Validity of a two-antibody testing algorithm for mismatch repair deficiency testing in cancer; a systematic literature review and meta-analysis.

Reflex mismatch repair immunohistochemistry (MMR IHC) testing for MLH1, PMS2, MSH2 and MSH6 is used to screen for Lynch syndrome. Recently MMR-deficiency (MMRd) has been approved as a pan-cancer predictive biomarker for checkpoint inhibitor therapy, leading to a vast increase in the use of MMR IHC in clinical practice. We explored whether immunohistochemical staining with PMS2 and MSH6 can be used as a reliable substitute. This two-antibody testing algorithm has the benefit of saving tissue, cutting costs and saving time. PubMed, Embase and Cochrane library were systematically searched for articles reporting on MMR IHC. The weighed percentage of cases with isolated MLH1 or MSH2 loss or combined MLH1/MSH2 loss alone was analyzed using a random effects model meta-analysis in R. The search yielded 1704 unique citations, of which 131 studies were included, describing 9014 patients. A weighed percentage of 1.1% (95% CI 0.53-18.87, I = 87%) of cases with isolated MLH1 or MSH2 loss or combined MLH1/MSH2 loss alone was observed. In the six articles with the main aim of investigating the two-antibody testing algorithm all MMRd cases were detected with the two-antibody testing algorithm, there were no cases with isolated MLH1 or MSH2 loss or combined MLH1/MSH2 loss alone. This high detection rate of MMRd of the two-antibody testing algorithm supports its use in clinical practice by specialized pathologists. Staining of all four antibodies should remain the standard in cases with equivocal results of the two-antibody testing algorithm. Finally, educational sessions in which staining pattern pitfalls are discussed will continue to be important.

Eliminating Cervical Cancer: Progress and Challenges for High-income Countries.

In 2020, the World Health Organization launched a major initiative to eliminate cervical cancer globally. The initiative is built around the three key pillars of human papillomavirus (HPV) vaccination, cervical screening and treatment, with associated intervention targets for the year 2030. The '90-70-90' targets specify that 90% of adolescent girls receive prophylactic HPV vaccination, 70% of adult women receive a minimum twice-in-a-lifetime cervical HPV test and 90% receive appropriate treatment for preinvasive or invasive disease. Modelling has shown that if these targets are met, the elimination of cervical cancer, defined as fewer than four cases per 100 000 women per annum, will be achieved within a century. Many high-income countries are well positioned to eliminate cervical cancer within the coming decades, but few have achieved '90-70-90' and many challenges must still be addressed to deliver these critical interventions effectively. This review considers the current status of cervical cancer control in relation to each of the three elimination pillars in high-income countries and discusses some of the developments that will assist countries in reaching these ambitious targets by 2030.

European guidelines from the EHTG and ESCP for Lynch syndrome: an updated third edition of the Mallorca guidelines based on gene and gender.

BACKGROUND: Lynch syndrome is the most common genetic predisposition for hereditary cancer but remains underdiagnosed. Large prospective observational studies have recently increased understanding of the effectiveness of colonoscopic surveillance and the heterogeneity of cancer risk between genotypes. The need for gene- and gender-specific guidelines has been acknowledged. METHODS: The European Hereditary Tumour Group (EHTG) and European Society of Coloproctology (ESCP) developed a multidisciplinary working group consisting of surgeons, clinical and molecular geneticists, pathologists, epidemiologists, gastroenterologists, and patient representation to conduct a graded evidence review. The previous Mallorca guideline format was used to revise the clinical guidance. Consensus for the guidance statements was acquired by three Delphi voting rounds. RESULTS: Recommendations for clinical and molecular identification of Lynch syndrome, surgical and endoscopic management of Lynch syndrome-associated colorectal cancer, and preventive measures for cancer were produced. The emphasis was on surgical and gastroenterological aspects of the cancer spectrum. Manchester consensus guidelines for gynaecological management were endorsed. Executive and layperson summaries were provided. CONCLUSION: The recommendations from the EHTG and ESCP for identification of patients with Lynch syndrome, colorectal surveillance, surgical management of colorectal cancer, lifestyle and chemoprevention in Lynch syndrome that reached a consensus (at least 80 per cent) are presented.

