Neil AJ Ryan

Gynaecological cancer surveillance for women with Lynch syndrome: systematic review and cost-effectiveness evaluation

Background Lynch syndrome is an inherited condition which leads to an increased risk of colorectal, endometrial and ovarian cancer. Risk-reducing surgery is generally recommended to manage the risk of gynaecological cancer once childbearing is completed. The value of gynaecological colonoscopic surveillance as an interim measure or instead of risk-reducing surgery is uncertain. We aimed to determine whether gynaecological surveillance was effective and cost-effective in Lynch syndrome. Methods We conducted systematic reviews of the effectiveness and cost-effectiveness of gynaecological cancer surveillance in Lynch syndrome, as well as a systematic review of health utility values relating to cancer and gynaecological risk reduction. Study identification included bibliographic database searching and citation chasing (searches updated 3 August 2021). Screening and assessment of eligibility for inclusion were conducted by independent researchers. Outcomes were prespecified and were informed by clinical experts and patient involvement. Data extraction and quality appraisal were conducted and results were synthesised narratively. We also developed a whole-disease economic model for Lynch syndrome using discrete event simulation methodology, including natural history components for colorectal, endometrial and ovarian cancer, and we used this model to conduct a cost–utility analysis of gynaecological risk management strategies, including surveillance, risk-reducing surgery and doing nothing. Results We found 30 studies in the review of clinical effectiveness, of which 20 were non-comparative (single-arm) studies. There were no high-quality studies providing precise outcome estimates at low risk of bias. There is some evidence that mortality rate is higher for surveillance than for risk-reducing surgery but mortality is also higher for no surveillance than for surveillance. Some asymptomatic cancers were detected through surveillance but some cancers were also missed. There was a wide range of pain experiences, including some individuals feeling no pain and some feeling severe pain. The use of pain relief (e.g. ibuprofen) was common, and some women underwent general anaesthetic for surveillance. Existing economic evaluations clearly found that risk-reducing surgery leads to the best lifetime health (measured using quality-adjusted life-years) and is cost-effective, while surveillance is not cost-effective in comparison. Our economic evaluation found that a strategy of surveillance alone or offering surveillance and risk-reducing surgery was cost-effective, except for path_PMS2 Lynch syndrome. Offering only risk-reducing surgery was less effective than offering surveillance with or without surgery. Limitations Firm conclusions about clinical effectiveness could not be reached because of the lack of high-quality research. We did not assume that women would immediately take up risk-reducing surgery if offered, and it is possible that risk-reducing surgery would be more effective and cost-effective if it was taken up when offered. Conclusions There is insufficient evidence to recommend for or against gynaecological cancer surveillance in Lynch syndrome on clinical grounds, but modelling suggests that surveillance could be cost-effective. Further research is needed but it must be rigorously designed and well reported to be of benefit. Study registration This study is registered as PROSPERO CRD42020171098. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR129713) and is published in full in Health Technology Assessment; Vol. 28, No. 41. See the NIHR Funding and Awards website for further award information.

Controversies in the management of serous borderline tumors and low-grade serous ovarian cancer

Low-grade serous ovarian cancer has been recognized as a distinct oncologic entity for the last 20 years. Over the last 10 years, treatment strategies tailored to the biological and clinical characteristics of the disease have been tested and implemented. However, several key controversies remain. Here, we articulate the uncertainties surrounding the identification of the tissues of origin of low-grade serous ovarian cancer and its precursor lesion, the serous borderline tumor, the challenges in identifying molecular drivers of low-grade serous ovarian cancer, where a driver mutation in the mitogen-activated protein kinase pathway has not been identified, and discuss the phenomenon of co-existent low- and high-grade components in a tumor. In the clinical arena, we discuss the challenges surrounding fertility preservation in young patients, difficulties encountered in patients with unresectable disease, and the controversy surrounding the recommendation of adjuvant chemotherapy. We also discuss the role of secondary debulking surgery, how to order the administration of biological therapies, and the key issues in accelerating the discovery and development of new therapies. For many of these issues, the solution lies in improved international collaboration and cooperation. For each, we allude to how this might best be achieved.

