Investigator
Cancer Registry Of Norway
Statins and the risk of gynecological cancer: a Norwegian population-based cohort study
Abstract Background Endometrial, ovarian, and cervical cancers are the most common gynecological cancers, with 1.4 million diagnoses worldwide in 2022. Statins are widely used for cardiovascular conditions and have been studied for their association with gynecological cancer risk, but results to date have been inconclusive. Methods We conducted a population-based cohort study including data from the Norwegian Prescription Database and the Cancer Registry of Norway, and followed women aged ≥50 years from 2004 to 2018. We examined the association between statin use overall and by type (lipophilic, hydrophilic), and the risk of endometrial, ovarian, and cervical cancers overall and by age groups and histologic subgroup using Cox proportional hazard models. Results The cohort study included 1 083 629 women. During a median follow-up of 11.6 years, 334 582 (31%) used statins at least once. There were 7709 cases of endometrial, 4415 cases of ovarian, and 1603 cases of cervical cancers. Statin use was associated with reduced risk of endometrial cancer [current use hazard ratio (HR) = 0.90, 95% confidence interval (CI): 0.85–0.96; past use HR = 0.79, 95% CI: 0.71–0.88]; associations were observed only for the lipophilic statins, and with similar associations by age groups and for type I and II endometrial cancer. No consistent associations were found for ovarian or cervical cancers. We found no trends for cumulative defined daily doses of current use or time since cessation for any cancer type. Conclusion Statin use was associated with a reduced risk of endometrial cancer but not with the risk of ovarian cancer or cervical cancer.
Low-dose aspirin and non-aspirin non-steroidal anti-inflammatory drugs and epithelial ovarian cancer survival: a registry-based cohort study in Norway
Abstract Background Aspirin and non-aspirin non-steroidal anti-inflammatory drugs (NA-NSAID) have been associated with improved survival in individuals with epithelial ovarian cancer (EOC); however, findings to date are inconsistent. Methods We conducted a registry-based cohort study evaluating survival following an incident invasive EOC diagnosis including individuals diagnosed between 2004–2018 (n = 4325; n = 2206 deaths; n = 1973 EOC deaths). Evaluated exposures were low-dose aspirin and NA-NSAIDs. Two primary post-diagnosis exposure windows were evaluated: fixed post-diagnostic baseline exposure ≤ 305 days after diagnosis (use, non-use) and updated “time-varying” exposure (never, past, current use; cumulative defined daily dose (DDD)). Pre-diagnostic exposure (use, non-use) was further evaluated. Multivariable Cox-proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals [95% CIs]. The primary outcome was cause-specific survival. Restricted mean survival time (RMST) in exposure groups was estimated at 5 years following start of follow-up. Results Baseline post-diagnosis aspirin use was not associated with survival following an EOC diagnosis (e.g., use vs. no use: aspirin, HR = 1.02 [95% CI = 0.84–1.24]). Inverse associations were observed between current aspirin use post-diagnosis and survival in the time-varying exposure models (HR 0.68 [0.57–0.81]), and with higher post-diagnosis cumulative DDD of aspirin. Findings for NA-NSAIDs were less consistent. No associations were observed for pre-diagnostic use. Results for overall survival were similar to those for cause-specific survival. Compared to never use, post-diagnosis low-dose aspirin use was associated with a longer RMST (e.g., ever vs. never use, difference in RMST = 2.67 months). Conclusions This study provides further evidence of a potential beneficial effect of post-diagnosis low-dose aspirin use for ovarian cancer survival.