A mismatch in care: results of a United Kingdom-wide patient and clinician survey of gynaecological services for women with Lynch syndrome.

OBJECTIVE: To describe the current testing practice, referral pathways and gynaecological services available to women with Lynch syndrome (LS) in the UK. DESIGN: Cross-sectional nationwide survey of gynaecological oncologists and women with LS. SETTING: United Kingdom. METHODS: Gynaecological oncologists were contacted directly. Women with LS were identified from national and regional clinical databases and the patient support group, Lynch syndrome UK. MAIN OUTCOME MEASURES: Gynaecological oncologists were asked to report rates of LS testing and current practice regarding risk-reducing strategies and gynaecological surveillance for women with LS. Women with LS were asked to describe their experiences of gynaecological care. RESULTS: In total, 41 gynaecological oncologists and 298 women with LS responded to the survey. Of the gynaecological oncologists surveyed, 37% were unfamiliar with any clinical guidelines for the management of LS. Only 29% of gynaecological oncologists supported universal testing of endometrial cancer for LS; one centre routinely performed such testing. In all, 83% said they perform risk-reducing gynaecological surgery and 43% were aware of a local gynaecological surveillance service for women with LS. Of women with LS, most had undergone a hysterectomy (n = 191/64.1%), most frequently to reduce their gynaecological cancer risk (n = 86/45%). A total of 10% were initially referred for LS testing by their gynaecologist and 55% of those eligible regularly attended gynaecological surveillance; however, 62% wanted more regular surveillance. Regional variation was evident across all standards of care. CONCLUSIONS: There is widespread variation in the services offered to women with LS in the UK. As a community, gynaecological oncologists should move towards a nationally agreed provision of services. TWEETABLE ABSTRACT: A mismatch in care for mismatch repair. Survey finds significant variation in gynaecological care for #Lynchsyndrome in the UK.

Impact of socio-economic deprivation on endometrial cancer survival in the North West of England: a prospective database analysis.

OBJECTIVE: To assess the impact of socio-economic deprivation on endometrial cancer survival. DESIGN: Single-centre prospective database study. SETTING: North West England. POPULATION: Women with endometrial cancer treated between 2010 and 2015. METHODS: Areal-level socio-economic status, using the English indices of multiple deprivation from residential postcodes, was analysed in relation to survival using Kaplan-Meier estimation and multivariable Cox regression. MAIN OUTCOME MEASURES: Overall survival, cancer-specific survival and patterns and rates of recurrence. RESULTS: A total of 539 women, with a median age of 66 years (interquartile range, IQR 56-73 years) and a body mass index (BMI) of 32 kg/m2 (IQR 26-39 kg/m2 ), were included in the analysis. Women in the most deprived social group were younger (median 64 years, IQR 55-72 years) and more obese (median 34 kg/m2 , IQR 28-42 kg/m2 ) than women in the least deprived group (median age 68 years, IQR 60-74 years; BMI 29 kg/m2 , IQR 25-36 kg/m2 ; P = 0.002 and <0.001, respectively). There were no differences in endometrial cancer type, stage or grade between social groups. There was no difference in recurrence rates, however, women in the middle and most deprived social groups were more likely to present with distant/metastatic recurrence (80.6 and 79.2%, respectively) than women in the least deprived group (43.5%, P < 0.001). Women in the middle and most deprived groups had a two-fold (adjusted hazard ratio, HR = 2.00, 95% CI 1.07-3.73, P = 0.030) and 53% (adjusted HR = 1.53, 95% CI 0.77-3.04, P = 0.221) increase in cancer-specific mortality compared with women in the least deprived group. There were no differences in overall survival. CONCLUSIONS: We found that socio-economically deprived women with endometrial cancer were more likely to develop fatal recurrence. Larger studies are needed to confirm these findings and to identify modifiable contributing factors. TWEETABLE ABSTRACT: Socio-economic deprivation is linked to an increased risk of death from endometrial cancer in the North West of England.