BRCA1 and BRCA2 pathogenic variant carriers and endometrial cancer risk: A cohort study

An association between BRCA pathogenic variants and an increased endometrial cancer risk, specifically serous-like endometrial cancer, has been postulated but remains unproven, particularly for BRCA2 carriers. Mechanistic evidence is lacking, and any link may be related to tamoxifen exposure or testing bias. Hysterectomy during risk-reducing bilateral salpingo-oophorectomy is, therefore, of uncertain benefit. Data from a large, prospective cohort will be informative. Data on UK BRCA pathogenic variant carriers were interrogated for endometrial cancer diagnoses. Standardised incidence ratios (SIRs) were calculated in four distinct cohorts using national endometrial cancer rates; either from 1/1/1980 or age 20, prospectively from date of personal pathogenic variant report, date of family pathogenic variant report or date of risk-reducing salpingo-oophorectomy. Somatic BRCA sequencing of 15 serous endometrial cancers was performed to detect pathogenic variants. Fourteen cases of endometrial cancer were identified in 2609 women (1350 BRCA1 and 1259 BRCA2), of which two were prospectively diagnosed. No significant increase in either overall or serous-like endometrial cancer risk was identified in any of the cohorts examined (SIR = 1.70, 95% confidence interval = 0.74-3.33; no cases of serous endometrial cancer diagnosed). Results were unaffected by the BRCA gene affected, previous breast cancer or tamoxifen use. No BRCA pathogenic variants were detected in any of the serous endometrial cancers tested. Women with a BRCA pathogenic variant do not appear to have a significant increased risk of all-type or serous-like endometrial cancer compared with the general population. These data provide some reassurance that hysterectomy is unlikely to be of significant benefit if performed solely as a preventive measure.

The prevalence of mismatch repair deficiency in ovarian cancer: A systematic review and meta‐analysis

AbstractOvarian cancer (OC) is the least survivable gynecological malignancy and presents late. Five‐year survival for OC is around 45% increasing the need for innovative treatments. Checkpoint inhibitors have shown significant clinical efficacy in mismatch repair deficient (MMRd) cancers and could be a powerful treatment in OC. However, their application in OC is limited due to the lack of data on the prevalence of MMRd. The aim of our study was to conduct a systematic review of the literature and meta‐analysis to provide an accurate estimate of the prevalence of MMRd in OC. We followed PRISMA guidelines throughout. Studies were identified by electronic searches of Medline, Embase, Cochrane CENTRAL and Web of Science followed by citation searching. Studies not written in English were excluded. All studies were reviewed by at least two independent reviewers. Proportions of test positivity were calculated by random and fixed‐effects meta‐analysis models.I2score was used to assess heterogeneity across studies. In total 54 studies were included with 17 532 analyzed for MMRd. The overall proportions of MMRd by immunohistochemistry and microsatellite instability analysis were 6.7% and 10.4%, respectively. MMRd was reported in all histotypes of epithelial OC but was most common in endometrioid OC. We estimate that on average 46.7% (95% CI: 28.8‐65.4) of ovarian carcinomas showing MMRd by IHC had a germline path_MMR variant identified. OC in those with Lynch syndrome seems to present at an earlier age and stage. Studies however were generally of low quality and there was a high degree of heterogeneity. A significant minority (up to 16%) of OC displays MMRd and, therefore, could be amenable to checkpoint inhibition therapy. However, the current literature base is of limited quality and therefore high‐quality prospective studies exploring MMRd in OC with the use of multimodal testing are required. In addition, trials researching efficacy of checkpoint inhibition in MMRd OC are needed.

Current Management Practices for Endometrial Cancer (EC) in the UK: A National Healthcare Professional Survey (KNOW-EC)

The clinical landscape for endometrial cancer in the UK is evolving to include new management guidelines and targeted treatment options. An understanding of current treatment and management practices in the UK will help services plan and adapt to upcoming changes. The purpose of this survey was to understand current and anticipated real-world practices for endometrial cancer care in the UK and potential areas for optimisation. Telephone interviews were conducted in November/December 2021 with UK-based healthcare professionals involved in endometrial cancer management. Questions were aligned with the British Gynaecological Cancer Society/European Society for Medical Oncology recommendations, covering the pathway from diagnosis and treatment to follow-up. A total of 63 healthcare professionals (HCPs) involved in the management of patients with endometrial cancer participated in telephone interviews. The results highlighted variations in management and treatment practices for endometrial cancer and suggest that current UK practice appears to diverge from national and international guidance in some instances. While somatic mismatch repair deficiency testing was used by 89.7% of respondents as mainstream testing, the survey highlighted a lack of access to other key molecular biomarker tests, such as polymerase epsilon (POLE) sequencing (used by only 9.8% of HCPs at the time of the survey). The results highlighted several perceived practical barriers to the swift adoption of new therapeutic options, including funding access, limited staff, treatment-related resources, staff education, and support. Our findings support the need for better access to biomarkers that could enable more effective and targeted treatments.