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

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.

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.

The United States Preventive Services Task Force updated its lung cancer screening (LCS) recommendations in 2021, and the American Cancer Society (ACS) updated its LCS guidelines in 2023. Each update expanded screening eligibility criteria, thus increasing the total number of individuals eligible for LCS. However, it is not clear whether different population subgroups benefit equally from the recent updates of LCS recommendations in terms of becoming newly eligible. We identified 85,395 individuals who were between 50 and 80 years old, smoked cigarettes formerly or currently, and did not have a history of lung cancer from the Behavioral Risk Factor Surveillance System survey of 2022. We used descriptive analysis to illustrate the weighted proportions of the newly screening-eligible population among different subgroups. We also applied multivariable logistic regression models to estimate the ORs of being newly eligible for LCS under each LCS recommendation update in 2021 and 2023. For both LCS updates, individuals who were non-Hispanic White males and had chronic obstructive pulmonary disease were significantly more likely to become newly eligible for LCS. A significantly larger proportion of older-age individuals became newly eligible under the 2023 ACS guideline. Noticeably, both guideline updates substantially increased the population eligible for screening among males and older individuals, two groups experiencing the majority of lung cancer incidence and mortality. Results also indicate that the screening eligibility criteria updates did not increase the OR of being eligible among racial/ethnic minority and female subgroups. Prevention Relevance: This study examines the evolving LCS guidelines and their public health impact. Analyzing the 2021 United States Preventive Services Task Force and 2023 ACS updates, we show expanded eligibility but persistent disparities among sociodemographic groups. Our findings highlight the need for targeted interventions to improve screening uptake and promote equitable, inclusive prevention strategies.

Screening digital breast tomosynthesis (DBT) aims to identify breast cancer early when treatment is most effective, leading to reduced mortality. In addition to early detection, the information contained within DBT images may also inform subsequent risk stratification and guide risk-reducing management. Using transfer learning, we refined a model in the Joanne Knight Breast Health Cohort at Washington University, a cohort of 5,066 women with DBT screening (mean age, 54.6), among whom 105 were diagnosed with breast cancer (26 ductal carcinoma in situ). We applied the model to external data from the Emory Breast Imaging Dataset, a cohort of 7,017 women free from cancer (mean age, 55.4), among whom 111 pathology-confirmed breast cancer cases were diagnosed more than 6 months after initial DBT (17 ductal carcinoma in situ). We obtained a 5-year AUC of 0.75 [95% confidence interval (CI), 0.73-0.78] in the internal validation. The model validated in external data gave an AUC of 0.72 (95% CI, 0.69-0.75). The AUC was unchanged when age and Breast Imaging-Reporting and Data System density were added to the model with synthetic DBT images. The model significantly outperforms the Tyrer-Cuzick model, with a 5-year AUC of 0.56 (95% CI, 0.54-0.58; P < 0.01). Our model extends risk prediction applications to synthetic DBT, provides 5-year risk estimates, and is readily calibrated to national risk strata for clinical translation and guideline-driven risk management. The model could be implemented within any digital mammography program. Prevention Relevance: We develop and externally validate a 5-year risk prediction model for breast cancer using synthetic DBT and demonstrate clinical utility by calibrating to the national risk strata as defined in breast cancer risk management guidelines.

Cancer screening lowers morbidity and mortality from cancer and is cost-effective. The COVID-19 pandemic upended cancer screening utilization in 2020 with data showing a deficit in screened patients in 2020 and 2021 as compared with 2019, with return to 2019 baseline screening levels by December 2022. The cumulative shortfall in screenings, lasting nearly 3 years into the pandemic, is predicted by models to generate an incremental population cancer burden in the out-years of the models. Recovery of screening rates may vary based on the racial or ethnic population, and time will tell if there is an uneven burden of future cancers that worsen cancer incidence and mortality in those populations, some even after years of gains of reducing disparities for cancer screening. For some cancer screenings, particularly cervical and colorectal cancers, use of at-home noninvasive tests may increase screening participation overall across multiple populations and help mitigate some of the screening shortfalls from 2020 to 2022 by elevating numbers of the population screened. For colorectal cancer, new additional comparably sensitive or ease-of-use noninvasive screening tests are being added for utilization.

Colorectal cancer is highly preventable with timely screening, but screening modalities are widely underused, especially among those of low individual-level socioeconomic status (SES). In addition to individual-level SES, neighborhood-level SES may also play a role in colorectal cancer screening completion through less geographic access to health care, transportation, and community knowledge of and support for screenings. We investigated the associations of neighborhood SES using a census tract-level measure of social and economic conditions with the uptake of colonoscopy and stool-based testing. We utilized data from the Southern Community Cohort Study, a large, prospective study of English-speaking adults ages 40 to 79 from the southeastern United States with 65% of participants identifying as non-Hispanic Black and 53% having annual household income <$15,000. Neighborhood SES was measured via a neighborhood deprivation index compiled from principal component analysis of 11 census-tract variables in the domains of education, employment, occupation, and poverty; screening was self-reported at the baseline interview (2002-2009) and follow-up interview (2008-2012). We found that participants residing in the lowest SES areas had lower odds of ever undergoing colonoscopy (ORQ5vsQ1 = 0.75; 95% confidence interval, 0.68-0.82) or stool-based colorectal cancer testing (ORQ5vsQ1 = 0.71; 95% confidence interval, 0.63-0.80) while adjusting for individual-level SES factors. Associations were consistent between neighborhood SES and screening in subgroups defined by race, sex, household income, insurance, or education (P > 0.20 for all interaction tests). Our findings suggest that barriers to screening exist at the neighborhood level and that residents of lower SES neighborhoods may experience more barriers to screening using colonoscopy and stool-based modalities. Prevention Relevance: This study presents evidence that persons living in lower SES neighborhoods use colorectal cancer screening modalities at lower rates. Screening is highly preventive of colorectal cancer, but it has limited benefit if it cannot be utilized. Addressing neighborhood-level barriers to screening may improve socioeconomic disparities in colorectal cancer.

Experimental studies have shown that dietary isothiocyanates reduced cellular proliferative marker Ki-67 and increased apoptotic markers caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) in animals, but human data are lacking. The present study was to assess whether sulforaphane would stop/reverse the progression of bronchial histopathology, reduce the Ki-67 index, and/or increase caspase-3 and TUNEL indices in humans. A randomized clinical trial (NCT03232138) was conducted in former smokers. Forty-three subjects were randomly assigned to the placebo or the treatment with a potential daily dose of 95 μmol sulforaphane for 12 months. The endpoints were the changes in histopathology scores and Ki-67, caspase-3, and TUNEL indices in post- versus pretreatment bronchial biopsies. Thirty-seven participants (17 in the sulforaphane and 20 in the placebo group) completed the study. Supplementation of sulforaphane did not show significant impact on bronchial histopathology but significantly reduced the Ki-67 index with a 20% decrease in the sulforaphane group and a 65% increase in the placebo (P = 0.014). The difference was even greater in high-density (3+) positive Ki-67, with a 44% decrease in the sulforaphane group compared with a 71% increase in the placebo (P = 0.004). Higher bioavailability of sulforaphane was correlated with greater reduction of the Ki-67 index (P for trend = 0.019). Sulforaphane treatment had no impact on the caspase-3 or TUNEL index in bronchial biopsies. No severe adverse event was observed in the study participants. The findings of oral sulforaphane that significantly reduced the Ki-67 index in bronchial tissue support further development as a potential chemopreventive agent against lung cancer development. Prevention Relevance: High intake of cruciferous vegetables and their sulforaphane is associated with lower incidence of lung cancer in humans and animal models. This clinical trial has demonstrated that oral supplementation of sulforaphane for 12 months significantly reduced the Ki-67 index, a potential surrogate endpoint of biomarkers for lung cancer risk.