Ovarian cancer survival by residual disease following cytoreductive surgery: a nationwide study in Norway
Abstract Background Residual disease (RD) following cytoreductive surgery is prognostic for epithelial ovarian cancer (EOC) patients. Few studies have evaluated RD and survival by tumor histotype and across continuous RD diameter. Methods 2608 individuals with stages III-IV invasive EOC diagnosed between 2013 and 2022 were identified using the Cancer Registry of Norway. In flexible parametric models, we compared excess mortality comparing RD versus no macroscopic residual disease (NMRD); systemic anti-cancer therapy was evaluated in a sub-cohort from 2019. Excess mortality was assessed across continuous RD size using restricted cubic splines. Results Among 1849 patients with cytoreductive surgery, survival was worse for individuals with RD (vs. NMRD), excess hazard ratio (EHR) = 2.62 (95% confidence interval = (2.27–3.01)); no heterogeneity was observed by histotype (p = 0.21). Patients with 0.1–0.4 cm RD had 2-fold higher risk of death (EHR = 2.09 (1.63–2.68)) relative to women with NMRD; ~3-fold higher risk was observed for all other categories (e.g., 0.5–0.9 cm, EHR = 2.97 (2.26–3.89); 3.0–20 cm, 2.75 (2.05–3.70)). No significant difference in three-year survival was observed across continuous RD diameter (p ≥ 0.17). NMRD was associated with better survival regardless of neoadjuvant chemotherapy. Discussion Achieving NMRD resulted in the best survival outcomes. Among patients with RD, we observed no significant difference in survival by RD diameter.
Diabetes-Related Dietary Patterns and Endometrial Cancer Risk and Survival in the European Prospective Investigation into Cancer and Nutrition Study
Background/Objectives: Endometrial cancer (EC)’s major risk factors include obesity and diabetes, both strongly related with lifestyle choices and dietary factors. Our study aimed to evaluate the relationship between diabetes-related dietary patterns, EC risk, and survival in a population of middle-aged European women. Methods: A total of 285,418 female participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) study were included in the analysis. After a mean time of 10.6 years of follow-up, 1955 incident EC cases were registered; of those, 133 women died from EC. The Empirical Dietary Index for Insulin Resistance (EDIR), the Empirical Dietary Index for Hyperinsulinemia (EDIH), and the Diabetes Risk Reduction Diet (DRRD), were estimated from dietary information collected at baseline from EPIC participants. Cox proportional hazards regression models were used to evaluate the association between the dietary patterns and EC risk, using hazard ratios (HR), 95% confidence intervals (CI), and adjusting for relevant confounders. Cox and Fine–Gray models were used to assess the association with overall and EC-specific mortality, respectively. Results: Higher adherence to EDIR was associated with an increased risk of EC, multivariable HR for T3vsT1 were 1.17 (95% CI = 1.04 to1.31). However, when BMI was included in the models, these associations became weaker and no longer statistically significant. No associations were observed in relation to adherence to EDIH, DRRD, and EC risk. No associations were found in relation to diabetes-related dietary patterns and mortality. Conclusions: This study highlights the potential role of diabetes related dietary patterns and EC etiology and prevention. Further studies are warranted to better understand the role of etiology-derived dietary patterns and disease prevention and prognosis.
Theoretical potential for endometrial cancer prevention through primary risk factor modification: Estimates from the EPIC cohort
Endometrial cancer (EC) incidence rates vary ~10‐fold worldwide, in part due to variation in EC risk factor profiles. Using an EC risk model previously developed in the European EPIC cohort, we evaluated the prevention potential of modified EC risk factor patterns and whether differences in EC incidence between a European population and low‐risk countries can be explained by differences in these patterns. Predicted EC incidence rates were estimated over 10 years of follow‐up for the cohort before and after modifying risk factor profiles. Risk factors considered were: body mass index (BMI, kg/m2), use of postmenopausal hormone therapy (HT) and oral contraceptives (OC) (potentially modifiable); and, parity, ages at first birth, menarche and menopause (environmentally conditioned, but not readily modifiable). Modeled alterations in BMI (to all ≤23 kg/m2) and HT use (to all non‐HT users) profiles resulted in a 30% reduction in predicted EC incidence rates; individually, longer duration of OC use (to all ≥10 years) resulted in a 42.5% reduction. Modeled changes in not readily modifiable exposures (i.e., those not contributing to prevention potential) resulted in ≤24.6% reduction in predicted EC incidence. Women in the lowest decile of a risk score based on the evaluated exposures had risk similar to a low risk countries; however, this was driven by relatively long use of OCs (median = 23 years). Our findings support avoidance of overweight BMI and of HT use as prevention strategies for EC in a European population; OC use must be considered in the context of benefits and risks.
