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Background: Black men consistently have higher rates of prostate cancer (PCA)- related mortality. Advances in PCA treatment, screening, and hereditary cancer assessment center around germline testing (GT). Of concern is the significant under-engagement of Black males in PCA GT, limiting the benefit of precision therapy and tailored cancer screening despite longstanding awareness of these disparities. To address these critical disparities, the Socioecological Model (SEM) was employed to develop comprehensive recommendations to overcome barriers and implement equitable strategies to engage Black males in PCA GT. Methods: Clinical/research experts, national organization leaders, and community stakeholders spanning multiple regions in US and Africa participated in developing a framework for equity in PCA GT grounded in the SEM. A novel mixed-methods approach was employed to generate key areas to be addressed and informed statements for consensus consideration utilizing the modified Delphi model. Statements achieving strong consensus (> =75% agreement) were included in final equity frameworks addressing clinical/community engagement and research engagement. Results: All societal levels of the SEM (interpersonal, institutional, community, and policy/advocacy) must deliver information about PCA GT to Black males that address benefits/limitations, clinical impact, hereditary cancer implications, with acknowledgment of mistrust (mean scores [MS] 4.57-5.00). Interpersonal strategies for information delivery included engagement of family/friends/peers/Black role models to improve education/awareness and overcome mistrust (MS 4.65-5.00). Institutional strategies included diversifying clinical, research, and educational programs and integrating community liaisons into healthcare institutions (MS 4.57-5.00). Community strategies included partnerships with healthcare institutions and visibility of healthcare providers/researchers at community events (MS 4.65–4.91). Policy/advocacy included improving partnerships between advocacy and healthcare/community organizations while protecting patient benefits (MS 4.57-5.00). Media strategies were endorsed for the first time at every level (MS 4.56-5.00). Conclusion: The SEM-based equity frameworks proposed provide the first multidisciplinary strategies dedicated to increase engagement of Black males in PCA GT, which are critical to reduce disparities in PCA-mortality through informing tailored screening, targeted therapy, and cascade testing in families. [ABSTRACT FROM AUTHOR]

In 2018, the authors reported estimates of the number and proportion of cancers attributable to potentially modifiable risk factors in 2014 in the United States. These data are useful for advocating for and informing cancer prevention and control. Herein, based on up‐to‐date relative risk and cancer occurrence data, the authors estimated the proportion and number of invasive cancer cases (excluding nonmelanoma skin cancers) and deaths, overall and for 30 cancer types among adults who were aged 30 years and older in 2019 in the United States, that were attributable to potentially modifiable risk factors. These included cigarette smoking; second‐hand smoke; excess body weight; alcohol consumption; consumption of red and processed meat; low consumption of fruits and vegetables, dietary fiber, and dietary calcium; physical inactivity; ultraviolet radiation; and seven carcinogenic infections. Numbers of cancer cases and deaths were obtained from data sources with complete national coverage, risk factor prevalence estimates from nationally representative surveys, and associated relative risks of cancer from published large‐scale pooled or meta‐analyses. In 2019, an estimated 40.0% (713,340 of 1,781,649) of all incident cancers (excluding nonmelanoma skin cancers) and 44.0% (262,120 of 595,737) of all cancer deaths in adults aged 30 years and older in the United States were attributable to the evaluated risk factors. Cigarette smoking was the leading risk factor contributing to cancer cases and deaths overall (19.3% and 28.5%, respectively), followed by excess body weight (7.6% and 7.3%, respectively), and alcohol consumption (5.4% and 4.1%, respectively). For 19 of 30 evaluated cancer types, more than one half of the cancer cases and deaths were attributable to the potentially modifiable risk factors considered in this study. Lung cancer had the highest number of cancer cases (201,660) and deaths (122,740) attributable to evaluated risk factors, followed by female breast cancer (83,840 cases), skin melanoma (82,710), and colorectal cancer (78,440) for attributable cases and by colorectal (25,800 deaths), liver (14,720), and esophageal (13,600) cancer for attributable deaths. Large numbers of cancer cases and deaths in the United States are attributable to potentially modifiable risk factors, underscoring the potential to substantially reduce the cancer burden through broad and equitable implementation of preventive initiatives. [ABSTRACT FROM AUTHOR]

