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Purpose of Review This review focuses on describing the mechanisms and clinical manifestations that underlie accelerated aging associated with cancer and its treatment. Recent Findings The direct and indirect effects of cancer and its treatment are associated with late occurrence of comorbidities that happen earlier or more frequently in cancer survivors compared to cancer-free individuals, otherwise known as accelerated aging. Use of senolytics and dietary and exercise interventions including prehabilitation, caloric restriction, and rehabilitation are currently under investigation to reverse or decelerate the aging process and will be covered in this review. Summary Further research on how to decelerate or reverse aging changes associated with cancer and its treatment will be of paramount importance as the number of cancer survivors continues to grow.

The androgen receptor (AR) signaling pathway regulates the progression of prostate cancer (PC). Metastatic castration-resistant prostate cancer (mCRPC) patients generally receive AR-targeted therapies (ART) or androgen-deprivation therapies (ADT) with the initial response; however, resistance is inevitably observed. Prior studies have shown activity and upregulation of a family of androgen production, uptake, and conversion – APUC genes – based on genomic analyses of patient germlines. Genetic variants of some APUC genes, such as the conversion gene, HSD3B1, predict response to second-generation androgen-targeted therapies. Studies have begun to elucidate the overall role of APUC genes, each with unique actionable enzymatic activity, in mCRPC patient outcomes. The current role and knowledge of the genetic and genomic features of APUC genes in advanced prostate cancer and beyond are discussed in this review. These studies inform of how interpreting behavior of APUC genes through genomic tools will impact the treatment of advanced prostate cancer.

BACKGROUND: Limited data from prospective studies suggest that higher dietary intake of long-chain omega-3 polyunsaturated fatty acids (LCn3PUFA), which hold anti-inflammatory properties, may reduce endometrial cancer risk; particularly among certain subgroups characterized by body mass and tumor pathology.MATERIALS AND METHODS: Data from 12 prospective cohort studies participating in the Epidemiology of Endometrial Cancer Consortium were harmonized as nested case-control studies, including 7268 endometrial cancer cases and 26,133 controls. Habitual diet was assessed by food frequency questionnaire, from which fatty acid intakes were estimated. Two-stage individual-participant data mixed effects meta-analysis estimated adjusted odds ratios (OR) and 95% confidence intervals (CI) through logistic regression for associations between study-specific energy-adjusted quartiles of LCn3PUFA and endometrial cancer risk.RESULTS: Women with the highest versus lowest estimated dietary intakes of docosahexaenoic acid, the most abundant LCn3PUFA in diet, had a 9% increased endometrial cancer risk (Quartile 4 vs. Quartile 1: OR 1.09, 95% CI: 1.01-1.19; P trend = 0.04). Similar elevated risks were observed for the summary measure of total LCn3PUFA (OR 1.07, 95% CI: 0.99-1.16; P trend = 0.06). Stratified by body mass index, higher intakes of LCn3PUFA were associated with 12-19% increased endometrial cancer risk among overweight/obese women and no increased risk among normal-weight women. Higher associations appeared restricted to White women. The results did not differ by cancer grade.CONCLUSION: Higher dietary intakes of LCn3PUFA are unlikely to reduce endometrial cancer incidence; rather, they may be associated with small to moderate increases in risk in some subgroups of women, particularly overweight/obese women.

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.

Disinfection byproducts (DBPs) andWe investigated the relationship of these exposures with endometrial cancer risk in a large prospective cohort.Among postmenopausal women in the Iowa Women's Health Study cohort, we evaluated two major classes of DBPs, total trihalomethanes (TTHM) and five haloacetic acids (HAA5), and nitrate-nitrogen (Higher average concentrations of DBPs (95th percentile: TTHMWe report novel associations between the highest DBP levels and endometrial cancer for our Iowa cohort that warrant future evaluation. https://doi.org/10.1289/EHP10207.

