As technological and genomic innovations continue to advance precision cancer prevention, psychosocial, ethical, and operational complexities increasingly accompany their development. Addressing these challenges will require intentional cross-disciplinary collaboration. We argue that the distinct yet complementary lenses of bioethics and implementation science will be crucial as precision cancer prevention technologies move toward clinical integration. We provide a framework for how this joint effort can be accomplished and sustained across the translational pipeline.
Non-invasive stool-based colorectal cancer (CRC) screening (e.g., fecal immunochemical test [FIT], guaiac fecal occult blood test [gFOBT], multitarget stool DNA [mt-sDNA]) reduces CRC mortality only when a positive result is followed by timely diagnostic colonoscopy. We synthesized barriers and facilitators to completing diagnostic colonoscopy after a positive stool-based screening test. Guided by Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR), we searched PubMed and MEDLINE (Ovid) for English-language, peer-reviewed studies (October 2008- June 2025) reporting barriers, facilitators, or determinants of colonoscopy completion after a positive non-invasive stool-based CRC screening test (FIT, gFOBT, or mt-sDNA). Two reviewers independently abstracted study characteristics and coded barriers/facilitators, which were categorized using a socioecological framework (intrapersonal, interpersonal, organizational, community/environmental, policy). 38 studies directly examined colonoscopy follow-up after a positive non-invasive test. Recurrent barriers included fear/anxiety and low perceived risk (intrapersonal), weak provider recommendation and support (interpersonal), referral and tracking failures and scheduling delays (organizational), transportation and distance (community/environmental), and cost-sharing/coverage gaps (policy). Evidence specifically assessing rural-urban differences was limited. Barriers to diagnostic colonoscopy after a positive stool-based CRC screening test are multi-level and potentially modifiable through improved communication, navigation, and closed-loop tracking. Multicomponent approaches that combine clear communication, navigation and reminder systems, transportation supports, and reduced financial barriers may improve diagnostic completion and equity.
Individuals with rheumatoid arthritis (RA), particularly those with a history of smoking, are at increased risk for lung cancer. However, real-world data on the use of low dose computed tomography (LDCT) screening for lung cancer in this population are lacking. Therefore, we assessed the rates, trends, and predictors of LDCT screening among patients with a smoking history and RA. A retrospective cohort study using the IQVIA PharMetrics® Plus for Academics Closed Health Plan claims database was conducted. Patients with RA diagnosed in 2014-2023, aged 50-77 years, and with a history of smoking and no prior cancer or advanced respiratory illness were identified. LDCT screening was identified using Healthcare Common Procedure Coding System codes. Among 15,341 eligible patients, 997 (6.5%) received LDCT screening; median time from RA diagnosis to first LDCT claim was 452 days. In a sensitivity analysis of 12,301 patients with continuous insurance coverage during the 12 months after RA diagnosis, only 367 (3%) underwent LDCT within the first year after RA diagnosis. Demographic factors such as male sex (aOR=1.24; p=0.003), age 55-69 (aOR=~1.90; p<0.0001), and residence outside the West region (p<0.0001) increased uptake. Clinical characteristics and healthcare utilization such as COPD (aOR=2.85; p<0.0001), more outpatient visits (aOR=2.15-2.41; p< 0.001) and DMARD use (aOR=1.27-1.52; p≤ 0.001) also increased odds, whereas greater comorbidity burden reduced screening (aOR=0.79-0.39; p≤0.006). In conclusion, LDCT rates in patients with RA remained low overall and varied according to demographic and clinical factors. Targeted efforts may be needed to improve screening uptake in this high-risk population.