Purpose: We examined the one-year test re-test reliability and validity criterion of survey-assessed sleep duration collected from two separate questions. Methods: The Activity Validation Sub Study included 751 participants of the Cancer Prevention Study-3 study to further investigate rest/activity cycles. Sleep duration was collected using three methods: survey, Daysimeter device, and sleep diary. Survey-assessed sleep duration was collected using 2 different questions, each with different response options (categorical and continuous). Selected participants (n = 170) were asked to wear a Daysimeter device for seven consecutive days for two non-consecutive quarters. Participants were excluded from the current study due to incomplete/implausible survey or device data or reported working night shift. We calculated reliability of pre- and post-survey sleep duration for both survey question using Spearman correlation. We used the method of triads to estimate the validity coefficient (VC) between the three sleep duration measurements in the present study and the "true" latent sleep duration measure, and bootstrapping methods to calculate the 95% confidence intervals (95%CI). Results: Of 119 participants included in the study (52.10% male), test-retest correlation showed strong and moderate correlations for sleep duration collected continuously and categorically, respectively. The VC for survey-assessed continuous sleep duration was 0.82 (95%CI 0.71, 0.90) for weekday and 0.68 (95%CI 0.46, 0.83) for weekend. Performance of the VC was slightly weaker for survey-assessed categorical sleep duration (weekday VC = 0.57 95%CI 0.42, 0.71; weekend VC = 0.47 95%CI 0.29, 0.62). Conclusion: The two survey-assessed sleep duration questions used in the AVSS and CPS-3 cohorts are valid approximations of sleep duration. [ABSTRACT FROM AUTHOR]

Background: Currently recommended cancer screening programs address only part of the overall population cancer burden. Even populations deemed high‐risk for certain individual cancers experience a considerable potential burden of other cancers. However, few published cancer screening trials report the incidence of untargeted cancers. Methods: The National Lung Screening Trial (NLST), initiated in 2002–2004, was a randomized controlled trial of lung cancer screening in adults with ≥30 pack‐years of smoking. Active follow‐up for incident invasive cancers continued through 2009. Results: Among 53,229 NLST subjects (median follow‐up 6.5 years after randomization), the incidence of lung cancer was 615 per 100,000 person‐years (32% of 6142 overall first primary incident invasive cancers), and that of non‐lung cancer was 1327 per 100,000 (68%). Non‐lung cancer incidence exceeded that for lung cancer in all 5‐year age categories and all quintiles of smoking pack‐years. Besides lung cancer, the most common cancers were prostate, breast, colon/rectum, bladder, and head/neck; 23% were smoking‐related cancers, and 54% were cancer types lacking recommended population‐based screening modalities (32% excluding prostate). Non‐lung cancer comprised 48% of 1793 cancer deaths. Conclusions: In the NLST, only 32% of first primary cancer incidence after study entry was lung, compared with 68% non‐lung. Even in a population at high risk for lung cancer, a single‐cancer screening test misses most cancers. Thus, in combination with existing single‐cancer screening modalities, multi‐cancer screening tests—which address many of the incident non‐lung cancers in this trial—have potential to address a currently inaccessible portion of cancer morbidity and mortality. [ABSTRACT FROM AUTHOR]

