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BACKGROUND: Universal tumor testing for defective DNA mismatch repair (MMR) is recommended for all women diagnosed with endometrial cancer to identify those with underlying Lynch syndrome. However, the effectiveness of these screening methods in identifying individuals with Lynch syndrome across the population has not been well studied. The aim of this study was to evaluate outcomes of MMR immunohistochemistry (IHC), mutL homolog 1 (MLH1) methylation, and microsatellite instability (MSI) analysis among patients with endometrial cancer. METHODS: A complete systematic search of online databases (PubMed, EMBASE, MEDLINE, and the Cochrane Library) for 1990-2018 was performed. A DerSimonian-Laird random effects model meta-analysis was used to estimate the weighted prevalence of Lynch syndrome diagnoses. RESULTS: The comprehensive search produced 4400 publications. Twenty-nine peer-reviewed studies met the inclusion criteria. Patients with endometrial cancer (n = 6649) were identified, and 206 (3%) were confirmed to have Lynch syndrome through germline genetic testing after positive universal tumor molecular screening. Among 5917 patients who underwent tumor IHC, 28% had abnormal staining. Among 3140 patients who underwent MSI analysis, 31% had MSI. Among patients with endometrial cancer, the weighted prevalence of Lynch syndrome germline mutations was 15% (95% confidence interval [CI], 11%-18%) with deficient IHC staining and 19% (95% CI, 13%-26%) with a positive MSI analysis. Among 1159 patients who exhibited a loss of MLH1 staining, 143 (13.7%) were found to be MLH1 methylation-negative among those who underwent methylation testing, and 32 demonstrated a germline MLH1 mutation (2.8% of all absent MLH1 staining cases and 22.4% of all MLH1 methylation-negative cases). Forty-three percent of patients with endometrial cancer who were diagnosed with Lynch syndrome via tumor typing would have been missed by family history-based screening alone. CONCLUSIONS: Despite the widespread implementation of universal tumor testing in endometrial cancer, data regarding testing results remain limited. This study provides predictive values that will help practitioners to evaluate abnormal results in the context of Lynch syndrome and aid them in patient counseling. Cancer 2019;125:3172-3183.

Purpose: To characterize the somatic mutational landscape, investigate associations between genetic alterations and clinical outcomes, and determine the prevalence of pathogenic germline mutations in low-grade serous ovarian carcinomas (LGSCs). Experimental design: Patients with LGSC tumors that underwent panel-based sequencing of up to 505 genes were identified. Data on somatic and germline mutations, copy number alterations, and clinicopathologic features, including age at diagnosis, platinum sensitivity, and overall survival (OS), were collected. Results: Following central pathology re-review, 119 patients with LGSC were identified for analysis. One hundred ten (92%) had advanced-stage disease (stages III/IV). Somatic KRAS (33%), NRAS (11%), EIF1AX (10%), and BRAF (11%) alterations were the most common; mitogen-activated protein kinase (MAPK) pathway alterations were found in 60% (n=71) of LGSCs. KRAS mutations were significantly associated with age at diagnosis >50 years (p=0.02) and platinum-sensitive disease (p=0.03). On multivariate analysis, MAPK pathway alterations (p=0.02) and platinum sensitivity (p=0.005) were significantly associated with improved OS. Seventy-nine patients (66%) underwent germline genetic testing; 7 pathogenic germline mutations, including 1 bi-allelic MUTYH mutation (c.1187G>A (p.Gly396Asp)) and 6 mono-allelic alterations, were identified. Somatic loss of the wildtype allele (loss of heterozygosity) in the tumor at the locus of the germline mutation was only observed in the bi-allelic MUTYH mutation carrier. There were no germline BRCA1/2 mutations. Conclusions: This study showed MAPK pathway alterations in LGSC, including KRAS mutations, are independently associated with platinum sensitivity and prolonged survival. Germline data, which were limited, identified few pathogenic germline mutations in patients with LGSC.

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The inclusion of DNA mismatch repair (MMR) evaluation as a standard of care for endometrial cancer management will result in a growing population of patients with MMR deficiency and negative germline Lynch syndrome testing (MMR-deficient). In this systematic review and study, the clinicopathologic features of endometrial cancer in patients with MMR-intact, MLH1 methylation positive, MMR-deficient or Lynch syndrome are evaluated. A systematic search of online databases between 1990 and 2018 identified studies of endometrial cancer patients with tumour testing (MMR protein immunohistochemistry or microsatellite instability) and germline assessment for Lynch syndrome. Extracted data included tumour testing, germline genetic testing, age, body mass index (BMI), family history, tumour stage, grade and histologic type. Associations between MMR-intact, MLH1 methylation positive, MMR-deficient and Lynch syndrome groups were analysed using descriptive statistics. The comprehensive search produced 4,400 publications, 29 met inclusion criteria. A total of 7,057 endometrial cancer cases were identified, 1,612 with abnormal immunohistochemistry, 977 with microsatellite instability. Nine-hundred patients underwent germline genetic testing, identifying 212 patients with Lynch syndrome. Patients in the Lynch syndrome and MMR-deficient groups were significantly younger than patients in the MMR-intact and MLH1 methylation positive groups. Patients with MMR-intact tumours had the highest BMI, followed by MMRdeficient, then Lynch syndrome. MMR-intact tumours were more likely to be grade I at diagnosis than other groups. Patients with Lynch syndrome and MMR-deficient tumours were less likely to have stage I disease as compared to patients with MMR-intact tumours. Endometrial cancer patients with MMR-deficient tumours have similar features to those with germline Lynch syndrome mutations, including age, grade, histology and stage. Even in the absence of a germline mutation, tumour evaluation for MMR status may have important clinical implications.