Colorectal cancer (CRC) develops predominantly through the adenoma-to-carcinoma sequence with immunological processes playing a central yet incompletely understood role in this progression. A systematic review was conducted of published academic literature using Medline, Embase, and Cochrane Library databases to identify studies which examined immune cell infiltration, cytokine profiling, and immune surveillance in colorectal pre-cancers. Studies published between October 1974 and July 2021 were included. Adaptive immune cells demonstrate dynamic infiltration patterns at various points along the adenoma-carcinoma sequence, with certain subsets of these lymphocytes facilitating tumor progression through immunosuppression while others confer protection. In contrast, innate immune cells demonstrate context-dependent roles in which pre-cancers may or may not develop into malignancies. Cytokine networks, particularly IL-6, IL-8, and IL-17, further modulate the tumor microenvironment. The immunological landscape of colorectal pre-cancers is complex, bidirectional, and non-linear in its relationships. Understanding these mechanisms provides a foundation for the development of immunologically informed prevention and early detection and intervention to mitigate CRC burden.
Limited access to healthcare due to poverty, lack of insurance, and/or excessive distance from healthcare services has been highlighted as a significant contributor to poor outcomes related to cancer incidence and cancer-related morbidity, survival, and mortality. Moreover, America's primary reliance on employer-based health insurance means that those living without employment or in poverty frequently cannot afford healthcare and therefore experience poorer health outcomes. Because cancer screening that allows for early cancer detection saves lives, it is imperative that research on how to improve and increase cancer-related screening and early detection services for the medically underserved be prioritized and acted upon by policymakers and others responsible for implementing scientific discoveries to improve cancer-related population health.
Our purpose was to better characterize the prevalence and size distributions of TP53-mutated preneoplastic colonies in relationship to risk for lung cancer (LC) and chronic obstructive pulmonary disease (COPD). Ultra-sensitive next-generation sequencing (US-NGS) was used to assess TP53-mutated preneoplastic colonies comprising as few as 100 cells in airway epithelium. Specimens from 59 subjects with heavy smoking history were assessed in four cohorts: LC with (N=14) or without COPD (N=16) and non-LC with (N=7) or without COPD (N=22). TP53-mutated preneoplastic colony prevalence was higher in LC subjects with or without COPD and in COPD subjects without LC (P<0.01). A higher prevalence of colonies driven by the subset of TP53 mutations known to be neoantigenic in cancer tissue was nominally significant (P<0.05). TP53-mutated colony distributions skewed to larger sizes among LC subjects and skewed greater among subjects with both COPD and active cigarette smoking (P<0.01), each of which is associated with adaptive immune inflammation. Thus, consistent with prior studies, TP53-mutated colony prevalence and size distribution measured in non-malignant airway epithelium improved characterization of LC and COPD risk. Further, these colonies may stimulate adaptive immune response and inflammation that is mechanistically associated with COPD. A skew to larger colonies is consistent with selection for immune surveillance avoidance characteristics and may provide a metric for both LC risk and immune surveillance function. Among healthier non-COPD smokers who are ineligible for lung cancer screening based on demographic criteria, a positive TP53 biomarker test may identify LC risk sufficiently high to warrant screening eligibility.
Early detection of cancer saves lives and reduces healthcare costs. In the U.S., adherence to cancer screening recommendations is associated with many structural and individual-level factors. People who smoke cigarettes are less likely to engage in cancer screening. E-cigarette use (vaping) has become popular in the U.S. We evaluated whether vaping is associated with cancer screening. Data from the 2023 National Health Interview Survey were used to identify adults who met criteria to receive preventative cancer screening for colorectal (N=14,561), breast (N=6,572), cervical (N=8,637), or prostate (N=3,556) cancer. Nationally representative cancer screening adherence rates were determined for each cancer site, by smoking and vaping status. Multivariable logistic regression analyses were used to examine differences in screening adherence, controlling for social determinants of health. Smoking was associated with lower cancer screening adherence across all sites (colorectal, males: AOR=0.66, 95%CI: 0.55-0.79; colorectal, females: AOR=0.60, 95%CI: 0.50-0.73; breast: AOR=0.45, 95%CI: 0.36-0.56; cervical: AOR=0.77, 95%CI: 0.64-0.93; prostate: AOR=0.56, 95%CI: 0.42-0.74). Among males who smoke, current vaping (versus never or former vaping) may signal greater engagement in colorectal and prostate cancer screening, a finding not observed among males who formerly smoked. Among females who smoke, vaping appears unrelated to engagement in breast cancer screening or cervical cancer screening. However, among females who formerly smoked, current vaping (versus never or former vaping) may signal lower engagement in breast cancer screening. Smoking remains a robust target for improving cancer screening adherence across multiple cancer sites while vaping may signal emerging differences in cancer screening adherence.