Background: Performing physical activity may provide analgesic benefit, although this effect is more established for noncancer pain rather than cancer pain. The relationship between physical activity and pain outcomes in adults with and without a history of cancer was examined. Methods: Totals of 51,439 adults without a cancer history and 10,651 adults with a cancer history from the Cancer Prevention Study II Nutrition Cohort were included. Exposures included self‐reported moderate to vigorous physical activity (MVPA) as well as 2‐year change in MVPA. Pain outcomes included pain intensity (primary outcome) and analgesic use (secondary outcome). Results: MVPA was inversely associated with pain intensity for adults with (odds ratio [OR], 0.84 [≥15 metabolic equivalent of task (MET) h/week vs. <7.5 MET h/week]; 95% confidence interval [CI], 0.76–0.93) and without (OR, 0.79; 95% CI, 0.75–0.82) a history of cancer. Compared to remaining inactive, participants who became sufficiently active (cancer: OR, 0.76; 95% CI, 0.68–0.86; no cancer: OR, 0.73; 95% CI, 0.69–0.77), became inactive (cancer: OR, 0.79; 95% CI, 0.71–0.88; no cancer: OR, 0.84; 95% CI, 0.80–0.89), or remained sufficiently active (cancer: OR, 0.66; 95% CI, 0.60–0.72; no cancer: OR, 0.62; 95% CI, 0.60–0.65) also reported less pain. Physical activity was not related to analgesic use. Conclusions: The relationship between physical activity and pain intensity was not substantially different between people with and without a history of cancer. Cancer survivors who perform more activity, or who increase their activity, may experience less pain than cancer survivors who consistently perform less. Plain language summary: People who have had cancer often experience ongoing pain.Being physically active may help reduce the intensity of the pain they experience. This study examined physical activity and pain in people with and without a history of cancer. More physical activity was related to less pain in both groups. [ABSTRACT FROM AUTHOR]

In 2021, the American Cancer Society published its first biennial report on the status of cancer disparities in the United States. In this second report, the authors provide updated data on racial, ethnic, socioeconomic (educational attainment as a marker), and geographic (metropolitan status) disparities in cancer occurrence and outcomes and contributing factors to these disparities in the country. The authors also review programs that have reduced cancer disparities and provide policy recommendations to further mitigate these inequalities. There are substantial variations in risk factors, stage at diagnosis, receipt of care, survival, and mortality for many cancers by race/ethnicity, educational attainment, and metropolitan status. During 2016 through 2020, Black and American Indian/Alaska Native people continued to bear a disproportionately higher burden of cancer deaths, both overall and from major cancers. By educational attainment, overall cancer mortality rates were about 1.6-2.8 times higher in individuals with ≤12 years of education than in those with ≥16 years of education among Black and White men and women. These disparities by educational attainment within each race were considerably larger than the Black-White disparities in overall cancer mortality within each educational attainment, ranging from 1.03 to 1.5 times higher among Black people, suggesting a major role for socioeconomic status disparities in racial disparities in cancer mortality given the disproportionally larger representation of Black people in lower socioeconomic status groups. Of note, the largest Black-White disparities in overall cancer mortality were among those who had ≥16 years of education. By area of residence, mortality from all cancer and from leading causes of cancer death were substantially higher in nonmetropolitan areas than in large metropolitan areas. For colorectal cancer, for example, mortality rates in nonmetropolitan areas versus large metropolitan areas were 23% higher among males and 21% higher among females. By age group, the racial and geographic disparities in cancer mortality were greater among individuals younger than 65 years than among those aged 65 years and older. Many of the observed racial, socioeconomic, and geographic disparities in cancer mortality align with disparities in exposure to risk factors and access to cancer prevention, early detection, and treatment, which are largely rooted in fundamental inequities in social determinants of health. Equitable policies at all levels of government, broad interdisciplinary engagement to address these inequities, and equitable implementation of evidence-based interventions, such as increasing health insurance coverage, are needed to reduce cancer disparities. [ABSTRACT FROM AUTHOR]

Background The incidence of differentiated thyroid cancer (DTC) is higher in women than in men but whether sex steroid hormones contribute to this difference remains unclear. Studies of reproductive and hormonal factors and thyroid cancer risk have provided inconsistent results. Methods Original data from 1 252 907 women in 16 cohorts in North America, Europe, Australia and Asia were combined to evaluate associations of DTC risk with reproductive and hormonal factors. Multivariable-adjusted Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% CIs. Results During follow-up, 2142 women were diagnosed with DTC. Factors associated with higher risk of DTC included younger age at menarche (<10 vs 10–11 years; HR, 1.28; 95% CI, 1.00–1.64), younger (<40; HR, 1.31; 95% CI, 1.05–1.62) and older (≥55; HR, 1.33; 95% CI, 1.05–1.68) ages at menopause (vs 40–44 years), ever use of menopausal hormone therapy (HR, 1.16; 95% CI, 1.02–1.33) and previous hysterectomy (HR, 1.25; 95% CI, 1.13–1.39) or bilateral oophorectomy (HR, 1.14; 95% CI, 1.00–1.29). Factors associated with lower risk included longer-term use (≥5 vs <5 years) of oral contraceptives (HR, 0.86; 95% CI, 0.76–0.96) among those who ever used oral contraception and baseline post-menopausal status (HR, 0.82; 95% CI, 0.70–0.96). No associations were observed for parity, duration of menopausal hormone therapy use or lifetime number of reproductive years or ovulatory cycles. Conclusions Our study provides some evidence linking reproductive and hormonal factors with risk of DTC. Results should be interpreted cautiously considering the modest strength of the associations and potential for exposure misclassification and detection bias. Prospective studies of pre-diagnostic circulating sex steroid hormone measurements and DTC risk may provide additional insight. [ABSTRACT FROM AUTHOR]

