Dataset Information

Clinicopathologic Significance of Mismatch Repair Defects in Endometrial Cancer: An NRG Oncology/Gynecologic Oncology Group Study.

ABSTRACT: PURPOSE:The clinicopathologic significance of mismatch repair (MMR) defects in endometrioid endometrial cancer (EEC) has not been definitively established. We undertook tumor typing to classify MMR defects to determine if MMR status is prognostic or predictive. METHODS:Primary EECs from NRG/GOG0210 patients were assessed for microsatellite instability (MSI), MLH1 methylation, and MMR protein expression. Each tumor was assigned to one of four MMR classes: normal, epigenetic defect, probable mutation (MMR defect not attributable to MLH1 methylation), or MSI-low. The relationships between MMR classes and clinicopathologic variables were assessed using contingency table tests and Cox proportional hazard models. RESULTS:A total of 1,024 tumors were assigned to MMR classes. Epigenetic and probable mutations in MMR were significantly associated with higher grade and more frequent lymphovascular space invasion. Epigenetic defects were more common in patients with higher International Federation of Gynecology and Obstetrics stage. Overall, there were no differences in outcomes. Progression-free survival was, however, worse for women whose tumors had epigenetic MMR defects compared with the MMR normal group (hazard ratio, 1.37; P < .05; 95% CI, 1.00 to 1.86). An exploratory analysis of interaction between MMR status and adjuvant therapy showed a trend toward improved progression-free survival for probable MMR mutation cases. CONCLUSION:MMR defects in EECs are associated with a number of well-established poor prognostic indicators. Women with tumors that had MMR defects were likely to have higher-grade cancers and more frequent lymphovascular space invasion. Surprisingly, outcomes in these patients were similar to patients with MMR normal tumors, suggesting that MMR defects may counteract the effects of negative prognostic factors. Altered immune surveillance of MMR-deficient tumors, and other host/tumor interactions, is likely to determine outcomes for patients with MMR-deficient tumors.

SUBMITTER: McMeekin DS

PROVIDER: S-EPMC5012715 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Clinicopathologic Significance of Mismatch Repair Defects in Endometrial Cancer: An NRG Oncology/Gynecologic Oncology Group Study.

McMeekin D Scott DS Tritchler David L DL Cohn David E DE Mutch David G DG Lankes Heather A HA Geller Melissa A MA Powell Matthew A MA Backes Floor J FJ Landrum Lisa M LM Zaino Richard R Broaddus Russell D RD Ramirez Nilsa N Gao Feng F Ali Shamshad S Darcy Kathleen M KM Pearl Michael L ML DiSilvestro Paul A PA Lele Shashikant B SB Goodfellow Paul J PJ

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20160620 25

<h4>Purpose</h4>The clinicopathologic significance of mismatch repair (MMR) defects in endometrioid endometrial cancer (EEC) has not been definitively established. We undertook tumor typing to classify MMR defects to determine if MMR status is prognostic or predictive.<h4>Methods</h4>Primary EECs from NRG/GOG0210 patients were assessed for microsatellite instability (MSI), MLH1 methylation, and MMR protein expression. Each tumor was assigned to one of four MMR classes: normal, epigenetic defect, ...[more]

PMID: 27325856

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Project description:BackgroundBlack women with endometrial cancer are more likely to die of their disease compared with white women with endometrial cancer. These survival disparities persist even when disproportionately worse tumor characteristics among black women are accounted. Receipt of less complete adjuvant treatment among black patients with endometrial cancer could contribute to this disparity.ObjectiveWe assessed the hypothesis that black women with endometrial cancer are less likely than their white counterparts to receive adjuvant treatment within subgroups defined by tumor characteristics in the NRG Oncology/Gynecology Oncology Group 210 Study.Study designOur analysis included 615 black and 4283 white women with endometrial cancer who underwent hysterectomy. Women completed a questionnaire that assessed race and endometrial cancer risk factors. Tumor characteristics were available from pathology reports and central review. We categorized women as low-, intermediate-, or high-risk based on the European Society for Medical Oncology definition. Adjuvant treatment was documented during postoperative visits and was categorized as no adjuvant treatment (54.3%), radiotherapy only (16.5%), chemotherapy only (15.2%), and radiotherapy plus chemotherapy (14.0%). We used polytomous logistic regression to estimate odds ratios and 95% confidence intervals for multivariable-adjusted associations between race and adjuvant treatment in the overall study population and stratified by tumor subtype, stage, or European Society for Medical Oncology risk category.ResultsOverall, black women were more likely to have received chemotherapy only (odds ratio, 1.40; 95% confidence interval, 1.04-1.86) or radiotherapy plus chemotherapy (odds ratio, 2.01; 95% confidence interval, 1.54-2.62) compared with white women in multivariable-adjusted models. No racial difference in the receipt of radiotherapy only was observed. In tumor subtype-stratified models, black women had higher odds of receiving radiotherapy plus chemotherapy than white women when diagnosed with low-grade endometrioid (odds ratio, 2.04; 95% confidence interval, 1.06-3.93) or serous tumors (odds ratio, 1.81; 95% confidence interval, 1.07-3.08). Race was not associated with adjuvant treatment among women who had been diagnosed with other tumor subtypes. In stage-stratified models, we observed no racial differences in the receipt of adjuvant treatment. In models that were stratified by European Society for Medical Oncology risk group, black women with high-risk cancer were more likely to receive radiotherapy plus chemotherapy compared with white women (odds ratio, 1.41; 95% confidence interval, 1.03-1.94).ConclusionContrary to our hypothesis, we observed higher odds of specific adjuvant treatment regimens among black women as compared with white women within specific subgroups of endometrial cancer characteristics.