Chemoprevention for gastric cancer remains underdeveloped despite a well-defined premalignant window and a substantial burden in high-risk populations. Two phase IIa trials conducted in Puerto Rico and Honduras evaluated curcuminoids and eflornithine in patients with gastric premalignant conditions. Curcuminoids reduced IL1β, whereas eflornithine showed a possible delayed reduction in pH2AX-defined DNA damage. Both agents were generally well tolerated, although hearing-related adverse events were more frequent in eflornithine. Together, these studies support the feasibility of mechanism-based chemoprevention for gastric cancer while highlighting key challenges in patient selection, surrogate endpoint validation, long-term safety, and, critically, the demonstration of durable cancer prevention beyond short-term biomarker modulation. See related article by Morgan et al., p. 391 See related article by Gonzalez-Pons et al., p. 403.
Screening for pathogenic variants (PV) associated with hereditary cancer syndromes has a positive impact on public health by identifying patients at risk of developing the associated cancers. This survey assesses the current practice of screening for hereditary cancer syndromes and the acceptability of chatbot utilization among primary care providers and residents in rural Southwest Virginia. A two-part survey was conducted among primary care providers and residents in rural Southwest Virginia to assess demographics, health practices, genetic screening practices, and interest in chatbot technology in a geographically underserved population. The response rates for the provider and resident surveys were 8.9% and 19.9%, respectively. A total of 66 providers responded to the survey. One third (32.3%) of providers in our study never screen for hereditary cancer syndromes, and almost two thirds (63.1%) screen their patients for cancer syndromes less than half the time. About 77% of providers felt that chatbots would be useful in identifying patients who need testing and directing what testing to order. Surveys of 476 residential responders showed that 81.9% of residents felt that chatbot technology sounds somewhat to very useful for genetic screening and counseling. More than 57% of residents noted that they would feel comfortable with utilizing chatbot technology to discuss results of genetic screening. Residents and their providers in geographically underserved populations are interested in using chatbots to improve access to genetic testing. Implementation of technology, such as chatbots, in these underresourced settings has the potential to amplify access to genetic counseling and testing. PREVENTION RELEVANCE:This article describes survey results for acceptability of using chatbots for assessing risk and early detection of PVs associated with hereditary cancer syndromes in a rural population. The results could guide further implementation of technology in assisting with early detection and prevention of hereditary cancer syndromes.
Individuals with germline BRCA1 or BRCA2 pathogenic variants (PV) may struggle with risk management decision-making. Advancements in technology could provide more specific risk information to patients, but the impact of this information is unknown. The Clinical Application of Refined Risk Estimates Study is a two-arm randomized controlled trial in women with a BRCA1/BRCA2 PV. The primary objective was to determine whether genotype-informed personalized cancer risk estimates (GRE) compared with standard lifetime cancer risk estimates (SRE) decreased decisional conflict related to cancer risk management decision-making. Women were recruited following the disclosure of their PV results. Participants completed a baseline survey and were randomized 1:1 to receive a GRE or SRE. After receiving their results, participants completed a follow-up survey. Likert and continuous data measures were analyzed using linear regression. There were no differences in decisional conflict between study arms at follow-up. However, individuals in the SRE arm showed an increased need for personal structure compared with those in the GRE arm (P = 0.02). Compared with baseline, individuals within the SRE arm showed decreased decisional conflict (P = 0.003) and increased perceived stress (P = 0.02) at follow-up. A more personalized cancer risk estimate did not decrease decisional conflict in women with BRCA1/BRCA2 PVs. Future studies will determine whether a GRE affects actual decision-making behaviors. PREVENTION RELEVANCE:Women with a germline PV in BRCA1 or BRCA2 have significantly elevated risks of developing breast and ovarian cancers. This randomized controlled trial evaluates the impact of polygenic risk scores on decisional conflict related to breast and ovarian cancer prevention and risk management in those with BRCA1/BRCA2 PVs.