Background: Multimorbidity is associated with premature mortality and excess health care costs. The burden of multimorbidity is highest among patients with cancer, yet trends and determinants of multimorbidity over time are poorly understood. Methods: Via Medicare claims linked to Cancer Prevention Study II data, group‐based trajectory modeling was used to compare National Cancer Institute comorbidity index score trends for cancer survivors and older adults without a cancer history. Among cancer survivors, multinomial logistic regression analyses evaluated associations between demographics, health behaviors, and comorbidity trajectories. Results: In 82,754 participants (mean age, 71.6 years [SD, 5.1 years]; 56.9% female), cancer survivors (n = 11,265) were more likely than older adults without a cancer history to experience the riskiest comorbidity trajectories: (1) steady, high comorbidity scores (remain high; odds ratio [OR], 1.36; 95% CI, 1.29–1.45), and (2) high scores that increased over time (start high and increase; OR, 1.51; 95% CI, 1.38–1.65). Cancer survivors who were physically active postdiagnosis were less likely to fall into these two trajectories (OR, 0.73; 95% CI, 0.64–0.84, remain high; OR, 0.42; 95% CI, 0.33–0.53, start high and increase) compared to inactive survivors. Cancer survivors with obesity were more likely to have a trajectory that started high and increased (OR, 2.83; 95% CI, 2.32–3.45 vs. normal weight), although being physically active offset some obesity‐related risk. Cancer survivors who smoked postdiagnosis were also six times more likely to have trajectories that started high and increased (OR, 6.86; 95% CI, 4.41–10.66 vs. never smokers). Conclusions: Older cancer survivors are more likely to have multiple comorbidities accumulated at a faster pace than older adults without a history of cancer. Weight management, physical activity, and smoking avoidance postdiagnosis may attenuate that trend. Older cancer survivors are more likely to have multiple comorbidities accumulated at a faster pace than older adults without a history of cancer. Weight management, physical activity, and smoking avoidance postdiagnosis may attenuate the trend. [ABSTRACT FROM AUTHOR]