Thyroid hormones and epithelial ovarian cancer risk and survival: results from the European Prospective Investigation into Cancer and Nutrition study
Abstract Background Thyroid-stimulating hormone (TSH) and thyroid hormones (free triiodothyronine [fT3] and free thyroxine [fT4]) may influence cancer outcomes, but evidence for ovarian cancer is limited. Methods We conducted a nested case–control study comparing 578 epithelial ovarian cancer (EOC) cases with matched controls within the European Prospective Investigation into Cancer and Nutrition (EPIC). To examine associations between circulating TSH, fT3, and fT4 levels and EOC risk, we estimated risk ratios (RRs) and 95% confidence intervals (CIs) per SD using conditional logistic regression. Among cases, we evaluated all-cause and EOC-specific survival by prediagnostic hormone levels. Hazard ratios (HRs) and 95% confidence intervals were calculated using multivariable Cox regression. We also estimated covariate-adjusted restricted mean survival time (RMST) and survival probabilities at 5 and 10 years. Results Thyroid hormones were not associated with EOC risk (RR [95% CI] per SD increase: TSH = 0.99 [0.87 to 1.12], fT3 = 1.12 [0.70 to 1.79], and fT4 = 1.08 [0.56 to 2.07]) levels. However, higher TSH levels were associated with better survival (HR [95% CI] per SD: all-cause death = 0.90 [0.82 to 0.99], EOC-specific = 0.88 [0.79 to 0.97]), whereas higher fT4 levels were associated with worse survival (all-cause = 1.10 [1.00 to 1.22], EOC-specific = 1.17 [1.05 to 1.30]), but no association for fT3. RMST and survival probabilities showed similar patterns: for TSH, 10-year RMST and survival increased from 5.3 years and 42.2% in Quartile 1 (Q1) to 6.4 years and 50.7% in Q4. Conversely, for fT4, 10-year RMST declined from 5.6 years (Q1) to 5.1 years Q4, and survival from 46.3% to 37.8%. Conclusion TSH and thyroid hormones might not affect ovarian cancer risk. However, high fT4 and low TSH concentrations may be associated with poorer survival. Further evaluation is suggested in other populations.
A Prospective Study Consortium for the Discovery and Validation of Early Detection Markers for Ovarian Cancer – Baseline Findings for CA125
Abstract Purpose: Epithelial ovarian cancer (EOC) is a lethal malignancy. Cancer antigen 125 (CA125), the “best” available marker for detecting EOC, has insufficient sensitivity and specificity for earlier-stage disease and is not a meaningful screening tool, motivating the search for further biomarkers. Cancer biomarker discovery is enhanced by “omics” technologies. Discovery studies for EOC biomarkers should be conducted in prediagnosis blood samples from prospective cohorts to maximize the likelihood of identifying markers that can detect disease before usual diagnosis and in earlier disease stage while reducing methodologic biases. Experimental Design: Individual cohorts with prediagnosis blood samples have insufficient sample size for such studies. Thus, we established “Prospective Early Detection Consortium for Ovarian Cancer” (“PREDICT”)—a collaboration of nine prospective studies—to assemble a sufficient number of EOC cases with blood samples collected ≤18 months before diagnosis plus controls. The 457 cases and 1,687 controls have circulating CA125 measured using a clinical assay. Results: The discrimination capacity for single CA125 measurements in samples collected <6 months prior to diagnosis was high (AUC; PREDICT overall = 0.92; range across cohorts of nonpregnant individuals = 0.89–0.98) and declined with extended time between blood collection and diagnosis. Between-cohort variability in CA125 levels and predictive performance was observed. Conclusions: Ongoing investigations in PREDICT are evaluating the early detection potential of tumor-associated autoantibodies and miRNAs using CA125 as a benchmark. PREDICT is a well-characterized resource for identifying and validating detection markers for EOC that may then be used in multimodal screening as a complement to CA125 and combined with imaging.