Project description:Stage is a critical determinant of treatment among endometrial carcinoma patients; understanding patterns of tumor spread may suggest approaches to improve staging. Specifically, the importance of exfoliation of endometrial carcinoma cells through the fallopian tubes into the peritoneum is ill defined. We assessed the hypothesis that tubal ligation (TL), which should impede transtubal passage of cells, is associated with lower endometrial carcinoma stage at presentation and, consequently, lower mortality.The NRG Oncology/Gynecologic Oncology Group (GOG) 210 Trial included 4489 endometrial carcinoma patients who completed a risk factor questionnaire that included TL history. Pathology data were derived from clinical reports and central review. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between TL with stage and peritoneal metastasis, overall and by tumor subtype. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals for TL and mortality. All statistical tests were two-sided.Compared with stage I, TL was inversely associated with stage III (OR = 0.63, 95% CI = 0.52 to 0.78) and stage IV carcinomas (OR = 0.14, 95% CI = 0.08 to 0.24) overall and among individual tumor subtypes. TL was inversely related to peritoneal metastasis overall (OR = 0.39, 95% CI = 0.22 to 0.68) and among serous carcinomas (OR = 0.28, 95% CI = 0.11 to 0.68). In multivariable models unadjusted for stage, TL was associated with lower endometrial carcinoma-specific mortality (HR = 0.74, 95% CI = 0.61 to 0.91); however, adjustment for stage eliminated the survival advantage. Similar relationships with all-cause mortality were observed.TL is associated with lower stage and mortality among women with aggressive endometrial carcinomas, suggesting transtubal spread is clinically important. Future studies should evaluate whether detection of intraluminal tumor cells is prognostically relevant.

Project description:ObjectiveTolerance of and complications caused by minimally invasive hysterectomy and staging in the older endometrial cancer population is largely unknown despite the fact that this is the most rapidly growing age group in the United States. The objective of this retrospective review was to compare operative morbidity by age in patients on the Gynecologic Oncology Group Laparoscopic Surgery or Standard Surgery in Treating Patients With Endometrial Cancer or Cancer of the Uterus (LAP2) trial.Study designThis is a retrospective analysis of patients from Gynecologic Oncology Group LAP2, a trial that included clinically early-stage uterine cancer patients randomized to laparotomy vs laparoscopy for surgical staging. Differences in the rates and types of intraoperative and perioperative complications were compared by age. Specifically complications between patients <60 vs ≥60 years old were compared caused by toxicity analysis showing a sharp increase in toxicity starting at age 60 years in the laparotomy group.ResultsLAP2 included 1477 patients ≥60 years old. As expected, with increasing age there was worsening performance status and disease characteristics including higher rates of serous histology, high-stage disease, and lymphovascular space invasion. There was no significant difference in lymph node dissection rate by age for the entire population or within the laparotomy or laparoscopy groups. Toxicity analysis showed a sharp increase in toxicity seen in patients ≥60 years old in the laparotomy group. Further analysis showed that when comparing laparotomy with laparoscopy in patients <60 years old vs ≥60 years old and controlling for race, body mass index, stage, grade, and performance status, patients <60 years old undergoing laparotomy had more hospital stays >2 days (odds ratio, 17.48; 95% confidence interval, 11.71-27.00, P < .001) compared with patients <60 years old undergoing laparoscopy. However, when comparing laparotomy with laparoscopy in patients ≥60 years old, in addition to hospital stay >2 days (odds ratio, 12.77; 95% confidence interval, 8.74-19.32, P < .001), there were higher rates of the following postoperative complications: antibiotic administration (odds ratio, 1.63; 95% confidence interval, 1.24-2.14, P < .001), ileus (odds ratio, 2.16; 95% confidence interval, 1.42-3.31, P <0.001), pneumonias (odds ratio, 2.36; 95% confidence interval, 1.01-5.66, P = .048), deep vein thromboses (odds ratio, 2.87; 95% confidence interval, 1.08-8.03, P = .035), and arrhythmias (odds ratio, 3.21; 95% confidence interval, 1.60-6.65, P = .001) in the laparotomy group.ConclusionLaparoscopic staging for uterine cancer is associated with decreased morbidity in the immediate postoperative period in patients ≥60 years old. These results allow for more accurate preoperative counseling. A minimally invasive approach to uterine cancer staging may decrease morbidity that could affect long-term survival.

Project description: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 MMR-deficient, 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.

Dataset Information

Clinicopathologic Significance of Mismatch Repair Defects in Endometrial Cancer: An NRG Oncology/Gynecologic Oncology Group Study.

Publications

Clinicopathologic Significance of Mismatch Repair Defects in Endometrial Cancer: An NRG Oncology/Gynecologic Oncology Group Study.

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