Postmenopausal bleeding triggers urgent investigation by sequential invasive tests that are avoidable for the 90-95% of women who do not have endometrial cancer. A simple, non-invasive tool that ...accurately identifies cancer and safely reassures healthy women could transform patient care. Here we report, in a cross-sectional diagnostic accuracy study of 103 women with known cancer and 113 with unexplained postmenopausal bleeding, that urine and vaginal cytology has a combined sensitivity of 91.7% (95% CI 85.0%, 96.1%) and specificity of 88.8% (81.2%, 94.1%) for gynecological cancer detection. Cytology identifies 91 endometrial, two fallopian tube and one cervical cancer from 103 known cancer cases. In women with unexplained postmenopausal bleeding, cytology identifies all four endometrial cancers and three others (cervical, ovarian and bladder), for a 12/107 (11.2%) false positive rate. We show proof-of-principle that endometrial cancer can be detected in urine and vaginal fluid. Prospective validation of these findings will support incorporation of this non-invasive test into clinical practice.
Selecting test populations by age and/or family history, failure to apply reference standard tests consistently, and poor conversion to definitive testing are all potential sources of bias 13. Most ...previous studies involve insurance-based healthcare systems; this is fraught with difficulty because fear of lack of reimbursement by services 17 and increased insurance premiums in individuals 18 influences testing decisions. ...the aims of this prospective study were to (1) establish the prevalence of LS and (2) evaluate the diagnostic accuracy of common LS testing strategies in an unselected EC population within a non–insurance-based healthcare system. All women gave written, informed consent to participate, providing blood-DNA, tumour, and clinical data (age, body mass index BMI, self-reported ethnicity) including detailed family histories (pedigrees). Diagnostic accuracy measures were conducted to establish the utility of clinical parameters and tumour triage strategies for risk stratifying women with EC for MMR germline sequencing, including age, family history, histological subtype, density of TILs, MMR deficiency by IHC, MSI status, and MLH1-methylation status.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Lynch syndrome is a hereditary cancer syndrome caused by constitutional pathogenic variants in the DNA mismatch repair (MMR) system, leading to increased risk of colorectal, endometrial and other ...cancers. The study aimed to identify the incremental costs and consequences of strategies to identify Lynch syndrome in women with endometrial cancer.
A decision-analytic model was developed to evaluate the relative cost-effectiveness of reflex testing strategies for identifying Lynch syndrome in women with endometrial cancer taking the NHS perspective and a lifetime horizon. Model input parameters were sourced from various published sources. Consequences were measured using quality-adjusted life years (QALYs). A cost-effectiveness threshold of £20 000/QALY was used.
Reflex testing for Lynch syndrome using MMR immunohistochemistry and MLH1 methylation testing was cost-effective versus no testing, costing £14 200 per QALY gained. There was uncertainty due to parameter imprecision, with an estimated 42% chance this strategy is not cost-effective compared with no testing. Age had a significant impact on cost-effectiveness, with testing not predicted to be cost-effective in patients aged 65 years and over.
Testing for Lynch syndrome in younger women with endometrial cancer using MMR immunohistochemistry and MLH1 methylation testing may be cost-effective. Age cut-offs may be controversial and adversely affect implementation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
•Endometrial cancer risk was not increased in BRCA1/2 pathogenic variant carriers.•Results were unaffected by BRCA gene, previous breast cancer or tamoxifen use.•No specific increase in serous-like endometrial cancer risk was identified.•Sequencing of 15 serous endometrial tumours revealed no pathogenic BRCA1/2 variants.
Around 30% of endometrial cancers (EC) are mismatch repair (MMR) deficient, mostly as a consequence of mutations acquired during tumorigenesis, but a significant minority is caused by Lynch syndrome ...(LS). This inherited cancer predisposition syndrome primes an anti-cancer immune response, even in healthy carriers. We sought to explore the intra-tumoral immunological differences between genetically confirmed LS-associated MMR-deficient (MMRd), sporadic MMR-deficient, and MMR-proficient (MMRp) EC. Endometrial tumors from women with known LS were identified (
= 25). Comparator tumors were recruited prospectively and underwent microsatellite instability (MSI) testing, immunohistochemistry (IHC) for MMR expression and
methylation testing. Those found to have
hypermethylation formed the sporadic MMR-deficient group (
= 33). Those found to be mismatch repair proficient and microsatellite stable formed the MMR-proficient group (
= 35). A fully automated monoplex IHC panel was performed on sequential formalin-fixed paraffin-embedded tumor sections to identify CD3+, CD8+, CD45RO+, FoxP3+, and PD-1+ immune cells, and PD-L1 expression by tumor/immune cells. Two independent observers quantified immune marker expression at the tumor center and invasive margin. Mean and overall compartmental T-cell counts generated standard (binary: Low/High) and higher resolution (quaternary: 0-25, 25-50, 50-75, 75-100%) immune scores, which were used as explanatory features in neural network, support vector machine, and discriminant predictive modeling. Overall T-cell counts were significantly different between the three cohorts: CD3+ (
= <0.0001), CD8+ (
= <0.0001), CD45RO+ (<0.0001), FoxP3+ (
= <0.0001), and PD1+ (
= <0.0001), with LS-associated MMR-deficient tumors having highest infiltrations. There were significant differences in CD8+ (
= 0.02), CD45RO+ (
= 0.007), and PD-1+ (
= 0.005) T-cell counts at the invasive margin between LS-associated and sporadic MMR-deficient tumors, but not between sporadic MMR-deficient and MMR-proficient tumors. Predictive modeling could accurately determine MMR status based on CD8+ T-cell counts within the tumor center alone. This study shows that LS-associated and sporadic MMR-deficient EC are distinct immunological entities, which has important implications for treatment and prognosis.