Characterization of ovarian cancer survival by histotype and stage: A nationwide study in Norway
AbstractContemporary population‐based data on ovarian cancer survival using current subtype classifications and by surgical status are sparse. We evaluated 1‐, 3‐, 5‐ and 7‐year relative (and overall) survival, and excess hazards in patients with borderline tumors or invasive epithelial ovarian cancer diagnosed 2012 to 2021 in a nationwide registry‐based cohort in Norway. Outcomes were evaluated by histotype, FIGO stage, cytoreduction surgery and residual disease. Overall survival was evaluated for non‐epithelial ovarian cancer. Survival of women with borderline ovarian tumors was excellent (≥98.0% 7‐year relative survival). Across all evaluated invasive epithelial ovarian cancer histotypes, 7‐year relative survival for cases diagnosed with stages I or II disease was ≥78.3% (stage II high‐grade serous). Survival for ovarian cancers diagnosed at stage ≥III differed substantially by histotype and time since diagnosis (eg, stage III, 5‐year relative survival from 27.7% [carcinosarcomas] to 76.2% [endometrioid]). Overall survival for non‐epithelial cases was good (91.8% 5‐year overall survival). Women diagnosed with stage III or IV invasive epithelial ovarian cancer and with residual disease following cytoreduction surgery had substantially better survival than women not operated. These findings were robust to restriction to women with high reported functional status scores. Patterns for overall survival were similar to those for relative survival. We observed relatively good survival with early stage at diagnosis even for the high grade serous histotype. Survival for patients diagnosed at stage ≥III invasive epithelial ovarian cancer was poor for all but endometrioid disease. There remains an urgent need for strategies for risk reduction and earlier detection, together with effective targeted treatments.
Sexually Transmitted Infections and Risk of Epithelial Ovarian Cancer: Results From the Finnish Maternity Cohort
Abstract Background Sexually transmitted infections, specifically Chlamydia trachomatis (CT), may be associated with epithelial ovarian cancer (EOC) risk. The association between CT and EOC subtypes is unclear. Our aim was to investigate whether history of CT and other infections (Mycoplasma genitalium [MG], herpes simplex virus type 2 [HSV-2], and human papillomavirus [HPV]) are associated with EOC risk by histotype. Methods We measured antibodies (Abs) to CT, MG, HSV-2, and HPV-16/18 in serum samples in a nested case-control study in the Finnish Maternity Cohort (N = 484 cases 1:1 matched to controls). Logistic regression was used to calculate relative risks (RRs) and 95% confidence intervals (CIs) in seropositive versus seronegative individuals in all cases, as well as serous (n = 249), clear cell and endometrioid (n = 91), and mucinous (n = 144) EOC. Results CT seropositivity was not associated with EOC risk (eg, CT pGP3-Ab: RR, 0.92 [95% CI, .72–1.19]), regardless of disease subtype. We observed a positive association between MG seropositivity and mucinous EOC (RR, 1.66 [95% CI, 1.09–2.54]; P for heterogeneity by histotype ≤ .001), but not other subtypes. No associations were observed with seropositivity to multiple STIs. Conclusions CT infection was not associated with EOC risk, with associations observed only for MG and mucinous EOC. Mechanisms linking MG to mucinous EOC remain to be elucidated.
Ovarian Cancer Risk Factor Associations by Primary Anatomic Site: The Ovarian Cancer Cohort Consortium
Abstract Background: Epithelial ovarian, fallopian tube, and primary peritoneal cancers have shared developmental pathways. Few studies have prospectively examined heterogeneity in risk factor associations across these three anatomic sites. Methods: We identified 3,738 ovarian, 337 peritoneal, and 176 fallopian tube incident cancer cases in 891,731 women from 15 prospective cohorts in the Ovarian Cancer Cohort Consortium. Associations between 18 putative risk factors and risk of ovarian, peritoneal, and fallopian tube cancer, overall and for serous and high-grade serous tumors, were evaluated using competing risks Cox proportional hazards regression. Heterogeneity was assessed by likelihood ratio tests. Results: Most associations did not vary by tumor site (Phet ≥ 0.05). Associations between first pregnancy (Phet = 0.04), tubal ligation (Phet = 0.01), and early-adult (age 18–21 years) body mass index (BMI; Phet = 0.02) and risk differed between ovarian and peritoneal cancers. The association between early-adult BMI and risk further differed between peritoneal and fallopian tube cancer (Phet = 0.03). First pregnancy and tubal ligation were inversely associated with ovarian, but not peritoneal, cancer. Higher early-adult BMI was associated with higher risk of peritoneal, but not ovarian or fallopian tube, cancer. Patterns were generally similar when restricted to serous and high-grade serous cases. Conclusions: Ovarian, fallopian tube, and primary peritoneal cancers appear to have both shared and distinct etiologic pathways, although most risk factors appear to have similar associations by anatomic site. Impact: Further studies on the mechanisms underlying the differences in risk profiles may provide insights regarding the developmental origins of tumors arising in the peritoneal cavity and inform prevention efforts.