More than 80% of adult patients diagnosed with cancer survive long term. Long-term complications of cancer and its therapies may increase the risk of cardiovascular disease (CVD), but prospective studies using adjudicated cancer and CVD events are lacking.The aim of this study was to assess the risk of CVD in cancer survivors in a prospective community-based study.We included 12,414 ARIC (Atherosclerosis Risk In Communities) study participants. Cancer diagnoses were ascertained via linkage with state registries supplemented with medical records. Incident CVD outcomes were coronary heart disease (CHD), heart failure (HF), stroke, and a composite of these. We used multivariable Poisson and Cox regressions to estimate the association of cancer with incident CVD.Mean age was 54 years, 55% were female, and 25% were Black. A total of 3,250 participants (25%) had incident cancer over a median 13.6 years of follow-up. Age-adjusted incidence rates of CVD (per 1,000 person-years) were 23.1 (95% CI: 24.7-29.1) for cancer survivors and 12.0 (95% CI: 11.5-12.4) for subjects without cancer. After adjustment for cardiovascular risk factors, cancer survivors had significantly higher risks of CVD (HR: 1.37; 95% CI: 1.26-1.50), HF (HR: 1.52; 95% CI: 1.38-1.68), and stroke (HR: 1.22; 95% CI: 1.03-1.44), but not CHD (HR: 1.11; 95% CI: 0.97-1.28). Breast, lung, colorectal, and hematologic/lymphatic cancers, but not prostate cancer, were significantly associated with CVD risk.Compared with persons without cancer, adult cancer survivors have significantly higher risk of CVD, especially HF, independent of traditional cardiovascular risk factors. There is an unmet need to define strategies for CVD prevention in this high-risk population.

Background: Longer lifespan and improved cancer treatment led to a rapid rise in the number of cancer survivors. However, many cancer survivors have physiological dysregulations at earlier chronological ages than those without cancer, suggesting that cancer survivors’ biological age is higher than their chronological age, i.e., they have accelerated aging. Cancer survivors’ biological age may be estimated by a novel proteomic aging clock (PAC). The deviation of PAC from chronological age is called proteomic age acceleration (PAA). To our knowledge, no studies examined whether PAA in cancer survivors is associated with increased all-cause mortality. We studied PAAs of two PACs – a newly created clock in ARIC (so called, “new” PAC) and the published 491-protein clock by Lehallier [2020] in relation to all-cause mortality in cancer survivors. Methods: ARIC is a prospective cohort of White and Black women and men, followed in 1987-2019. In 2011-13 (Visit 5), 5000 plasma proteins were measured using SomaScan, an aptamer-based assay. Using elastic net regression (alpha=0.5), we constructed a new PAC in a training set of two-thirds randomly selected cancer-free participants (N = 2466). This clock included 619 proteins and was internally validated in the remaining 1233 cancer-free participants (test set). We also computed Lehallier’s PAC using weights estimated in ARIC. We calculated PAA as residuals after regressing PAC on chronological age. We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality per 1 standard deviation (SD, ~2.6 yrs for PAAs for both PACs) increase in PAA in 806 survivors of all cancer at Visit 5, and survivors of breast, prostate, and colorectal cancer. HRs were adjusted for chronological age, sex, race, center, education, BMI, smoking status, alcohol intake, eGFR, physical activity, time since cancer diagnosis, diabetes, and aspirin use. Results: 272 deaths were identified in 4963 person-yrs (median follow-up=6.98 yrs). In the test set, both PACs were correlated with chronological age [Pearson correlation coefficient (r): new PAC=0.75; Lehallier’s PAC=0.70] and with each other [r=0.89]. For both PACs, those with higher PAA tended to be White and have lower physical activity and a lower eGFR. Both PAAs were significantly associated with all-cause mortality in cancer survivors [per 1 SD: HR (95% CI): new PAC=1.42 (1.24-1.62); Lehallier’s PAC=1.40 (1.22-1.61)]. The HRs were not modified by sex or race. Both PAAs were significantly associated with all-cause mortality in 169 breast cancer survivors [HR: new PAC=1.54 (1.05-2.25); Lehallier’s PAC=1.72 (1.13-2.64)]. PAA of the new PAC was also associated with all-cause mortality in 78 colorectal cancer survivors [HR=1.96 (1.19-3.22)]. PAA for each PAC was not associated with all-cause mortality in 255 prostate cancer survivors. Conclusion: Proteomic aging clocks hold the promise as a potential biomarker for premature mortality in cancer survivors. Funding: NHLBI, NCI, NPCR Citation Format: Shuo Wang, Anne H. Blaes, Josef Coresh, Corinne E. Joshu, James S. Pankow, Bharat Thyagarajan, Elizabeth A. Platz, Weihua Guan, Anna Prizment. Proteomic age acceleration associated with all-cause mortality in cancer survivors in the Atherosclerosis Risk in Communities (ARIC) Study. [R] [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A022.

