Tianyi Wang

Lifetime Exposure to Cigarette Smoke, B-Cell Tumor Immune Infiltration, and Immunoglobulin Abundance in Ovarian Tumors

Abstract Background: Cigarette smoke exposure has been linked to systemic immune dysfunction, including for B-cell and immunoglobulin (Ig) production, and poor outcomes in patients with ovarian cancer. No study has evaluated the impact of smoke exposure across the life-course on B-cell infiltration and Ig abundance in ovarian tumors. Methods: We measured markers of B and plasma cells and Ig isotypes using multiplex immunofluorescence on 395 ovarian cancer tumors in the Nurses’ Health Study (NHS)/NHSII. We conducted beta-binomial analyses evaluating odds ratios (OR) and 95% confidence intervals (CI) for positivity of immune markers by cigarette exposure among cases and Cox proportional hazards models to evaluate hazard ratios (HR) and 95% CI for developing tumors with low (<median) or high (≥median) immune cell/Ig percentage. Results: There were no associations between smoke exposure and B-cell or IgM infiltration in ovarian tumors. Among cases, we observed higher odds of IgA+ among ever smokers (OR, 1.54; 95% CI, 1.14–2.07) and ever smokers with no parental smoke exposure (OR, 2.03; 95% CI, 1.18–3.49) versus never smokers. Women with parental cigarette smoke exposure versus not had higher risk of developing ovarian cancer with low IgG+ (HR, 1.51; 95% CI, 1.10–2.09), whereas ever versus never smokers had a lower risk (HR, 0.74; 95% CI, 0.56–0.99). Conclusions: Ever smoking was associated with increased odds of IgA in ovarian tumors. Impact: IgA has been associated with improved ovarian cancer outcomes, suggesting that although smoking is associated with poor outcomes in patients with ovarian cancer, it may lead to improved tumor immunogenicity.

Associations between prediagnostic aspirin use and ovarian tumor gene expression

AbstractBackgroundAspirin use has been associated with reduced ovarian cancer risk, yet the underlying biological mechanisms are not fully understood. To gain mechanistic insights, we assessed the association between prediagnosis low and regular‐dose aspirin use and gene expression profiles in ovarian tumors.MethodsRNA sequencing was performed on high‐grade serous, poorly differentiated, and high‐grade endometrioid ovarian cancer tumors from the Nurses' Health Study (NHS), NHSII, and New England Case–Control Study (n = 92 cases for low, 153 cases for regular‐dose aspirin). Linear regression identified differentially expressed genes associated with aspirin use, adjusted for birth decade and cohort. False discovery rates (FDR) were used to account for multiple testing and gene set enrichment analysis was used to identify biological pathways.ResultsNo individual genes were significantly differentially expressed in ovarian tumors in low or regular‐dose aspirin users accounting for multiple comparisons. However, current versus never use of low‐dose aspirin was associated with upregulation of immune pathways (e.g., allograft rejection, FDR = 5.8 × 10−10; interferon‐gamma response, FDR = 2.0 × 10−4) and downregulation of estrogen response pathways (e.g., estrogen response late, FDR = 4.9 × 10−8). Ovarian tumors from current regular aspirin users versus never users were also associated with upregulation in interferon pathways (FDR <1.5 × 10−4) and downregulation of multiple extracellular matrix (ECM) architecture pathways (e.g., ECM organization, 4.7 × 10−8).ConclusionOur results suggest low and regular‐dose aspirin may impair ovarian tumorigenesis in part via enhancing adaptive immune response and decreasing metastatic potential supporting the likely differential effects on ovarian carcinogenesis and progression by dose of aspirin.

Prediagnosis and postdiagnosis smoking and survival following diagnosis with ovarian cancer

Little is known about the influence of prediagnosis and postdiagnosis smoking and smoking cessation on ovarian cancer survival. We investigated this relationship in two prospective cohort studies, the Nurses’ Health Study (NHS) and NHSII. Analyses included 1,279 women with confirmed invasive, Stage I–III epithelial ovarian cancer. We used Cox proportional hazards regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for ovarian cancer‐specific mortality by smoking status, adjusting for age and year of diagnosis, tumor stage, histologic subtype, body mass index and nonsteroidal anti‐inflammatory use (postdiagnosis models only). When examining prediagnosis smoking status (assessed a median of 12 months before diagnosis), risk of death was significantly increased for former smokers (HR = 1.19, 95% CI: 1.02–1.39), and suggestively for current smokers (HR = 1.21, 95% CI: 0.96–1.51) vs. never smokers. Longer smoking duration (≥20 years vs. never, HR = 1.23, 95% CI: 1.05–1.45) and higher pack‐years (≥20 pack‐years vs. never, HR = 1.28, 95% CI: 1.07–1.52) were also associated with worse outcome. With respect to postdiagnosis exposure, women who smoked ≥15 cigarettes per day after diagnosis (assessed a median of 11 months after diagnosis) had increased mortality compared to never smokers (HR = 2.34, 95% CI: 1.63–3.37). Those who continued smoking after diagnosis had 40% higher mortality (HR = 1.40, 95% CI: 1.05–1.87) compared to never smokers. Overall, our results suggest both prediagnosis and postdiagnosis smoking are associated with worse ovarian cancer outcomes.