Dietary and Circulating Fatty Acids and Ovarian Cancer Risk in the European Prospective Investigation into Cancer and Nutrition
AbstractBackground:Fatty acids impact obesity, estrogens, and inflammation, which are risk factors for ovarian cancer. Few epidemiologic studies have investigated the association of fatty acids with ovarian cancer.Methods:Within the European Prospective Investigation into Cancer and Nutrition (EPIC), 1,486 incident ovarian cancer cases were identified. Cox proportional hazard models with adjustment for ovarian cancer risk factors were used to estimate HRs of ovarian cancer across quintiles of intake of fatty acids. False discovery rate was computed to control for multiple testing. Multivariable conditional logistic regression models were used to estimate ORs of ovarian cancer across tertiles of plasma fatty acids among 633 cases and two matched controls in a nested case–control analysis.Results:A positive association was found between ovarian cancer and intake of industrial trans elaidic acid [HR comparing fifth with first quintileQ5-Q1 = 1.29; 95% confidence interval (CI) = 1.03–1.62; Ptrend = 0.02, q-value = 0.06]. Dietary intakes of n-6 linoleic acid (HRQ5-Q1 = 1.10; 95% CI = 1.01–1.21; Ptrend = 0.03) and n-3 α-linolenic acid (HRQ5-Q1 = 1.18; 95% CI = 1.05–1.34; Ptrend = 0.007) from deep-frying fats were also positively associated with ovarian cancer. Suggestive associations were reported for circulating elaidic (OR comparing third with first tertileT3-T1 = 1.39; 95% CI = 0.99–1.94; Ptrend = 0.06) and α-linolenic acids (ORT3-T1 = 1.30; 95% CI = 0.98–1.72; Ptrend = 0.06).Conclusions:Our results suggest that higher intakes and circulating levels of industrial trans elaidic acid, and higher intakes of linoleic acid and α-linolenic acid from deep-frying fat, may be associated with greater risk of ovarian cancer.Impact:If causal, eliminating industrial trans-fatty acids could offer a straightforward public health action for reducing ovarian cancer risk.
Development and Validation of the Gene Expression Predictor of High-grade Serous Ovarian Carcinoma Molecular SubTYPE (PrOTYPE)
Abstract Purpose: Gene expression–based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features. Experimental Design: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting. Results: Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations. Conclusions: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications. See related commentary by McMullen et al., p. 5271
Serologic markers of Chlamydia trachomatis and other sexually transmitted infections and subsequent ovarian cancer risk: Results from the EPIC cohort
AbstractA substantial proportion of epithelial ovarian cancer (EOC) arises in the fallopian tube and other epithelia of the upper genital tract; these epithelia may incur damage and neoplastic transformation after sexually transmitted infections (STI) and pelvic inflammatory disease. We investigated the hypothesis that past STI infection, particularly Chlamydia trachomatis, is associated with higher EOC risk in a nested case‐control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort including 791 cases and 1669 matched controls. Serum antibodies against C. trachomatis, Mycoplasma genitalium, herpes simplex virus type 2 (HSV‐2) and human papillomavirus (HPV) 16, 18 and 45 were assessed using multiplex fluorescent bead‐based serology. Conditional logistic regression was used to estimate relative risks (RR) and 95% confidence intervals (CI) comparing women with positive vs. negative serology. A total of 40% of the study population was seropositive to at least one STI. Positive serology to C. trachomatis Pgp3 antibodies was not associated with EOC risk overall, but with higher risk of the mucinous histotype (RR = 2.30 [95% CI = 1.22‐4.32]). Positive serology for chlamydia heat shock protein 60 (cHSP60‐1) was associated with higher risk of EOC overall (1.36 [1.13‐1.64]) and with the serous subtype (1.44 [1.12‐1.85]). None of the other evaluated STIs were associated with EOC risk overall; however, HSV‐2 was associated with higher risk of endometrioid EOC (2.35 [1.24‐4.43]). The findings of our study suggest a potential role of C. trachomatis in the carcinogenesis of serous and mucinous EOC, while HSV‐2 might promote the development of endometrioid disease.