Detection of MCM5 as a novel non-invasive aid for the diagnosis of endometrial and ovarian tumours.

BACKGROUND: MCM5 is a protein involved in DNA replication, facilitating cell proliferation. In normal epithelium MCM5 expression is restricted to the cells in the basal proliferative compartments, however in the presence of a tumour MCM5 positive cells are present at the surface epithelium and are shed into bodily fluids. The aim of this study was to determine the sensitivity of MCM5 as a biomarker for the detection of endometrial and ovarian cancer. METHODS: Patients with known ovarian or endometrial cancers, or known benign gynaecological conditions, were enrolled. Informed consent was obtained prior to the collection of full void urine, and either a vaginal tampon (worn for 6-8 h), or a vaginal swab. Vaginal secretions were extracted from the tampon or swab, centrifuged and lysed. Urine samples were centrifuged and lysed. MCM5 levels were determined by MCM5-ELISA (Arquer Diagnostics Ltd). RESULTS: 125 patients completed the study protocol, 41 patients had endometrial cancer, 26 ovarian cancer, and 58 benign controls. All patients provided a urine sample and either a tampon or vaginal swab sample. Urine MCM5 levels were higher in cancer patients than controls (p < 0.0001), there was no significant difference in levels between tampon samples or vaginal swab samples in cancer patients when compared to controls. Performance of MCM5 to discriminate cancer from benign disease was high with an area under the ROC curve of 0.83 for endometrial cancer and 0.68 for ovarian cancer. Using a cut off of 12 pg/mL, overall sensitivity for endometrial cancer was 87.8, and 61.5% for ovarian cancer with a specificity of 75.9%. CONCLUSIONS: MCM5 is a novel sensitive and specific biomarker for the detection of ovarian and endometrial tumours in urine samples, which is likely to have clinical utility as a diagnostic aid.

Research priority setting in women's health: a systematic review.

BACKGROUND: Developing a shared agenda is an important step in ensuring future research has the necessary relevance. OBJECTIVE: To characterise research priority setting partnerships (PSPs) relevant to women's health. SEARCH STRATEGY: Included studies were identified by searching MEDLINE and the James Lind Alliance (JLA) database. SELECTION CRITERIA: Priority setting partnerships using formal consensus methods. DATA COLLECTION AND ANALYSIS: Descriptive narrative to describe the study characteristics, methods, and results. MAIN RESULTS: Ten national and two international PSPs were identified. All PSPs used the JLA method to identify research priorities. Nine PSPs had published a protocol. Potential research uncertainties were gathered from guidelines (two studies), Cochrane reviews (five studies), and surveys (12 studies). The number of healthcare professionals (31-287), patients (44-932), and others (33-139) who responded to the survey, and the number of uncertainties submitted (52-4767) varied. All PSPs entered confirmed research uncertainties (39-104) into interim priority setting surveys and healthcare professionals (31-287), patients (44-932), and others (33-139) responded. All PSPs entered a short list of research uncertainties into a consensus development meeting, which enabled healthcare professionals (six to 21), patients (eight to 14), and others (two to 13) to identify research priorities (ten to 15). Four PSPs have published their results. CONCLUSION: Future research priority setting studies should publish a protocol, use formal consensus development methods, and ensure their methods and results are comprehensively reported. TWEETABLE ABSTRACT: Research published in @BJOGtweets highlights future research priorities across women's health, including @FertilityTop10, @jamesmnduffy.

The proportion of endometrial cancers associated with Lynch syndrome: a systematic review of the literature and meta-analysis.