Abstract Hepatocellular carcinoma (HCC) is a lethal cancer with an increasing burden. Few clinical trials have evaluated preventive strategies for HCC in high-risk patients with liver cirrhosis. Observational studies show that statins are associated with a reduced HCC risk although a causal link has yet to be established. This multicenter randomized double-blinded, placebo-controlled phase II trial of 40 mg/day oral simvastatin to reduce the likelihood of hepatocarcinogenesis was conducted at four sites in the United States. The primary outcome was the change in serum α-fetoprotein (AFP)-L3% from baseline to 6 months. Secondary biomarker endpoints include changes in serum AFP, serum IL6, serum deoxycholic acid, liver stiffness, Model for End-Stage Liver Disease score, and Fibrosis-4 index score. Comparisons were made using paired t tests or the Wilcoxon rank-sum test. Forty-five participants completed the intervention and final study assessments [mean age, 58 years; female, 42%; Asian, 2.2%; Black or African American, 11%; White, 87%; Hispanic or Latino, 51%; Child-Pugh (CP) A, 69%; CP B, 16%]. Of 45 participants, 10 (22%) had detectable AFP-L3%, which did not differ between the intervention arms. Serum IL6 levels, detectable in all participants, decreased significantly in the simvastatin group compared with the placebo group (P = 0.02). The number and grade of adverse events did not differ between groups. In this randomized controlled trial, simvastatin was well tolerated in patients with liver cirrhosis but did not result in a decrease in AFP-L3%, potentially owing to the low number of participants with detectable AFP/AFP-L3%. Simvastatin did result in a decrease in IL6, offering one potential anticancer mechanism of simvastatin in the setting of cirrhosis. Prevention Relevance: Increasing liver cancer incidence parallels cirrhosis related to nonalcoholic steatohepatitis. Statins have the potential to arrest cirrhosis progression and prevent liver cancer. In a phase IIB trial randomizing patients with cirrhosis to simvastatin versus placebo, we found that simvastatin decreased the inflammation biomarker IL6, but not the primary endpoint of AFP-L3.
Early detection of colorectal cancer remains critical for reducing disease-specific mortality, yet current noninvasive screening approaches have limitations in sensitivity (Sens), patient adherence, and scalability. We developed and clinically evaluated a non-next-generation sequencing (non-NGS) liquid biopsy assay for colorectal cancer detection based on methylation profiling of circulating cell-free DNA (cfDNA). The assay focuses on 40 CpG regions selected via bioinformatics analysis of public methylome datasets and uses a ten-eleven translocation methylcytosine dioxygenase 2-apolipoprotein B mRNA editing enzyme, catalytic polypeptide enzymatic conversion method to maintain cfDNA integrity and enhance amplification efficiency, enabling a rapid and cost-effective quantitative PCR (qPCR)-based workflow. Methylation signals were quantified by qPCR and integrated with patient age using neural network-based predictive models. The assay was evaluated in a cohort of 216 plasma samples, including 86 colorectal cancer cases and 130 healthy controls. In the validation subset, 14 high-performing models demonstrated sensitivities ranging from 80.8% to 92.3% and specificities from 84.6% to 97.4%. A representative model achieved a validation Sens of 92.3% [95% confidence interval (CI), 75%-99%], with early-stage (stage I/II) Sens of 100% (95% CI, 72%-100%) at a specificity of 97.4% (95% CI, 87%-100%). These findings support the potential of an enzymatic conversion-based, machine learning-guided cfDNA methylation assay as a practical, scalable, and minimally invasive approach for colorectal cancer detection. However, the relatively limited number of early-stage cases in this study highlights the need for larger, prospectively collected cohorts to refine performance estimates and confirm clinical utility. PREVENTION RELEVANCE:We present a noninvasive cfDNA methylation assay for early colorectal cancer detection using a non-NGS platform. Improved Sens for early-stage disease may enhance screening uptake and enable timely intervention, supporting colorectal cancer prevention.