The Risk of Ovarian Cancer Increases with an Increase in the Lifetime Number of Ovulatory Cycles: An Analysis from the Ovarian Cancer Cohort Consortium (OC3)
Abstract Repeated exposure to the acute proinflammatory environment that follows ovulation at the ovarian surface and distal fallopian tube over a woman's reproductive years may increase ovarian cancer risk. To address this, analyses included individual-level data from 558,709 naturally menopausal women across 20 prospective cohorts, among whom 3,246 developed invasive epithelial ovarian cancer (2,045 serous, 319 endometrioid, 184 mucinous, 121 clear cell, 577 other/unknown). Cox models were used to estimate multivariable-adjusted HRs between lifetime ovulatory cycles (LOC) and its components and ovarian cancer risk overall and by histotype. Women in the 90th percentile of LOC (>514 cycles) were almost twice as likely to be diagnosed with ovarian cancer than women in the 10th percentile (<294) [HR (95% confidence interval): 1.92 (1.60–2.30)]. Risk increased 14% per 5-year increase in LOC (60 cycles) [(1.10–1.17)]; this association remained after adjustment for LOC components: number of pregnancies and oral contraceptive use [1.08 (1.04–1.12)]. The association varied by histotype, with increased risk of serous [1.13 (1.09–1.17)], endometrioid [1.20 (1.10–1.32)], and clear cell [1.37 (1.18–1.58)], but not mucinous [0.99 (0.88–1.10), P-heterogeneity = 0.01] tumors. Heterogeneity across histotypes was reduced [P-heterogeneity = 0.15] with adjustment for LOC components [1.08 serous, 1.11 endometrioid, 1.26 clear cell, 0.94 mucinous]. Although the 10-year absolute risk of ovarian cancer is small, it roughly doubles as the number of LOC rises from approximately 300 to 500. The consistency and linearity of effects strongly support the hypothesis that each ovulation leads to small increases in the risk of most ovarian cancers, a risk that cumulates through life, suggesting this as an important area for identifying intervention strategies. Significance: Although ovarian cancer is rare, risk of most ovarian cancers doubles as the number of lifetime ovulatory cycles increases from approximately 300 to 500. Thus, identifying an important area for cancer prevention research.
High Prediagnosis Inflammation-Related Risk Score Associated with Decreased Ovarian Cancer Survival
Abstract Background: There is suggestive evidence that inflammation is related to ovarian cancer survival. However, more research is needed to identify inflammation-related factors that are associated with ovarian cancer survival and to determine their combined effects. Methods: This analysis used pooled data on 8,147 women with invasive epithelial ovarian cancer from the Ovarian Cancer Association Consortium. The prediagnosis inflammation-related exposures of interest included alcohol use; aspirin use; other nonsteroidal anti-inflammatory drug use; body mass index; environmental tobacco smoke exposure; history of pelvic inflammatory disease, polycystic ovarian syndrome, and endometriosis; menopausal hormone therapy use; physical inactivity; smoking status; and talc use. Using Cox proportional hazards models, the relationship between each exposure and survival was assessed in 50% of the data. A weighted inflammation-related risk score (IRRS) was developed, and its association with survival was assessed using Cox proportional hazards models in the remaining 50% of the data. Results: There was a statistically significant trend of increasing risk of death per quartile of the IRRS [HR = 1.09; 95% confidence interval (CI), 1.03–1.14]. Women in the upper quartile of the IRRS had a 31% higher death rate compared with the lowest quartile (95% CI, 1.11–1.54). Conclusions: A higher prediagnosis IRRS was associated with an increased mortality risk after an ovarian cancer diagnosis. Further investigation is warranted to evaluate whether postdiagnosis exposures are also associated with survival. Impact: Given that pre- and postdiagnosis exposures are often correlated and many are modifiable, our study results can ultimately motivate the development of behavioral recommendations to enhance survival among patients with ovarian cancer.