Background: Individuals of the same chronological age may have a different pace of physiological dysregulation, so chronological age is not a perfect measure of the aging process. A measure of physiological aging – aging clock – has been proposed, including a novel proteomic aging clock (PAC). The deviation of PAC from chronological age is called proteomic age acceleration. PACs have been linked to age-related diseases, but, to our knowledge, no studies tested their association with cancer risk. We examined the associations of proteomic age acceleration for two PACs – a newly created PAC in ARIC (so called, “new” PAC) and the published 491-protein PAC by Lehallier et al [2020]) with cancer risk in the ARIC study. Methods: ARIC is a prospective cohort of White and Black women and men initiated in 1987, followed for cancer until 2015 (median follow-up=17.89 yrs). At Visit 2 (1990-92), about 5000 plasma proteins were measured in 10834 participants: 3347 who developed cancer during follow-up and 7487 who stayed cancer-free, using an aptamer-based assay SomaScan. Using elastic net regression (alpha=0.5), we constructed a new PAC in the training set of two-thirds randomly selected cancer-free participants. This PAC included 1282 proteins and was internally validated in the remaining one-third cancer-free participants (test set). We also constructed Lehallier’s PAC using weights estimated in ARIC. We calculated proteomic age acceleration as residuals after regressing PAC on chronological age. We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for overall cancer risk per 1 standard deviation (SD, ~2.7 yrs for age acceleration for both PACs) increase in age acceleration in participants after excluding the training set. HRs were adjusted for chronological age, sex, race, center, education, BMI, smoking status, alcohol intake, eGFR, diabetes, and aspirin use. We also estimated HRs for the most common cancers (breast, prostate, colorectal, and lung cancer). Results: In the test set, both PACs were correlated with chronological age [Pearson correlation coefficient (r): new PAC=0.82; Lehallier’s PAC=0.76] and with each other [r=0.90]. For both PACs, those with higher age acceleration were more likely to be White, aspirin users, and have diabetes and a lower eGFR. Age acceleration of the new PAC was significantly associated with overall cancer risk [per 1 SD: HR (95% CI)=1.04 (1.00-1.08)] but not Lehallier’s PAC. This association was not modified by sex, race, or smoking status. Age acceleration for both PACs were associated with lung cancer risk [HRs: new PAC=1.23 (1.12-1.36); Lehallier’s PAC=1.20 (1.09-1.32)] and remained among never smokers [HRs=1.40-1.42]. Age acceleration of the new PAC was also associated with colorectal cancer risk [HR=1.15 (1.02-1.30)]. Neither of age accelerations was associated with breast or prostate cancer risk. Conclusion: PAC holds promise as a potential biomarker for cancer risk. Funding: NHLBI, NCI, NPCR Citation Format: Shuo Wang, Anne H. Blaes, Josef Coresh, Corinne E. Joshu, James S. Pankow, Bharat Thyagarajan, Elizabeth A. Platz, Weihua Guan, Anna Prizment. Proteomic age acceleration associated with cancer risk in the Atherosclerosis Risk in Communities (ARIC) study. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P029.

Background and purpose: The cystic fibrosis transmembrane conductance regulator (CFTR) gene is a tumor suppressor in colorectal cancer (CRC). People with cystic fibrosis, caused by biallelic germline mutations in CFTR, have a higher risk developing CRC. We also found that loss of CFTR is implicated in sporadic CRC. In a study of 90 persons diagnosed with stage II CRC, the 23% of patients with lowest CFTR expression had 30% lower disease-free survival at 3 years. The cause of decreased CFTR expression in this group is not known. We analyzed the TCGA COADREAD study to identify associations between low expression of CFTR and cancer-causing genetic alterations. Of these alterations, only BRAF-V600E mutation correlated with low expression of CFTR. The BRAF-V600E mutation is found in ~10% of CRC and is associated with global promoter hypermethylation leading to down regulation of tumor suppressor genes. Accordingly, our hypothesis was that BRAF-V600E mutation contributes to low expression of CFTR via CFTR promoter DNA methylation. Methods: In the TCGA COADREAD database 283 primary colorectal cancers diagnosed at stages II, III and IV had full information needed for this study: CFTR mRNA expression, somatic mutation, overall survival (OS), and DNA methylation status. OS was visualized using Kaplan-Meier analysis. Association between CFTR expression and methylation was determined by Pearson correlation coefficient (PCC) analysis. Associations between mutations and CFTR expression or methylation were determined by Point Biserial correlation coefficient (PBS) analysis. Results: Kaplan-Meier analysis of the 283 cases showed that overall survival was worse in the 25% of cases with lowest CFTR expression (p=0.035). The BRAF-V600E mutation was significantly associated with lower CFTR expression (PBS r=-0.38, p Citation Format: Patricia Scott, Anna Prizment, Rahul Bhattacharya, Zachary Blankenheim, Nathan Pankratz, Timothy Starr, Robert Cormier. The oncogenic mutation BRAF-V600E is associated with colorectal cancers expressing low levels of CFTR mRNA [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr A027.