Dataset Information

GOG 8020/210: Risk stratification of lymph node metastasis, disease progression and survival using single nucleotide polymorphisms in endometrial cancer: An NRG oncology/gynecologic oncology group study.

ABSTRACT:

Objectives

The ability to stratify a patient's risk of metastasis and survival permits more refined care. A proof of principle study was undertaken to investigate the relationship between single nucleotide polymorphisms (SNPs) in literature based candidate cancer genes and the risk of nodal metastasis and clinical outcome in endometrioid endometrial cancer (EEC) patients.

Methods

Surgically-staged EEC patients from the Gynecologic Oncology Group or Washington University School of Medicine with germline DNA available were eligible. Fifty-four genes represented by 384 SNPs, were evaluated by Illumina Custom GoldenGate array. Association with lymph node metastases was the primary outcome. Progression-free survival (PFS) and overall survival (OS) was also evaluated.

Results

361 SNPs with high quality genotype data were evaluated in 337 patients with outcome data. Five SNPs in CXCR2 had an odds ratio (OR) between 0.68 and 0.70 (p-value ≤ 0.025). The A allele rs946486 in ABL had an OR of 1.5 (p-value = 0.01) for metastasis. The G allele in rs7795743 in EGFR had an OR for metastasis of 0.68 (p-value = 0.02) and hazard ratio (HR) for progression of 0.66 (p-value = 0.004). Importantly, no SNP met genome wide significance after adjusting for multiple test correcting and clinical covariates. The A allele in rs2159359 SNP in NME1 and the G allele in rs13222385 in EGFR were associated with worse OS. Both exhibited genome wide significance; rs13222385 remained significant after adjusting for prognostic clinical variables.

Conclusion

SNPs in cancer genes including rs2159359 SNP in NME1 and rs13222385 in EGFR may stratify risk in EEC and are prioritized for further investigation.

SUBMITTER: Brooks RA

PROVIDER: S-EPMC6486855 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Publications

GOG 8020/210: Risk stratification of lymph node metastasis, disease progression and survival using single nucleotide polymorphisms in endometrial cancer: An NRG oncology/gynecologic oncology group study.

Brooks Rebecca A RA Tritchler David S DS Darcy Kathleen M KM Lankes Heather A HA Salani Ritu R Sperduto Paul P Guntupalli Saketh S DiSilvestro Paul P Kesterson Joshua J Olawaiye Alexander B AB Moxley Katherine K Waggoner Steven S Santin Alessandro A Rader Janet S JS Kizer Nora T NT Thaker Premal H PH Powell Matthew A MA Mutch David G DG Birrer Michael J MJ Goodfellow Paul J PJ

Gynecologic oncology 20190228 2

<h4>Objectives</h4>The ability to stratify a patient's risk of metastasis and survival permits more refined care. A proof of principle study was undertaken to investigate the relationship between single nucleotide polymorphisms (SNPs) in literature based candidate cancer genes and the risk of nodal metastasis and clinical outcome in endometrioid endometrial cancer (EEC) patients.<h4>Methods</h4>Surgically-staged EEC patients from the Gynecologic Oncology Group or Washington University School of ...[more]

PMID: 30827726

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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:PurposeThe 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.MethodsPrimary 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.ResultsA 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.ConclusionMMR 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.

Dataset Information

GOG 8020/210: Risk stratification of lymph node metastasis, disease progression and survival using single nucleotide polymorphisms in endometrial cancer: An NRG oncology/gynecologic oncology group study.

Objectives

Methods

Results

Conclusion

Publications

GOG 8020/210: Risk stratification of lymph node metastasis, disease progression and survival using single nucleotide polymorphisms in endometrial cancer: An NRG oncology/gynecologic oncology group study.

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