately to clinical genetics by their oncologist, for some the referral was delayed. Most women with a BRCA VUS were not referred to clinical genetics. It is unclear how oncologists interpret VUS and/or use them for clinical management. The interpretation of VUS results is a challenge for genetics and other areas of clinical medicine.13 The pathogenicity of a VUS should be reviewed periodically, as in time it may be reclassified as either deleterious or benign. This is usually carried out within a clinical genetics service. In some families segregation analysis of the variant among cancer-affected relatives may help clarify pathogenicity.14
Future directions for MGT
Offering BRCA testing to women with high-grade EOC in the oncology setting (MGT) is being adopted across the UK. Research continues to identify other genes that contribute to EOC. Testing for moderate-risk genes conferring lifetime risks of 6%–13% (RAD51C, RAD51D and BRIP1) is now offered alongside BRCA1/BRCA2.15 16 Testing of multiple cancer susceptibility genes using next-generation sequencing panels is increasingly being offered. However there remain counselling issues; the penetrance of some of these genes is uncertain, as well as how they might influence ovarian cancer management.
Currently UK clinical genetics services are commissioned to provide BRCA germline testing in individuals with a pretest BRCA1/BRCA2 carrier probability of 10% or more, as recommended in the NICE guidelines.8 17 This includes all women with high-grade non-mucinous EOC. Tumour BRCA testing is available in Europe, but is not offered routinely in the UK. Within this cohort of MGT patients, two with a normal BRCA germline result were later found to carry somatic BRCA mutations. It is estimated 5%–7% of women with high-grade serous ovarian cancer who do not carry a BRCA germline mutation are found to have a somatic BRCA mutation.18 These patients would be eligible for olaparib therapy or other PARP inhibitor clinical trials, calling for greater access to tumour testing in ovarian cancer.
This evaluation demonstrates that MGT is a feasible way of providing BRCA testing to patients with ovarian cancer and led to 33% of mutation carriers accessing targeted therapies. Greater clarity of how oncologists use VUS results is needed, as is ensuring these are reviewed. Timing of MGT may be important to ensure all eligible patients are offered BRCA testing, including newly diagnosed women and those some years from diagnosis. Further research is needed to explore the psychosocial experiences of women with ovarian cancer who have MGT, in particular those who receive mutation-positive results.
Footnotes
↵i Olaparib was approved by the UK NICE guidelines in January 2016 for patients with relapsed, platinum-sensitive ovarian, fallopian tube or peritoneal cancer who have BRCA1/BRCA2 mutations and whose disease has responded to platinum-based chemotherapy after three or more courses of platinum-based chemotherapy. Rucaparib was approved by the US Food and Drug Administration in December 2016 for treatment of patients with deleterious BRCA mutation-associated (germline and/or somatic) advanced ovarian cancer who have been treated with two or more chemotherapies. Rucaparib is currently accessed via Clovis-named patient compassionate use programme or clinical trials, and niraparib via Clinigen and TESARO managed access programme.
Contributors BR conducted the service evaluation. BR, AL and LS wrote the report. RSK, JAL, ML, MMC and TM contributed to drafting the report and participated in final draft revisions.
Funding The first 12 months of BRCA germline testing for patients with ovarian cancer at UCLH were kindly funded by the University College London Hospitals Charity (Grant 7146).
Competing interests None declared.
Patient consent Detail has been removed from this case description/these case descriptions to ensure anonymity. The editors and reviewers have seen the detailed information available and are satisfied that the information backs up the case the authors are making.
Ethics approval UCLH Applied Health Research in Cancer Governance Group.
Provenance and peer review Not commissioned; externally peer reviewed.
Correction notice This article has been corrected since it was published Online First. A second affiliation (Barts Cancer Institute, Queen Mary University of London, UK) has been added to author Michelle Lockley.