(Abstracted from Cancer 2019;125(18):3172–3183) Lynch syndrome caused by germline mutations in several DNA mismatch repair (MMR) proteins is the most common cause of hereditary and endometrial cancers. Lynch syndrome accounts for approximately 2% to 3% of all endometrial cancers, although the lifetime risk of endometrial cancer for patients with Lynch syndrome varies depending on the specific mutation.

Objectives: Cervical cancer in the setting of uterovaginal prolapse is exceedingly rare. Altered anatomy can complicate treatment of underlying cancer. We first present a rare case of cervical cancer with invasion of uterovaginal prolapse as well as a systematic review of similar reported cases in the literature. The objective of this study was to compare the practice patterns and outcomes regarding cervical cancer with invasion of procidentia. Methods:We conducted a systematic search of online databases (PubMed, Embase, Medline and the Cochrane Library) from 1990 to 2018 of all the cases of cervical cancer associated with stage III-IV uterovaginal prolapse. Patient demographics, pathology, surgical management, chemotherapy, radiation and disease-free survival were compared. Results:Fifteen reported cases of cervical cancer in the setting of procidentia were identified (squamous cell carcinoma-14, clear cell carcinoma-1). The mean age at diagnosis was 74 years (range 54-89). Thirteen percent (n = 2) of cases presented with FIGO stage I disease, 67% (n = 10) with stage II, and 20% (n = 3) with stage III. All cases had stage III-IV uterovaginal prolapse. 73% (11) were treated surgically including nine patients who underwent vaginal hysterectomy. Among patients who underwent primary surgery, 7% (1) received adjuvant chemotherapy, 33% (5) adjuvant radiotherapy and 21% (3) both adjuvant chemotherapy and radiation. 33% (5) of surgical cases included procedures to address the pelvic organ prolapse (colpoclesis (n = 3), uterosacral suspension (n = 1) and anterior posterior repair (n = 1)). Two patients died from the disease within 12 months, one patient died from other causes within 1 month, and the remainder of patients were free of disease at last reported follow-up (Table 1). Conclusions:Cervical cancer in the setting of stage III-IV uterovaginal prolapse can be managed successfully with standard treatment strategies (primary surgery with adjuvant therapy as necessary versus chemoradiation). When patients are surgical candidates, techniques to address the underlying prolapse can be used for symptomatic improvement.

Purpose: Microsatellite instability–high (MSI-H) endometrial carcinomas are underpinned by distinct mechanisms of DNA mismatch repair deficiency (MMR-D). We sought to characterize the clinical and genetic features of MSI-H endometrial cancers harboring germline or somatic mutations in MMR genes or MLH1 promoter hypermethylation (MLH1ph). Design: Of > 1,100 patients with endometrial cancer that underwent clinical tumor-normal sequencing, 184 had MSI-H endometrial cancers due to somatic MMR mutations or MLH1ph, or harbored pathogenic germline MMR mutations. Clinicopathologic features, mutational landscape, and tumor-infiltrating lymphocyte (TIL) scores were compared among MMR-D groups using nonparametric tests. Log-rank tests were used for categorical associations; Kaplan–Meier method and Wald test based on Cox proportional hazards models were employed for continuous variables and survival analyses. Results: Compared with patients with germline (n = 25) and somatic (n = 39) mutations, patients with MLH1ph endometrial cancers (n = 120) were older (P < 0.001), more obese (P = 0.001) and had more advanced disease at diagnosis (P = 0.025). MLH1ph endometrial cancers were enriched for JAK1 somatic mutations as opposed to germline MMR-D endometrial cancers which showed enrichment for pathogenic ERBB2 mutations. MLH1ph endometrial cancers exhibited lower tumor mutational burden and TIL scores compared with endometrial cancers harboring germline or somatic MMR mutations (P < 0.01). MLH1ph endometrial cancer patients had shorter progression-free survival (PFS) on univariate analysis, but in multivariable models, stage at diagnosis remained the only predictor of survival. For stage I/II endometrial cancer, two-year PFS was inferior for patients with MLH1ph endometrial cancers compared with germline and somatic MMR groups (70% vs. 100%, respectively). Conclusions: MLH1ph endometrial cancers likely constitute a distinct clinicopathologic entity compared with germline and somatic MMR-D ECs with potential treatment implications.