Long-term patterns of excess mortality among endometrial cancer survivors

Background: We investigated excess mortality after endometrial cancer using conditional relative survival estimates and standardized mortality ratios (SMR). Methods: Women diagnosed with endometrial cancer during 2000-2017 (N ¼ 183,153) were identified in the Surveillance Epidemiology and End Results database. SMRs were calculated as observed deaths among endometrial cancer survivors over expected deaths among demographically similar women in the general U.S. population. Five-year relative survival was estimated at diagnosis and each additional year survived up to 12 years post-diagnosis, conditional on survival up to that year. Results: For the full cohort, 5-year relative survival was 87.7%, 96.2%, and 97.1% at 1, 5, and 10 years post-diagnosis, respectively. Conditional 5-year relative survival first exceeded 95%, reflecting minimal excess mortality compared with the general population, at 4 years post-diagnosis overall. However, in subgroup analyses, conditional relative survival remained lower for Black women (vs. White) and for those with regional/distant stage disease (vs. localized) throughout the study period. The overall SMR for all-cause mortality decreased from 5.90 [95% confidence interval (CI), 5.81-5.99] in the first year after diagnosis to 1.16 (95% CI, 1.13-1.19) at 10þ years; SMRs were consistently higher for non-White women and for those with higher stage or grade disease. Conclusions: Overall, endometrial cancer survivors had only a small survival deficit beyond 4 years post-diagnosis. However, excess mortality was greater in magnitude and persisted longer into survivorship for Black women and for those with more advanced disease. Impact: Strategies to mitigate disparities in mortality after endometrial cancer will be needed as the number of survivors continues to increase

Cardiovascular disease diagnoses among older women with endometrial cancer

Background: Endometrial cancer (EC) shares risk factors (e.g. obesity) with cardiovascular disease (CVD), yet little research has investigated CVD diagnoses among EC survivors. We aimed to describe the burden of CVD diagnoses among older women with EC compared to women without a cancer history. Methods: Women aged 66+ years with an EC diagnosis during 2004–2017 (N = 44,386) and matched women without cancer (N = 221,219) were identified in the SEER-Medicare linked data. An index date was defined as the cancer diagnosis date of the EC case in that matched set. ICD-9/10 diagnosis codes were used to define CVD outcomes in the Medicare claims. Prevalent CVD was identified using diagnosis codes in the year before the index date. Hazard ratios (HRs) for incident CVD diagnoses after the index date were estimated using multivariable Cox proportional hazards regression. Women with a prevalent CVD were excluded from incidence analyses for that outcome. Results: Compared to women without cancer, women with EC had a higher prevalence of CVD diagnoses at the index date. In analyses beginning follow-up at 1 year post-index date, EC survivors had an increased risk of incident CVD diagnoses including ischemic heart diseases (HR = 1.73; 95% CI: 1.69–1.78), pulmonary heart disease (HR = 1.95; 95% CI: 1.88–2.02), and diseases of the veins and lymphatics (HR = 2.71; 95% CI: 95% CI: 2.64–2.78). Risk of CVD diagnoses among women with EC was also elevated within the first year post-index date. Conclusions: Management of pre-existing CVD and monitoring for incident CVD may be critical during EC treatment and throughout long-term survivorship