Structural barriers to cancer screening at federally qualified health centers (FQHC) have contributed to lower screening rates than those among the broader populace, which were exacerbated by the COVID-19 pandemic. We apply the complex adaptive systems (CAS) theory to understand how one FQHC system in California reshaped its breast and cervical cancer screening programs to minimize health disruptions during the pandemic. This qualitative study, conducted between March 2022 and January 2023, consisted of interviews with clinic leadership and first-line staff, asking them to retrospectively reflect on the clinic's experiences with breast and cervical cancer screening delivery both immediately before and during the pandemic. Interviews were recorded and transcribed, and we performed content analysis and then applied the CAS theory. Participants (n = 20) ranged in age from 26 to 56 years, were mostly female (85%), and held leadership positions (65%). Participants indicated that cervical cancer screening rebounded more quickly than breast cancer screening programs. Results suggest that this difference could potentially be associated with new workflows that were in process prepandemic in the cervical cancer program to address existing screening barriers, as well as the FQHC's flexible approach to pandemic barriers, which included bolstering screening registries, hiring additional female providers, and bundling Pap smears into routine visits. In contrast, breast cancer screening relied on external radiology vendors, which may have reduced its flexibility to adjust to care disruptions. We highlight how healthcare delivery is shaped by interactions among diverse agents and nonlinear processes that occur in a dynamic and interconnected healthcare system. PREVENTION RELEVANCE:We apply the CAS theory to better understand the trajectory of FQHC preventive cancer screening programs during the COVID-19 pandemic. By extending beyond the identification of stand-alone barriers and facilitators, we highlight the ways in which healthcare delivery is shaped by interactions among diverse agents and nonlinear processes.
The recently published 2-year outcomes of the COMET trial provide evidence for the non-inferiority of active monitoring of ductal carcinoma in situ (DCIS), compared with excision. These findings raise questions for the management of atypical ductal hyperplasia (ADH). To assess whether active monitoring is a safe strategy in selected patients with ADH, we used observational data on women diagnosed at an academic comprehensive cancer center and emulated a target trial of surgical excision versus active monitoring. Eligibility criteria were adapted from the COMET trial: age 40 years or older, without concurrent malignancy or a history of ipsilateral breast cancer or DCIS within the prior 5 years, without breast symptoms, with no mass on physical examination or imaging, and without a history of recent endocrine therapy use. We estimated the risk of ipsilateral invasive carcinoma. There were 673 women with low-risk ADH, 238 (35.4%) of whom underwent surgical excision within 6 months. The risk of ipsilateral invasive carcinoma was 2.4% (95% CI: 0.8, 4.1%) at 2 years with surgical excision and 0.4% (95% CI: 0.0, 0.9%) with active monitoring (difference: 2.0; 95% CI: 0.3, 3.8). At 5 years, the risk was 2.4% (95% CI: 0.8, 4.2%) with surgical excision and 1.8% (0.7, 3.3%) with active monitoring (difference: 0.5; 95% CI: -1.6, 2.6). All cancers diagnosed at surgical excision or during follow-up were stage I. These findings provide evidence that active monitoring is safe and does not increase the risk of invasive carcinoma compared with surgical excision in patients with low-risk ADH.