PURPOSE: Endometrial cancer (EC) is often the sentinel cancer in women with Lynch syndrome (LS). However, efforts to implement universal LS screening in EC patients have been hampered by a lack of evidence detailing the proportion of EC patients that would be expected to screen positive for LS. METHODS: Studies were identified by electronic searches of Medline, Embase, Cochrane CENTRAL and Web of Science. Proportions of test positivity were calculated by random and fixed-effects meta-analysis models. I2 score was used to assess heterogeneity across studies. RESULTS: Fifty-three studies, including 12,633 EC patients, met the inclusion criteria. The overall proportion of endometrial tumors with microsatellite instability or mismatch repair (MMR) deficiency by immunohistochemistry (IHC) was 0.27 (95% confidence interval [CI] 0.25-0.28, I2: 71%) and 0.26 (95% CI 0.25-0.27, I2: 88%), respectively. Of those women with abnormal tumor testing, 0.29 (95% CI 0.25-0.33, I2: 83%) had LS-associated pathogenic variants on germline testing; therefore around 3% of ECs can be attributed to LS. Preselection of EC cases did increase the proportion of germline LS diagnoses. CONCLUSION: The current study suggests that prevalence of LS in EC patients is approximately 3%, similar to that of colorectal cancer patients; therefore our data support the implementation of universal EC screening for LS.

Targeted lung cancer screening selects individuals at high risk of cardiovascular disease.

BACKGROUND: Cardiovascular disease (CVD) is a major cause of morbidity and mortality in populations eligible for lung cancer screening. The aim of this study was to determine whether a brief CV risk assessment, delivered as part of a targeted community-based lung cancer screening programme, was effective in identifying individuals at high risk who might benefit from primary prevention. METHODS: The Manchester Lung Screening Pilot consisted of annual low dose CT (LDCT) over 2 screening rounds, targeted at individuals in deprived areas at high risk of lung cancer (age 55-74 and 6-year risk ≥1.51%, using PLCOM2012 risk model). All participants of the second screening round were eligible to take part in the study. Ten-year CV risk was estimated using QRISK2 in participants without CVD and compared to age (±5 years) and sex matched Health Survey for England (HSE) controls; high risk was defined as QRISK2 score ≥10%. Coronary artery calcification (CAC) was assessed on LDCT scans and compared to QRISK2 score. RESULTS: Seventy-seven percent (n=920/1,194) of screening attendees were included in the analysis; mean age 65.6 ± 5.4 and 50.4% female. QRISK2 and lung cancer risk (PLCOM2012) scores were correlated (r = 0.26, p < 0.001). Median QRISK2 score was 21.1% (IQR 14.9-29.6) in those without established CVD (77.6%, n = 714/920), double that of HSE controls (10.3%, IQR 6.6-16.2; n = 714) (p < 0.001). QRISK2 score was significantly higher in those with CAC (p < 0.001). Screening attendees were 10-fold more likely to be classified high risk (OR 10.2 [95% CI 7.3-14.0]). One third (33.7%, n = 310/920) of all study participants were high risk but not receiving statin therapy for primary CVD prevention. DISCUSSION: Opportunistic CVD risk assessment within a targeted lung cancer screening programme is feasible and is likely to identify a very large number of individuals suitable for primary prevention.

The association between diabetes, comorbidities, body mass index and all-cause and cause-specific mortality among women with endometrial cancer.

OBJECTIVE: Although endometrial cancer (EC) is associated with relatively good survival rates overall, women diagnosed with high-risk subtypes have poor outcomes. We examined the relationship between lifestyle factors and subsequent all-cause, cancer-specific and non-cancer related survival. METHODS: In a cohort of 1359 Australian women diagnosed with incident EC between 2005 and 2007 pre-diagnostic information was collected by interview at recruitment. Clinical and survival information was abstracted from women's medical records, supplemented by linkage to the Australian National Death Index. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific survival (EC death vs. non-EC death) associated with each exposure, overall and by risk group (low-grade endometrioid vs. high-grade endometrioid and non-endometrioid). RESULTS: After a median follow-up of 7.1 years, 179 (13%) women had died, with 123 (69%) deaths from EC. As expected, elevated body mass index (BMI), diabetes and the presence of other co-morbidities were associated with a significantly increased risk of all-cause and non-cancer related death. Women with diabetes had higher cancer-specific mortality rates (HR 2.09, 95% CI 1.31-3.35), particularly those who had were not obese (HR 4.13, 95% CI 2.20-7.76). The presence of ≥2 other co-morbidities (excluding diabetes) was also associated with increased risk of cancer-specific mortality (HR 3.09, 95% CI 1.21-7.89). The patterns were generally similar for women with low-grade and high-grade endometrioid/non-endometrioid EC. CONCLUSION: Our findings demonstrate the importance of diabetes, other co-morbidities and obesity as negative predictors of mortality among women with EC but that the risks differ for cancer-specific and non-cancer related mortality.