Adverse Urinary System Diagnoses among Older Women with Endometrial Cancer

Background: Endometrial cancer and its treatment may impact urinary system function, but few large-scale studies have examined urinary diagnoses among endometrial cancer survivors. We investigated the risk of several urinary outcomes among older women with endometrial cancer compared with similar women without a cancer history. Methods: Women aged 66þ years with an endometrial cancer diagnosis during 2004–2017 (N ¼ 44,386) and women without a cancer history (N ¼ 221,219) matched 1:5 on exact age, race/ ethnicity, and state were identified in the Surveillance, Epidemiology, and End Results-Medicare linked data. ICD-9 and -10 diagnosis codes were used to define urinary outcomes in the Medicare claims. HRs for urinary outcomes were estimated using multivariable Cox proportional hazards regression models. Results: Relative to women without cancer, endometrial cancer survivors were at an increased risk of several urinary system diagnoses, including lower urinary tract infection [HR, 2.36; 95% confidence interval (CI), 2.32–2.40], urinary calculus (HR, 2.22; 95% CI, 2.13–2.31), renal failure (HR, 2.28; 95% CI, 2.23–2.33), and chronic kidney disease (HR, 1.85; 95% CI, 1.81–1.90). Similar associations were observed in sensitivity analyses limited to 1þ and 5þ years after endometrial cancer diagnosis. Black race, higher comorbidity index, higher stage or grade cancer, non-endometrioid histology, and treatment with chemotherapy and/or radiation were often significant predictors of urinary outcomes among endometrial cancer survivors. Conclusions: Our results suggest that, among older women, the risk of urinary outcomes is elevated after endometrial cancer. Impact: Monitoring for urinary diseases may be a critical part of long-term survivorship care for older women with an endometrial cancer history

Obesity is associated with worse quality of life in women with gynecologic malignancies: An opportunity to improve patient-centered outcomes

BACKGROUND: The objective of the current study was to evaluate the effect of obesity on pretreatment quality of life (QoL) in gynecologic oncology patients. METHODS: The authors analyzed collected data from an institution-wide cohort study of women with gynecologic cancers enrolled from August 2012 to June 2013. The Functional Assessment of Cancer Therapy-General, site-specific symptom scales, and the National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS) global mental and physical health tools were administered. Survey results were linked to clinical data abstracted from medical records (demographics and comorbid conditions). Bivariate tests and multivariate linear regression models were used to evaluate factors associated with QoL scores. RESULTS: A total of 182 women with ovarian, uterine, cervical, and vulvar/vaginal cancers were identified; of these, 152 (84%) were assessed before surgery. Mean body mass index was 33.5 kg/m2 and race included white (120 patients [79%]), black (22 patients [15%]), and other (10 patients [6.5%]). A total of 98 patients (64.5%) were obese (body mass index ≥30). On multivariate analysis, subscales for functional (17 vs 19; P=.04), emotional (16 vs 19; P=.008), and social (22 vs 24; P=.02) well-being as well as overall Functional Assessment of Cancer Therapy-General scores (77 vs 86; P5.002) and Patient-Reported Outcomes Measurement Information System global physical health scores (45 vs 49; P=.003) were found to be significantly lower in obese versus nonobese patients. CONCLUSIONS: Before cancer treatment, obese patients with gynecologic malignancies appear to have worse baseline QoL than their normal-weight counterparts. Emerging models of QoL-based cancer outcome measures may disproportionately affect populations with a high obesity burden. The potential disparate impact of cancer therapy on longitudinal QoL in the obese versus nonobese patients needs to be evaluated

A multi-omic single-cell landscape of human gynecologic malignancies

Deconvolution of regulatory mechanisms that drive transcriptional programs in cancer cells is key to understanding tumor biology. Herein, we present matched transcriptome (scRNA-seq) and chromatin accessibility (scATAC-seq) profiles at single-cell resolution from human ovarian and endometrial tumors processed immediately following surgical resection. This dataset reveals the complex cellular heterogeneity of these tumors and enabled us to quantitatively link variation in chromatin accessibility to gene expression. We show that malignant cells acquire previously unannotated regulatory elements to drive hallmark cancer pathways. Moreover, malignant cells from within the same patients show substantial variation in chromatin accessibility linked to transcriptional output, highlighting the importance of intratumoral heterogeneity. Finally, we infer the malignant cell type-specific activity of transcription factors. By defining the regulatory logic of cancer cells, this work reveals an important reliance on oncogenic regulatory elements and highlights the ability of matched scRNA-seq/scATAC-seq to uncover clinically relevant mechanisms of tumorigenesis in gynecologic cancers

Assessing associations between the AURKAHMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood appr

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat