Cancer prevention research (Philadelphia, Pa.)最新文献

Advanced age and obesity are major risk factors for breast cancer progression, including triple-negative breast cancer (TNBC). In this study, we interrogated (i) whether these factors interact to promote TNBC progression and (ii) whether weight loss mitigates the separate and combined effects of aging and obesity on TNBC. We demonstrate that aging and diet-induced obesity interact to promote TNBC growth in mice. Transcriptomic analysis revealed the suppression of antitumor immunity in tumors from aged and/or obese mice. Weight loss via intermittent calorie restriction reduced tumor growth and restored immune-related gene signatures to reverse the protumor effects of aging and/or obesity. Using publicly available genomic datasets from murine studies of obesity, weight loss, and TNBC, we identified a consensus transcriptomic signature of obesity-driven immunosuppression that predicted the survival of patients with breast cancer. This consensus signature was also suppressed by aging, obesity, and their combination. Intermittent calorie restriction reversed the effects of aging and/or obesity on the consensus signature. We conclude that aging and obesity interact to limit antitumor immunity and enhance TNBC progression and that these adverse effects can be disrupted by weight loss.

Prevention relevance: Advanced age and obesity are important risk factors for the development and progression of breast cancers, including TNBC. We demonstrate that the suppression of signatures of antitumor immunity is a common feature of accelerated tumor progression in TNBC. We show that weight loss achieved through calorie restriction can restore such markers. See related Spotlight, p. 437.

Colorectal cancer (CRC) incidence is rising in Korea, emphasizing the need to identify its risk factors. Serum lipids may influence CRC risk, but evidence is conflicting. We examined the associations between serum lipids and CRC risk in Koreans. Using data from Korean Genome and Epidemiology Study Health Examinee study, we assessed serum low-density lipoproteins (LDL), high-density lipoproteins (HDL), triglycerides (TG) and total cholesterol (TC) among those who did not use lipid-lowering drugs. Dyslipidemia and its subcategories were defined using established clinical thresholds. Cancer cases were identified via the national cancer registry. Associations between lipids and cancers were evaluated using Cox regression. Subgroup analyses were conducted by sex, age, diabetes, and prior screening experience, along with sensitivity analyses based on follow-up duration. During a median follow-up of 9.1-years, 821 new CRC cases occurred among 111,330 participants aged 40-69 years (38,455 men and 72,875 women). For CRC, elevated TG (Q4 vs. Q1 HR 1.32, 95% CI: 1.07-1.62; P-trend = 0.02) and TC (Q4 vs. Q1 HR 1.22, 95% CI: 1.00-1.51) increased risk. For colon cancer, high TG increased risk (Q4 vs. Q1 HR 1.42, 95% CI: 1.08-1.86, P-trend=0.01). Those with hyper-triglyceridemia, compared those without, showed increased risk (HR 1.42, 95% CI: 1.07-1.87) for rectal cancer, whereas other lipids showed no significant associations. Similar but attenuated results were found in the subgroup analyses among participants aged ≥50 years. TG was associated with colorectal, colon, and rectal cancer in Koreans. Findings suggest that lipid levels may be relevant to CRC prevention strategies.

The Tribally Engaged Approaches to Lung Cancer Screening study aimed to codesign and test a community-based lung cancer screening (LCS) program within a large, tribally operated health system. In 2020 to 2021, we conducted a pre-post quasi-experimental pilot implementation study of a tailored and comprehensive LCS program in two Choctaw Nation of Oklahoma primary care clinics in rural Oklahoma. The program included screening quality assessment, academic detailing, practice facilitation, health system enhancements, technology support, centralized LCS coordination, and community outreach. Eligibility for LCS was based on the 2013 U.S. Preventive Services Task Force guidelines. Participants completed pre- and post-intervention surveys on their knowledge, attitudes, and experiences regarding LCS. All participant charts were extracted to determine LCS completion. Postimplementation semi-structured interviews of patients and clinicians were conducted, and practice facilitator notes were analyzed. Participants (N = 57) averaged 67 years, and 66% were current smokers. The proportion of participants who were up-to-date with LCS increased from 39% to 58% (P < 0.01). About 18% of patients reported improvement in general care choice and treatment discussions with their doctor, and about 40% reported an improvement in their awareness or understanding of lung cancer and receipt of LCS. We also identified several key facilitators and barriers to LCS implementation at the practice and health system levels. LCS acceptance and uptake improved significantly in this community-engaged pilot intervention which informed a subsequent cluster-randomized trial. Comprehensive and community-engaged LCS programs may have the potential to improve the delivery of LCS in underserved community settings.

Prevention relevance: Our community-engaged, multicomponent, and multilevel pilot implementation study significantly improved lung cancer screening rates in a rural, tribal health system. A key feature of this pilot study was a centralized screening coordination service supported by a population screening registry. We believe that our study is replicable in other settings. See related Spotlight, p. 381.

Cancer screening practices are amalgamated into the entire spectrum of cancer prevention efforts that range from primary prevention (e.g., avoiding tobacco and limiting sun exposure) to screening measures after risk assessment (mammography, colonoscopy, pap smears, etc.) and tertiary measures (e.g., lesion ablation after identification and cancer follow-up examinations for secondary primaries). Marginalized groups often have difficulty gaining access to screening, and improving screening rates is challenging. The Tribally Engaged Approaches to Lung Screening (TEALS) study for lung cancer screening in the American Indian/Alaska Native population in Oklahoma represents a comprehensive effort that has significantly improved lung cancer screening for high-risk individuals on the Choctaw Nation. See related article by Nagykaldi et al., p. 423.

Historically, cancers diagnosed via the emergency department (ED) portend a poor prognosis. Recent data from the United States are sparse, and analyses of cancers detected in the years following ED visits are lacking. Thus, we analyzed data from nine rural U.S. Midwest counties included within the population-based Rochester Epidemiology Project (2015-2021). Participants without a history of cancer (N = 42,074) who did not receive ED care were matched 1:1 to ED participants on the date of ED visit, age, sex, race, ethnicity, and county of residence. Analyses were restricted to participants with records ≤2 years prior to ED or index visit and ≥30 days after. HRs and 95% confidence intervals (CI) comparing cancer incidence and deaths among ED and non-ED participants were estimated from Cox proportional hazards regression models, either unadjusted or adjusted for covariates. Cumulative cancer incidence curves accounting for competing risks of death and survival (all cause and cancer-specific) were estimated. The median follow-up was 6.3 years, with 2,719 (6.46%) cancers diagnosed among ED participants and 3,139 (7.46%) among non-ED participants. ED participants experienced lower cancer risk overall (HRAdjusted = 0.70; 95% CI, 0.66-0.74; P = 8.89 × 10-31), specifically for breast cancer, prostate cancer, melanoma, and secondary cancers. Cancer-specific mortality was higher among ED participants (HRAdjusted = 1.76; 95% CI, 1.49-2.08; P = 3.62 × 10-11). Compared with non-ED participants, ED participants experienced a lower incidence of cancer but higher overall cancer-specific mortality, suggesting that subsets of ED patients may benefit from postvisit preventive interventions.

Prevention relevance: This cohort analysis shows that cancer incidence over 6 years was lower among participants after an ED visit than among matched non-ED participants, whereas cancer-specific mortality was higher in the ED group (HRAdjusted = 1.76; 95% CI, 1.49-2.08; P = 3.62 × 10-11), suggesting the potential benefit of preventive interventions.

Meta-analyses have reported a decrease in overall cancer incidence of approximately 10% to 40% with metformin use among individuals with diabetes. Lifestyle change could potentially reduce cancer incidence. The objective was to determine whether metformin or intensive lifestyle (ILS) intervention reduces the risk of cancer among adults at high risk of diabetes. The Diabetes Prevention Program (1996-2001) randomized 3,234 participants to ILS, metformin (850 mg twice daily), or blinded placebo. During follow-up through the Diabetes Prevention Program Outcomes Study, all participants were offered a modified lifestyle intervention, and metformin continued in an open-label metformin group. Participants reported cancer cases annually. Medical records were adjudicated for all reported events. The primary endpoint was total cancer incidence, comparing metformin versus placebo, with ILS versus placebo as a secondary objective. After a median follow-up of 21 years, 546 participants (173 metformin, 182 ILS, and 191 placebo) were diagnosed with a first incident cancer. Incidence rates of cancer were 9.8, 10.5, and 10.8 per 1,000 person-years in metformin, ILS, and placebo, respectively, with a HR of 0.90 (95% confidence interval, 0.73-1.10) for metformin compared with placebo and 0.96 (95% confidence interval, 0.79-1.18) for ILS compared with placebo. There were no differences between any treatment groups for obesity-related cancer or in sex-specific analyses. Neither assignment to metformin nor ILS reduced cancer incidence among adults at high risk of diabetes. These results may be impacted by increased nonstudy metformin usage over time due to the development of diabetes and reduced intensity of the ILS intervention over time.

Prevention relevance: This study examines both metformin and ILS intervention as primary cancer prevention interventions in people at high risk for type 2 diabetes.