A cluster randomized trial of strategies to increase uptake amongst young women invited for their first cervical screen: The STRATEGIC trial.

Objectives To measure the feasibility and effectiveness of interventions to increase cervical screening uptake amongst young women. Methods A two-phase cluster randomized trial conducted in general practices in the NHS Cervical Screening Programme. In Phase 1, women in practices randomized to intervention due for their first invitation to cervical screening received a pre-invitation leaflet and, separately, access to online booking. In Phase 2, non-attenders at six months were randomized to one of: vaginal self-sample kits sent unrequested or offered; timed appointments; nurse navigator; or the choice between nurse navigator or self-sample kits. Primary outcome was uplift in intervention vs. control practices, at 3 and 12 months post invitation. Results Phase 1 randomized 20,879 women. Neither pre-invitation leaflet nor online booking increased screening uptake by three months (18.8% pre-invitation leaflet vs. 19.2% control and 17.8% online booking vs. 17.2% control). Uptake was higher amongst human papillomavirus vaccinees at three months (OR 2.07, 95% CI 1.69-2.53, p < 0.001). Phase 2 randomized 10,126 non-attenders, with 32-34 clusters for each intervention and 100 clusters as controls. Sending self-sample kits increased uptake at 12 months (OR 1.51, 95% CI 1.20-1.91, p = 0.001), as did timed appointments (OR 1.41, 95% CI 1.14-1.74, p = 0.001). The offer of a nurse navigator, a self-sample kits on request, and choice between timed appointments and nurse navigator were ineffective. Conclusions Amongst non-attenders, self-sample kits sent and timed appointments achieved an uplift in screening over the short term; longer term impact is less certain. Prior human papillomavirus vaccination was associated with increased screening uptake.

Markers of the p53 pathway further refine molecular profiling in high-risk endometrial cancer: A TransPORTEC initiative.

BACKGROUND: The morphological classification of high-risk endometrial cancer is of limited prognostic value. Recent attempts to stratify tumours according to molecular signatures have shown considerable promise. Here we attempted to further refine molecular classifications using markers of the p53 pathway. METHODS: We analysed the expression of p53 as well as three downstream markers of the p53 pathway, p21, mdm2 and phospho-p63 (pp63), by immunohistochemistry in a series of 114 endometrial cancers (86 endometrioid, 28 non-endometrioid subtype) with high-risk features (such as high tumour grade and deep myometrial invasion) and correlated results with clinical outcome. The Cancer Genome Atlas (TCGA) data were used to analyse TP63 mutations and copy-number alterations using cBioPortal. TP53 was silenced in two endometrial cancer cell lines to study its effect on p21 and p63. RESULTS: About half of the tumours showed a p53 mutant phenotype and there was a strong negative correlation with p21 expression. Being marker positive for pp63 or mdm2 was associated with a significantly increased likelihood of dying, [hazard ratios 5.93 (95% CI 2.37-7.27) and 7.48 (95% CI 3.04-9.39), respectively]. These findings were seen in both p53 wildtype and p53 mutant tumours. Only 11% of TCGA endometrial cancers had a functional TP63 alteration. Upon silencing of TP53, p21 expression was decreased in one cell line, but no effects on p63 were observed. CONCLUSION: Markers of the p53 pathway improve stratification of endometrial cancers and provide novel insights into the role of this pathway in the disease.