Background: Smoking cessation at any age has been shown to improve quality of life, decrease illness, and reduce mortality. About half of smokers attempt to quit each year, but only ∼ 7 % maintain long-term abstinence unaided. Few genetic factors have been consistently associated with smoking cessation, possibly due to poor phenotype definition., Methods: We performed a genome-wide association study (GWAS) with an alternative phenotype based on the difficulty of quitting smoking (DQS) in the Cancer Prevention Study-3 cohort. Difficult quitters were defined as having made at least ten quit attempts, whether successful or not, and easy quitters as having quit after only one attempt. Only individuals of European ancestry were selected for the study. Among 10,004 smokers (5,071 difficult quitters, 4,933 easy quitters), we assessed the genetic heritability of DQS and evaluated associations between DQS and each genome-wide variant using logistic regression while adjusting for confounders, including smoking intensity (cigarettes per day)., Results: The genetic heritability of the DQS phenotype was 13 %, comparable to, or higher than, the reported heritability of other smoking behaviors (e.g., smoking intensity, cessation). Although no variants were genome-wide significant, several genes were identified at a subthreshold level (p < 10 -4 ). A variant in MEGF9 (rs149760032), a transmembrane protein largely expressed in the central nervous system, showed the strongest association with DQS (OR = 0.60, p = 1.3x10 -7 ). Additional variants associated with DQS independently by smoking intensity were also detected in GLRA3 (rs73006492, OR = 0.77, p = 5.6x10 -7 ) and FOCAD (rs112251973, OR = 1.96, p = 1.8x10 -6 ) and are plausibly related to smoking cessation through pathways in the brain and respiratory system., Conclusions: The use of an alternative cessation phenotype based on difficulty quitting smoking facilitated the identification of new pathways that could lead to unique smoking treatments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Importance: Pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2 , and PALB2 are associated with increased breast cancer risk. However, it is unknown whether breast cancer risk differs by PV type or location in carriers ascertained from the general population., Objective: To evaluate breast cancer risks associated with PV type and location in ATM, BRCA1, BRCA2, CHEK2 , and PALB2 ., Design: Age adjusted case-control association analysis for all participants, subsets of PV carriers, and women with no breast cancer family history in population-based and clinical testing cohorts., Setting: Twelve US population-based studies within the Cancer Risk Estimates Related to Susceptibility (CARRIERS) Consortium, and breast cancer cases from the UK-Biobank and an Ambry Genetics clinical testing cohort., Participants: 32,247 women with and 32,544 age-matched women without a breast cancer diagnosis from CARRIERS; 237 and 1351 women with BRCA2 PVs and breast cancer from the UKBB and Ambry Genetics, respectively., Exposures: PVs in ATM, BRCA1, BRCA2, CHEK2, and PALB2., Main Outcomes and Measures: PVs were grouped by type and location within genes and assessed for risks of breast cancer (odds ratios (OR), 95% confidence intervals (CI), and p-values) using logistic regression. Mean ages at diagnosis were compared using linear regression., Results: Compared to women carrying BRCA2 exon 11 protein truncating variants (PTVs) in the CARRIERS population-based study, women with BRCA2 ex13-27 PTVs (OR=2.7, 95%CI 1.1-7.9) and ex1-10 PTVs (OR=1.6, 95%CI 0.8-3.5) had higher breast cancer risks, lower rates of ER-negative breast cancer (ex13-27 OR=0.5, 95%CI 0.2-0.9; ex1-10 OR=0.5, 95%CI 0.1-1.0), and earlier age of breast cancer diagnosis (ex13-27 5.5 years, p<0.001; ex1-10 2.4 years, p=0.17). These associations with ER-negative breast cancer and age replicated in a high-risk clinical cohort and the population-based UK Biobank cohort. No differences in risk or age at diagnosis by gene region were observed for PTVs in other predisposition genes., Conclusions and Relevance: Population-based and clinical high-risk cohorts establish that PTVs in exon 11 of BRCA2 are associated with reduced risk of breast cancer, later age at diagnosis, and greater risk of ER-negative disease. These differential risks may improve individualized risk prediction and clinical management for women carrying BRCA2 PTVs., Key Points: Question: Does ATM , BRCA1 , BRCA2 , CHEK2 and PALB2 pathogenic variant type and location influence breast cancer risk in population-based studies? Findings: Breast cancer risk and estrogen receptor status differ based on the type and location of pathogenic variants in BRCA2 . Women carrying protein truncating variants in exon 11 have a lower breast cancer risk in the population-based cohorts, older age at diagnosis and higher rates of estrogen receptor negative breast cancer than women with exon 1-10 or exon 13-27 truncation variants in population-based and clinical testing cohorts. Meaning: Incorporating pathogenic variant type and location in cancer risk models may improve individualized risk prediction.

Clinical genetic testing identifies variants causal for hereditary cancer, information that is used for risk assessment and clinical management. Unfortunately, some variants identified are of uncertain clinical significance (VUS), complicating patient management. Case-control data is one evidence type used to classify VUS, and previous findings indicate that case-control likelihood ratios (LRs) outperform odds ratios for variant classification. As an initiative of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Analytical Working Group we analyzed germline sequencing data of BRCA1 and BRCA2 from 96,691 female breast cancer cases and 303,925 unaffected controls from three studies: the BRIDGES study of the Breast Cancer Association Consortium, the Cancer Risk Estimates Related to Susceptibility consortium, and the UK Biobank. We observed 11,227 BRCA1 and BRCA2 variants, with 6,921 being coding, covering 23.4% of BRCA1 and BRCA2 VUS in ClinVar and 19.2% of ClinVar curated (likely) benign or pathogenic variants. Case-control LR evidence was highly consistent with ClinVar assertions for (likely) benign or pathogenic variants; exhibiting 99.1% sensitivity and 95.4% specificity for BRCA1 and 92.2% sensitivity and 86.6% specificity for BRCA2 . This approach provides case-control evidence for 785 unclassified variants, that can serve as a valuable element for clinical classification.