Multiple myeloma is preceded by monoclonal gammopathy of undetermined significance (MGUS). Only a minority of patients with MGUS will develop multiple myeloma, but precise prediction of progression is impossible using routine clinical biomarkers. Changes in the levels of blood immune markers can help predict disease progression. Data remain inconsistent for some markers of interest such as monocyte chemotactic protein-3 (MCP-3), macrophage inflammatory protein-1 alpha (MIP-1α), fibroblast growth factor-2 (FGF-2), vascular endothelial growth factor (VEGF), fractalkine, and transforming growth factor-alpha (TGF-α). We aimed to investigate the associations between the prediagnostic serum levels of these candidate biomarkers and future multiple myeloma risk, as well as to assess marker changes over time. We performed a nested case-control study using prospective samples from the Janus Serum Bank in Norway to investigate associations between multiple myeloma risk and prediagnostic serum levels of MCP-3, MIP-1α, FGF-2, VEGF, fractalkine, and TGF-α. The study included 293 future multiple myeloma cases with serum samples collected 20 years (median) before multiple myeloma diagnosis and 293 matched cancer-free controls. Patients with multiple myeloma had an additional prediagnostic sample collected up to 42 years before diagnosis to identify marker changes over time. Markers with >60% detection rate (MIP-1α, VEGF, and TGF-α) were included in the statistical analysis. We observed no statistically significant associations between multiple myeloma risk and serum levels of MIP-1α, VEGF, or TGF-α in samples collected 20 years before diagnosis. However, TGF-α levels decreased significantly closer to the diagnosis in patients with multiple myeloma (P < 0.001). The decrease in TGF-α levels may reflect subtle microenvironmental changes related to multiple myeloma progression.

Prevention relevance: This study observed a decline in TGF-α serum levels closer to multiple myeloma diagnosis, which may aid in predicting multiple myeloma progression and early detection, although validation in other longitudinal cohorts is needed.

Approximately half of high-grade ovarian cancers are characterized by genetic and epigenetic alterations in genes involved in homologous recombination repair (HRR), most commonly BRCA1 and BRCA2. HRR defects (HRD) identified by tests of genomic instability confer PARP inhibitor sensitivity in ovarian cancers. Commercial tests that combine tumor BRCA testing with a genomic instability score (HRD test) are available in clinical practice. We seek to determine the performance of three different HRD tests to improve therapy management and prevention of ovarian cancer. Tumor samples from 50 patients with high-grade ovarian cancers were investigated for tumoral BRCA status, genomic instability, and BRCA1 promoter methylation for treatment purposes. Patients with ovarian cancer that tested positive for BRCA variants and/or genomic instability defect were referred to the Cancer Genetics Service for germline testing. A positive HRD status was observed in 54% of cases, and pathogenic variants in BRCA genes were identified in 41% of cases presenting genomic instability. BRCA1 methylation assay revealed promoter hypermethylation in 20% of ovarian cancers that tested positive for HRD and negative for BRCA1/2 variants. Among 26 women referred to cancer genetic counseling, 10 carried germline variants in HRR genes. HRD status determined eligibility for PARP inhibitor treatment in all but two ovarian cancers. This study outlines that determining genomic instability helps identify inherited ovarian cancers. HRD testing, crucial for making high-grade ovarian cancer treatment choices, must be linked to an established path of cancer genetic counseling and management of individuals at high cancer risk.

Prevention relevance: Genomic instability status (HRD testing), which is essential for making therapy choices, is useful to identify inherited ovarian cancers. Identifying these families with high cancer risk is critical for implementing targeted cancer prevention strategies.

Aspirin reduces colorectal cancer risk but has a potential for adverse effects. Recent preclinical data suggest that intermittent dosing of aspirin may minimize adverse effects while maintaining efficacy. We conducted a three-arm double-blind randomized placebo-controlled phase II trial. The primary objective of the study was to test for the equivalency of two aspirin schedules, i.e., the effects of daily aspirin 325 mg/day continuously (cont-ASA) for 12 weeks or intermittently and 3 weeks on/3 weeks off on biomarkers related to colorectal carcinogenesis in rectal mucosa. A placebo group enabled the estimation of spontaneous biomarker variation. Eighty-one participants were randomized, of whom forty-five were evaluable. For the primary endpoint of decrease in the Ki-67:BCL2-associated X ratio, we could not establish equivalence for the two treatment regimens and also found no significant difference between them. For the secondary endpoint, cont-ASA treatment was significantly more effective in reducing the Ki-67:terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling ratio. Among exploratory endpoints, we found more reduction in epithelial COX-2 expression in the cont-ASA arm compared with the intermittent aspirin dosing arm. We did not observe significant differences in other secondary and exploratory endpoints. Intermittent aspirin dosing in 3-week cycles does not produce the same biologic effect as continuous dosing. Future studies should examine whether a 1-week on/1-week off schedule can maximize the efficacy and minimize the side effects. Prevention Relevance: In this three-arm double-blind randomized placebo-controlled phase II trial, we could not establish equivalence for daily aspirin 325 mg versus intermittent aspirin (3 weeks on/3 weeks off) on Ki-67:BCL2-associated X ratio. However, compared with intermittent aspirin administration, continuing aspirin was significantly more effective in reducing the Ki-67:terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling ratio and COX-2 in rectal mucosa.