Homozygous germ-line mutation of the PMS2 mismatch repair gene: a unique case report of constitutional mismatch repair deficiency (CMMRD).

BACKGROUND: Constitutional mismatch repair deficiency syndrome results from bi-allelic inheritance of mutations affecting the key DNA mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. Individuals with bi-allelic mutations have a dysfunctional mismatch repair system from birth; as a result, constitutional mismatch repair deficiency syndrome is characterised by early onset malignancies. Fewer than 150 cases have been reported in the literature over the past 20 years. This is the first report of the founder PMS2 mutation - NM_000535.5:c.1500del (p.Val501TrpfsTer94) in exon 11 and its associated cancers in this family. CASE PRESENTATION: The proband is 30 years old and is alive today. She is of Pakistani ethnic origin and a product of consanguinity. She initially presented aged 24 with painless bleeding per-rectum from colorectal polyps and was referred to clinical genetics. Clinical examination revealed two café-au-lait lesions, lichen planus, and a dermoid cyst. Her sister had been diagnosed in childhood with an aggressive brain tumour followed by colorectal cancer. During follow up, the proband developed 37 colorectal adenomatous polyps, synchronous ovarian and endometrial adenocarcinomas, and ultimately a metachronous gastric adenocarcinoma. DNA sequencing of peripheral lymphocytes revealed a bi-allelic inheritance of the PMS2 mutation NM_000535.5:c.1500del (p.Val501TrpfsTer94) in exon 11. Ovarian tumour tissue demonstrated low microsatellite instability. To date, she has had a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and a total gastrectomy. Aspirin and oestrogen-only hormone replacement therapy provide some chemoprophylaxis and manage postmenopausal symptoms, respectively. An 18-monthly colonoscopy surveillance programme has led to the excision of three high-grade dysplastic colorectal tubular adenomatous polyps. The proband's family pedigree displays multiple relatives with cancers including a likely case of 'true' Turcot syndrome. CONCLUSIONS: Constitutional mismatch repair deficiency syndrome should be considered in patients who present with early onset cancer, a strong family history of cancer, and cutaneous features resembling neurofibromatosis type I. Immunohistochemistry analysis of tumour and normal tissue is sensitive and specific for identifying patients with mismatch repair deficiency and should direct DNA sequencing of lymphocytic tissue to establish a diagnosis. Microsatellite instability status appears to be of little value in identifying patients who may have constitutional mismatch repair deficiency syndrome.

Pathological features and clinical behavior of Lynch syndrome-associated ovarian cancer.

OBJECTIVE: Lynch syndrome (LS) is an inherited tumor predisposition condition caused by mutations in the mismatch repair (MMR) genes. Mutation carriers are at increased risk of various malignancies, including ovarian cancer (OC). Relatively little is known about the pathological features and clinical behavior of LS associated OC. METHODS: We analyzed the data of 1047 proven MMR mutated individuals from a prospectively maintained database at a large referral center for genomic medicine in the North West of England. Data were crosschecked with pathology reports, the National Cancer Registry and death certificates, where appropriate. Data from gynecological surveillance and risk reducing surgery were analyzed. RESULTS: We identified 53 cases of LSAOC in proven MMR mutated individuals. The cumulative risk of LSAOC was 20% at age 80 in those who retained their ovaries. LSAOC presented at an earlier age (average 51, range 24-70years) than sporadic OC. The predominant histological subtype was endometrioid adenocarcinoma (53%). Most cases presented early (85% at stage I/II vs. 15% at stage III/IV, p<0.001) and overall survival was excellent (80% 5-year survival), however, patients with advanced disease had a poor prognosis (40% 5-year survival). Most women were found to have LS after their OC diagnosis, however, two were detected at Stage 1c through gynecological surveillance and a further three were detected following surgery for screen-detected synchronous endometrial pathology. CONCLUSION: The predominance of early stage disease in LSAOC is linked to its good prognosis. We support risk-reducing surgery for women whose families are complete especially if undertaking hysterectomy for endometrial risk, and ovarian surveillance as part of gynecological screening for those who have not.