Early life physical activity and risk of ovarian cancer in adulthood

AbstractEmerging data suggest that exposures in early life may affect ovarian development and contribute to ovarian cancer risk. We evaluated the association between early life physical activity and risk of ovarian cancer in adulthood in two large prospective cohorts, the Nurses' Health Study (NHS) and NHSII. In total, analyses included 28 232 NHS participants (followed from 2004 to 2016) and 56 553 NHSII participants (followed from 1997 to 2017). Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of ovarian cancer overall and by early life body mass index (BMI). Neither physical activity at ages 12‐13, 14‐17 or 18‐22 years nor average physical activity across these three periods was associated with ovarian cancer risk overall (≥78 vs <24 MET‐h/wk, HRs = 1.34, 1.21, 1.08 and 1.24, respectively), or by categories of early life BMI (Pheterogeneity ≥ .44). No association was observed with the risk of high‐grade serous or poorly differentiated tumors or postmenopausal ovarian cancer. Overall, early life physical activity was not clearly related to ovarian cancer risk during adulthood.

Prediagnosis and postdiagnosis leisure time physical activity and survival following diagnosis with ovarian cancer

AbstractLittle is known about the influence of prediagnosis and postdiagnosis physical activity on ovarian cancer survival. We investigated this association in two large cohorts, the Nurses' Health Study (NHS) and NHSII. Analyses included 1461 women with confirmed invasive, epithelial ovarian cancer and data on physical activity. Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for ovarian cancer‐specific mortality. Ovarian cancer‐specific mortality was not associated with physical activity reported 1‐8 years before diagnosis overall (≥7.5 vs <1.5 MET‐hours/week, HR = 0.96), for high‐grade serous/ poorly differentiated tumors, or non‐serous/ low‐grade serous tumors (P‐heterogeneity = .45). An inverse association was observed for activity 1‐4 years after diagnosis (≥7.5 vs <1.5 MET‐hours/week, HR = 0.67, 95%CI: 0.48‐0.94), with similar results by histotype (P‐heterogeneity = .53). Women who decreased their activity from ≥7.5 MET‐hours/week 1‐8 years before diagnosis to <7.5 MET‐hours/week 1‐4 years after diagnosis, compared to those with <7.5 MET‐hours/week across periods, had a 49% increased risk of death (HR = 1.49, 95%CI: 1.07‐2.08). Physical activity after, but not before, ovarian cancer diagnosis was associated with better prognosis.

The association of resistance training with risk of ovarian cancer

ABSTRACTBackgroundIncreasing evidence, including multiple putative inflammatory risk factors (e.g., c‐reactive protein, and adiposity), supports that inflammation plays an important role in ovarian carcinogenesis. Resistance training (RT) is associated with lower levels of circulating inflammatory markers, independent of physical activity.MethodsWe evaluated the relationship between RT and risk of ovarian cancer accounting for other physical activity (e.g., walking) in two large prospective cohorts, the Nurses’ Health Study (NHS) and NHSII.Key ResultsIn total, analyses included 42,005 NHS participants (2000–2016) and 67,289 NHSII participants (2001–2017) with RT assessed every 4 years. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of RT with ovarian cancer risk overall and by tumor subtype, adjusting for known and putative ovarian cancer risk factors. We identified a total of 609 cases over 1,748,884 person‐years. No association was observed with overall ovarian cancer risk (RT ≥60 vs 0 min/wk, HR = 0.95, 95%CI: 0.74–1.22) or by histotype (comparable HR = 0.86 and 0.98 for type I and II tumors, respectively). Results did not differ by body mass index (Pinteraction = 0.97), or other physical activity (Pinteraction = 0.31).Conclusions & InferencesWe observed no evidence that moderate levels of RT were associated with risk of ovarian cancer. Further investigations are required to confirm these findings.

Tobacco Smoking and Survival Following a Diagnosis with Ovarian Cancer

Abstract Background: Little is known about the influence of smoking on ovarian cancer survival. We investigated this relationship in a hospital-based study. Methods: Analyses included 519 women with ovarian cancer. We used multivariable adjusted Cox proportional hazards regression models to estimate HRs and 95% confidence intervals (CI). Results: Risk of all-cause mortality was increased for current smokers (HR = 1.70; 95% CI: 1.09–2.63) versus never smokers, especially for those with ≥15 cigarettes per day (HR = 1.92; 95% CI: 1.15–3.20). Results were largely similar after additional adjustment for debulking status (current vs. never smokers, HR = 2.96; 95% CI: 1.07–8.21) or neoadjuvant chemotherapy (comparable HR = 2.87; 95% CI: 1.02–8.06). Compared with never smokers, smoking duration ≥20 years (HR = 1.38; 95% CI: 0.94–2.03) and ≥20 pack-years (HR = 1.35; 95% CI: 0.92–1.99) were suggestively associated with worse outcomes. Current smoking was also positively associated with the risk of mortality among patients with ovarian cancer recurrence (current vs. never/past smokers, HR = 2.79; 95% CI: 1.44–5.41), despite the null association between smoking and recurrence (HR = 1.46; 95% CI: 0.86–2.48). Furthermore, no association was observed for smoking initiation before age 18 (HR = 1.22; 95% CI: 0.80–1.85), or either environmental smoke exposure at home (HR = 1.16; 95% CI: 0.76–1.78) or at work (HR = 1.10; 95% CI: 0.75–1.60). Conclusions: Our results suggest active tobacco smoking is associated with worse ovarian cancer outcomes, particularly after a recurrence. Impact: Our findings support structured smoking cessation programs for patients with ovarian cancer, especially in recurrent settings. Further research to confirm these findings and examine the interplay between smoking and the tumor immune microenvironment may help provide insight into ovarian cancer etiology.