Background: Pancreatic cancer is a leading cause of cancer-related death globally. Risk factors for pancreatic cancer include common genetic variants and potentially heavy alcohol consumption. We assessed if genetic variants modify the association between heavy alcohol consumption and pancreatic cancer risk., Methods: We conducted a genome-wide interaction analysis of single-nucleotide polymorphisms (SNP) by heavy alcohol consumption (more than three drinks per day) for pancreatic cancer in European ancestry populations from genome-wide association studies. Our analysis included 3,707 cases and 4,167 controls from case-control studies and 1,098 cases and 1,162 controls from cohort studies. Fixed-effect meta-analyses were conducted., Results: A potential novel region of association on 10p11.22, lead SNP rs7898449 (interaction P value (Pinteraction) = 5.1 × 10-8 in the meta-analysis; Pinteraction = 2.1 × 10-9 in the case-control studies; Pinteraction = 0.91 in the cohort studies), was identified. An SNP correlated with this lead SNP is an expression quantitative trait locus for the neuropilin 1 gene. Of the 17 genomic regions with genome-wide significant evidence of association with pancreatic cancer in prior studies, we observed suggestive evidence that heavy alcohol consumption modified the association for one SNP near LINC00673, rs11655237 on 17q25.1 (Pinteraction = 0.004)., Conclusions: We identified a novel genomic region that may be associated with pancreatic cancer risk in conjunction with heavy alcohol consumption located near an expression quantitative trait locus for neuropilin 1, a protein that plays an important role in the development and progression of pancreatic cancer., Impact: This work can provide insights into the etiology of pancreatic cancer, particularly in heavy drinkers., (©2024 American Association for Cancer Research.)

Background: Although the associations between genetic variations and lung cancer risk have been explored, the epigenetic consequences of DNA methylation in lung cancer development are largely unknown. Here, the genetically predicted DNA methylation markers associated with non-small cell lung cancer (NSCLC) risk by a two-stage case-control design were investigated., Methods: The genetic prediction models for methylation levels based on genetic and methylation data of 1595 subjects from the Framingham Heart Study were established. The prediction models were applied to a fixed-effect meta-analysis of screening data sets with 27,120 NSCLC cases and 27,355 controls to identify the methylation markers, which were then replicated in independent data sets with 7844 lung cancer cases and 421,224 controls. Also performed was a multi-omics functional annotation for the identified CpGs by integrating genomics, epigenomics, and transcriptomics and investigation of the potential regulation pathways., Results: Of the 29,894 CpG sites passing the quality control, 39 CpGs associated with NSCLC risk (Bonferroni-corrected p ≤ 1.67 × 10 -6 ) were originally identified. Of these, 16 CpGs remained significant in the validation stage (Bonferroni-corrected p ≤ 1.28 × 10 -3 ), including four novel CpGs. Multi-omics functional annotation showed nine of 16 CpGs were potentially functional biomarkers for NSCLC risk. Thirty-five genes within a 1-Mb window of 12 CpGs that might be involved in regulatory pathways of NSCLC risk were identified., Conclusions: Sixteen promising DNA methylation markers associated with NSCLC were identified. Changes of the methylation level at these CpGs might influence the development of NSCLC by regulating the expression of genes nearby., Plain Language Summary: The epigenetic consequences of DNA methylation in lung cancer development are still largely unknown. This study used summary data of large-scale genome-wide association studies to investigate the associations between genetically predicted levels of methylation biomarkers and non-small cell lung cancer risk at the first time. This study looked at how well larotrectinib worked in adult patients with sarcomas caused by TRK fusion proteins. These findings will provide a unique insight into the epigenetic susceptibility mechanisms of lung cancer., (© 2023 American Cancer Society.)