Modification of the Association Between Frequent Aspirin Use and Ovarian Cancer Risk: A Meta-Analysis Using Individual-Level Data From Two Ovarian Cancer Consortia
PURPOSE Frequent aspirin use has been associated with reduced ovarian cancer risk, but no study has comprehensively assessed for effect modification. We leveraged harmonized, individual-level data from 17 studies to examine the association between frequent aspirin use and ovarian cancer risk, overall and across subgroups of women with other ovarian cancer risk factors. METHODS Nine cohort studies from the Ovarian Cancer Cohort Consortium (n = 2,600 cases) and eight case-control studies from the Ovarian Cancer Association Consortium (n = 5,726 cases) were included. We used Cox regression and logistic regression to assess study-specific associations between frequent aspirin use (≥ 6 days/week) and ovarian cancer risk and combined study-specific estimates using random-effects meta-analysis. We conducted analyses within subgroups defined by individual ovarian cancer risk factors (endometriosis, obesity, family history of breast/ovarian cancer, nulliparity, oral contraceptive use, and tubal ligation) and by number of risk factors (0, 1, and ≥ 2). RESULTS Overall, frequent aspirin use was associated with a 13% reduction in ovarian cancer risk (95% CI, 6 to 20), with no significant heterogeneity by study design ( P = .48) or histotype ( P = .60). Although no association was observed among women with endometriosis, consistent risk reductions were observed among all other subgroups defined by ovarian cancer risk factors (relative risks ranging from 0.79 to 0.93, all P-heterogeneity > .05), including women with ≥ 2 risk factors (relative risk, 0.81; 95% CI, 0.73 to 0.90). CONCLUSION This study, the largest to-date on aspirin use and ovarian cancer, provides evidence that frequent aspirin use is associated with lower ovarian cancer risk regardless of the presence of most other ovarian cancer risk factors. Risk reductions were also observed among women with multiple risk factors, providing proof of principle that chemoprevention programs with frequent aspirin use could target higher-risk subgroups.
Concurrent RB1 Loss and BRCA Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma
Abstract Purpose: The purpose of this study was to evaluate RB1 expression and survival across ovarian carcinoma histotypes and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC). Experimental Design: RB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7,436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1,134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes, and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 patients with primary HGSC to characterize tumors with concurrent BRCA deficiency and RB1 loss. Results: RB1 loss was associated with longer OS in HGSC but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared with patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA deficiency correlated with transcriptional markers of enhanced IFN response, cell-cycle deregulation, and reduced epithelial–mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1. Conclusions: Co-occurrence of RB1 loss and BRCA deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.
Ovarian cancer survival in Germany: a nationwide analysis by stage and histotype
Previous population-based studies on ovarian cancer survival have evaluated less granular disease staging categories and histologic sub-types than are in current use, and there is a need to assess survival in the context of more contemporary treatment practices and histotype classifications. Using flexible parametric models, we assessed the 1-, 3-, 5-, and 10-year net survival and excess mortality hazards of 54,267 incident invasive ovarian cancer cases by stage and histology and 9478 borderline cases diagnosed between January 1, 2010 and December 31, 2021 recorded in Germany. Net survival differed markedly by stage, with consistently favorable long-term survival for early-stage (I to II) and poor outcomes for advanced-stage (III to IV) disease across histotypes. Although most stage I tumors showed high 10-year net survival (≥ 77%), carcinosarcomas represented a notable exception. Net survival declined with advancing stage, with 10-year estimates ranging from 46% to 76% for stage II, 18% to 55% for stage III, and poor 5-year survival for stage IV tumors (15% to 41%). Considering patterns by time since diagnosis, the excess mortality hazard was the highest across all histotype-stage groups during the first 3 years with variability suggestive of histotype-specific treatment resistance and disease recurrence. The influence of stage decreased over the follow-up, with the largest impact mostly observed during the first year after diagnosis. Net survival for borderline tumors was high (10-year survival = 92.9%). Net survival was favorable for patients with early-stage disease. Variability was observed across histotypes by stage. The early post-diagnosis period is a critical window for excess mortality, and the development of histotype-specific treatments is needed.