Lynch syndrome is caused by dominantly inherited germline mutations that predispose individuals to colorectal, endometrial, ovarian, and other cancers through inactivation of the cellular mismatch ...repair system. Lynch syndrome–associated cancers are amenable to surveillance strategies that may improve survival. The age at which surveillance should start is disputed.
To determine whether mutated gene and type of mutation influence age at onset of Lynch syndrome–associated cancers.
A retrospective cohort study of individuals with Lynch syndrome–associated colorectal, endometrial, and/or ovarian cancers whose medical records were included in the clinical database of a large quaternary referral center for genomic medicine in the Northwest of England.
Mutated gene (MLH1, MSH2, MSH6, and/or PMS2) and type of mutation (truncating, splicing, or large rearrangement).
Age at cancer diagnosis.
A total of 1063 individuals with proven Lynch syndrome were included, 495 male and 568 female (mean age 52 years; age range, 10-93 years children were included in the database, but no children developed cancer). There were 546 men and women with colorectal cancer, 162 women with endometrial cancer, and 49 women with ovarian cancer; mean follow-up was 68.2 months. Among MLH1 mutation carriers, mutations in MLH1 were associated with colorectal cancer in 249 (61%) of 409 men and women; endometrial cancer in 53 of 196 (27%) women; and ovarian cancer in 15 (8%) of 196 women. Among MSH2 mutation carriers, mutations in MSH2 (the most prevalent mutations overall) were most commonly associated with female-specific cancers: endometrial cancer in 83 (30%) of 279 women; ovarian cancer in 28 (10%) of 279 women; and colorectal cancer in 239 (50%) 479 men and women. Mutations in MSH6 were less prevalent, and MSH6 mutation carriers presented with colorectal and endometrial cancer at later ages than carriers of mutations in MSH2 or MLH1. When stratified by mutation type, women with truncating MLH1 mutations had later ages of onset of endometrial cancer than those with nontruncating mutations (median difference, 6.6 years; 95% CI, 2.7-10.4; P = .002). Carriers of truncating MLH1 mutations presented with colorectal cancer at later ages than those with other mutations, but the difference was not statistically significant.
Individuals with known Lynch syndrome could be risk stratified by mutated gene and mutation type in tailored surveillance programs. Specifically, individuals with MSH6 mutations could be offered cancer surveillance from a later age. Furthermore, those with truncating MLH1 mutations could begin endometrial cancer surveillance later than those with nontruncating mutations.
Ovarian 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. I2 score 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.
What's new?
Despite gains in ovarian cancer survival, overall prognosis remains poor. Thus, to further improve patient outcomes', efforts are being made to identify cancers amenable to targeted therapeutics. Ovarian cancers with a mismatch repair deficiency (MMRd) phenotype could respond to immotherapy and therefore defining the prevelance of MMRd in ovarian cancer is important. In the present meta‐analysis examining the prevalence of MMRd in ovarian cancer we found a significant minority of ovarian cancers are MMRd. MMRd was observed in all histotypes but was more common in endometrioid tumors. Knowledge of MMRd prevalence in ovarian cancer could help guide therapeutic decisions, particularly surrounding the use of checkpoint inhibitors which are most effective in MMRd cancers.
Hereditary causes of ovarian cancer include Lynch syndrome, which is due to inherited pathogenic variants affecting one of the four mismatch repair genes involved in DNA repair. The aim of this study ...was to evaluate tumour mismatch repair deficiency and prevalence of Lynch syndrome in high-risk women referred to the Manchester Centre for Genomic Medicine with ovarian cancer over the past 20 years.
Women with ovarian cancer diagnosed before the age of 35 years and/or with a suggestive personal or family history of Lynch syndrome cancers underwent tumour testing with immunohistochemistry for mismatch repair deficiency and, where indicated,
promoter methylation testing followed by constitutional testing for Lynch syndrome.
In total, 261 ovarian cancers were tested and 27 (10.3%; 95% CI 6.9% to 14.7%) showed mismatch repair deficiency by immunohistochemistry. Three of 7 with MLH1 loss showed
promoter hypermethylation, and 18 of the remaining 24 underwent constitutional testing for Lynch syndrome. A further 15 women with mismatch repair proficient tumours underwent constitutional testing because of a strong family history of Lynch syndrome cancers. Pathogenic variants were identified in 9/33 (27%) women who underwent constitutional testing, aged 33-59 years (median 48 years), including one whose tumour was mismatch repair proficient. Most Lynch syndrome tumours were of endometrioid histological subtype.
Tumour mismatch repair deficiency identified by immunohistochemistry is a useful prescreen for constitutional testing in women with ovarian cancer with personal or family histories suggestive of Lynch syndrome.
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