This study provides a molecular characterization of precancerous colorectal lesions in Lynch syndrome (LS) carriers to assess the preventive potential of Nous-209 immunotherapy against colorectal cancer development. A total of 50 adenomas and 12 advanced adenomas (AA) were collected from 26 LS carriers with pathogenic variants in either MLH1 or MSH2. Molecular analyses included assessment of mismatch repair (MMR) status, microsatellite instability (MSI), and detection of mutations targeted by Nous-209. We found that 83% of AAs and 58% of adenomas were MMR-deficient (dMMR). Notably, although all dMMR AA were MSI-high (MSI-H), only 66% of dMMR adenomas showed MSI-H. The presence of Nous-209 mutations correlated strongly with MSI status, with mutation counts ranging from 15 to 57 in dMMR/MSI-H lesions. dMMR adenomas classified as MSI-low carried a limited number of mutations (6-19), whereas microsatellite-stable lesions harbored very few (0-2) Nous-209 mutations, regardless of MMR proficiency. These findings confirm the molecular heterogeneity of precancerous lesions and support the potential of Nous-209 immunotherapy to prevent MSI colorectal cancer in LS by targeting the adenoma-carcinoma sequence at the time of MSI acquisition. PREVENTION RELEVANCE:Our study shows that MSI and neoantigen accumulation emerge during the evolution of precancerous lesions in LS. These findings support the clinical evaluation of Nous-209, a shared neoantigen vaccine, as an immunoprevention strategy for MSI-driven colorectal carcinogenesis, with important implications for cancer prevention research.
Efficient strategies for diagnostic evaluation of multicancer early detection (MCED) tests are needed to distinguish true-positive from apparent false-positive (FP) test results. Extending a previously published model, we compared 2 post-positive MCED test diagnostic evaluation strategies: a cancer signal origin (CSO)-guided approach with repeat MCED testing to resolve FPs (CSO-retest strategy) versus a whole-body imaging (WBI)-only strategy employing whole-body computed tomography (WBCT) followed by positron emission tomography (PET)/CT scans to resolve FPs. Analyses evaluated 2 scenarios with different test performance characteristics and specificities, with a number of imaging procedures required and radiation exposure for each strategy as outcomes measures. The CSO-retest strategy resulted in 10- to 20-fold reduction in the use of WBCT/PET/CT versus the WBI-only strategy across both scenarios. A 1% reduction in WBI-only test specificity from 99.5% to 98.5% led to a >3-fold increase in FPs and more than doubled WBI requirements. Estimated radiation exposure for initial diagnostic evaluations for the CSO-retest strategy were 0 to 26.1 millisieverts (mSv), whereas all initial diagnostic evaluations for the WBI-only strategy carried an obligatory exposure of 28 mSv. For the 50% of CSO predictions requiring initial imaging, dose exposure ranged from 0.28 mSv (mammography) to 26.1 mSv (triple-phase renal CT), or 1% to 93% of the dose required for the WBI-only strategy. The results suggest that CSO-guided diagnostic strategies incorporating targeted workups and MCED retesting markedly reduce radiation exposure compared with a WBI-only approach, and small changes in MCED test specificity lead to significantly more unnecessary workups. PREVENTION RELEVANCE:Using MCED tests with molecular CSO prediction and MCED retesting to resolve apparent FPs enables targeted evaluations via existing diagnostic pathways, reducing radiation exposure compared with MCED tests without this feature that rely on WBI. These findings have important implications for MCED implementation including safety, cost, and accessibility.
Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with significant lifelong risk of cancer, and individuals with LFS undergo recommended screening protocols that are heavily dependent upon radiologic imaging. Recently, liquid biopsy has emerged as a potential new screening technique for LFS. In this study, we conducted a survey of adults with LFS and caregivers of children with LFS to determine interest in a clinical trial evaluating liquid biopsy as an addition to standard-of-care cancer screening. We also assessed barriers to receiving recommended screening and consequent financial toxicity. A total of 81 adults with LFS and 28 parents/guardians ("caregivers") of children with LFS responded to the survey. Of these, the majority (93%) were interested in the addition of liquid biopsy and were willing to have additional screening as frequently as every 3 months. Although most respondents were able to complete standard-of-care cancer screening as planned, more than a third reported financial barriers to completion of screening. Other reported barriers included scheduling, transportation, and stress around screening results. Additionally, approximately one fifths of adults and one fourths of parents/caregivers reported financial toxicity, with the most prevalent being food insecurity. These results provide data for feasibility and high participant interest in a clinical trial of liquid biopsy for cancer screening in LFS. Additionally, any clinical trial will require planning around barriers to existing screening protocols. PREVENTION RELEVANCE:Liquid biopsy testing for circulating tumor DNA is a promising strategy for cancer screening. Prior to a clinical trial of liquid biopsy cancer screening in LFS, this prospective survey of individuals with LFS and their caregivers assessed trial interest and barriers to current standard-of-care screening practices.
Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers worldwide and carries substantial morbidity. Metformin, a widely used antidiabetic agent, shows promise for HNSCC prevention, but resistance arises in a subset of tumors. In a recent issue of Cancer Prevention Research, Hoang and colleagues use CRISPR screening to identify key mediators of metformin resistance, including AMPK and protein kinase A (PKA), and demonstrate that the cyclooxygenase 2-prostaglandin E2 axis acts upstream of PKA. Because this pathway is readily inhibited by common nonsteroidal anti-inflammatory drugs (NSAID), the findings support clinical evaluation of combined metformin and NSAID therapy to improve HNSCC chemoprevention. See related article by Hoang et al., p. 79 .
Obesity is associated with increased risk of at least 13 adult cancer types and is the second most common cause of cancer (after tobacco) in many populations. Uncertainty about the extent to which intentional weight loss leads to reduced cancer risk represents a gap in knowledge. Evidence from bariatric surgery studies shows that sustained weight reduction of 20% to 30% in individuals with severe obesity is associated with reduced risk of obesity-related cancers over 10 years. However, in terms of population health, this is not a viable cancer prevention strategy. Recently, glucagon-like peptide-1 receptor agonists (GLP-1RA), known to be effective antidiabetes drugs, have been shown in randomized trials to cause substantial weight loss (in the order of 15%) in obese individuals with or without diabetes. This is a rapidly evolving field, which has revolutionized the modern management of obesity. Much clinical experience has been with semaglutide (a GLP-1RA) and tirzepatide (a dual agonist of the GLP-1 receptor and the glucose-dependent insulinotropic polypeptide receptor), but newer drugs in the class are being developed. We review available data that provide a strong rationale for evaluating incretin-mimetic drugs in a cancer prevention trial but show that the feasibility of such a trial is questionable.
Abstract High endogenous estrogen levels contribute to the etiology of hormone-related cancers. 2-hydroxylation (2-OH) of estrogen exhibits potential antitumorigenic properties. We hypothesized that lifestyle patterns related to the ratio of 2-OH pathway estrogen metabolites (EM) to parent estrogens (2-OH EM/parent E ratio) might lower estrogen-related cancer risk. We applied elastic net regularized regression to derive lifestyle scores correlated with the 2-OH EM/parent E ratio separately using data from subsets of cancer-free, postmenopausal women in the Shanghai Women’s Health Study (SWHS, n = 723) and the Prostate, Lung, Colorectal and Ovarian Screening Trial (PLCO, n = 635), in which blood (PLCO) or urine (SWHS) samples collected at baseline were profiled for parent Es and EMs. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations of lifestyle scores with the risk of breast, endometrial, and ovarian cancers in SWHS (N = 35,453) and PLCO (N = 26,565). The lifestyle scores explained 10% to 11% of the total variance in the 2-OH EM/parent E ratio. In the SWHS, a higher score was associated with a 29% (HR = 0.71; 95% CI, 0.57–0.88; Ptrend < 0.001) and 61% (HR = 0.39; 95% CI, 0.21–0.71; Ptrend < 0.001) lower risk of breast and endometrial cancers when comparing the highest with the lowest quartile, respectively. The association was more apparent with estrogen receptor (ER)-positive than with ER-negative breast cancer. Similar inverse associations were observed in the PLCO. Lifestyle patterns linked to elevated 2-OH of estrogen were associated with a lower risk of postmenopausal breast and endometrial cancers. Our study provides evidence for lifestyle modifications for cancer prevention. Prevention Relevance: Elevated estrogen 2-OH has been linked to reduced breast cancer risk. We showed that lifestyle patterns increasing the 2-OH EM/parent E ratio were associated with lower postmenopausal breast and endometrial cancer risk. Our findings suggest that targeted lifestyle modifications may benefit postmenopausal women with a low 2-OH EM/parent E ratio.
