Benefits of nature-based walking for breast cancer survivors.

INTRODUCTION: Physical activity (PA) promotes significant physical and psychosocial benefits for breast cancer survivors. While evidence exists regarding recommendations for the frequency, duration and intensity of exercise that optimise PA benefits for cancer survivors, the role of the environment in achieving optimal outcomes has yet to be determined. This paper presents a protocol for a clinical trial to evaluate the feasibility of a 3-month nature-based walking programme for breast cancer survivors. Secondary outcomes assessed include the impact of the intervention on fitness, quality of life outcomes, and biomarkers of ageing and inflammation. METHODS AND ANALYSIS: The trial is a 12-week single-arm pilot study. Twenty female breast cancer survivors will engage in a supervised moderate intensity walking intervention in small groups in a nature reserve for 50 minutes three times per week. Data will be collected at baseline and end of study, and include assessment of inflammatory cytokines and anti-inflammatory myokines (TNF-α, IL-1ß, IL-6, CRP, TGF-ß, IL-10, IL-13), as well as ageing (DNA methylation, ageing genes) biomarkers; surveys (Patient-Reported Outcomes Measurement Information System-29, Functional Assessment of Cancer Therapy-General, Post-Traumatic Growth Inventory); and fitness assessments (6 min Walk Test, Grip-Strength, One Repetition-Maximum Leg Press). Participants will also complete weekly surveys assessing social support and participate in an exit interview. This is an important first step for future research on the influence of exercise environment on cancer survivor PA outcomes. ETHICS AND DISSEMINATION: This study was approved by the Cedars Sinai Medical Center Institutional Review Board (IIT2020-20). Findings will be disseminated through academic manuscripts, conferences, and community presentations. TRIAL REGISTRATION NUMBER: NCT04896580.

The 24-Hour Movement Paradigm: An integrated approach to the measurement and promotion of daily activity in cancer clinical trials.

Increased physical activity (PA), improved sleep, and decreased sedentary behavior (SB) are essential components of supportive care for cancer survivors. However, researchers and health care professionals have achieved limited success in improving these behaviors among cancer survivors. One potential reasoning is that, over the past two decades, guidelines for promoting and measuring PA, sleep, and SB have been largely siloed. With greater understanding of these three behaviors, health behavior researchers have recently developed a new paradigm: the 24-Hour movement approach. This approach considers PA, SB, and sleep as movement behaviors along a continuum that represent low through vigorous intensity activity. Together these three behaviors form the sum of an individual's movement across a 24-hour day. While this paradigm has been studied in the general population, its usage is still limited in cancer populations. Here, we seek to highlight (a) the potential benefits of this new paradigm for clinical trial design in oncology; (b) how this approach can allow for greater integration of wearable technology as a means of assessing and monitoring patient health outside the clinical setting, improving patient autonomy through self-monitoring of movement behavior. Ultimately, implementation of the 24-Hour movement paradigm will allow health behavior research in oncology to better promote and assess critical health behaviors to support the long-term well-being for cancer patients and survivors.

Melanoma awareness and prevention among latinx and non-latinx white adults in urban and rural California: A qualitative exploration.

BACKGROUND: Melanoma mortality rates in the US are highest among older men, individuals of lower socioeconomic status (SES), and people of color. To better understand these inequities, a qualitative exploratory study was conducted in Northern and Southern California to generate knowledge about barriers and facilitators of awareness, prevention, and early detection of melanoma in lower SES Latinx and non-Latinx White (NLW) individuals living in urban and semi-rural areas. METHODS: Nineteen focus groups were conducted (N = 176 adult participants), stratified by race/ethnicity (Latinx, low-income NLW), geography (semi-rural, urban), and language (English and Spanish). Inductive and deductive thematic analysis was conducted, and the findings were organized using the socioecological model framework: individual, interpersonal, community, and health system/policy levels. RESULTS: Four socioecological themes describe how key factors affect knowledge, perceived risk, preventive behaviors, and melanoma screening. Individual level findings revealed that many participants were not familiar with melanoma, yet were willing to learn through trusted sources. Having brown or darker skin tone was perceived as being associated with lower risk for skin cancer. Interpersonally, social relationships were important influences for skin cancer prevention practice. However, for several Latinx and semi-rural participants, conversations about melanoma prevention did not occur with family and peers. At the community level, semi-rural participants reported distance or lack of transportation to a clinic as challenges for accessing dermatology care. Healthcare systems barriers included burdens of additional healthcare costs for dermatology visits and obtaining referral. CONCLUSIONS: Varying factors influence the awareness levels, beliefs, and behaviors associated with knowledge, prevention, and early detection of melanoma among low-income Latinx and NLW individuals and in semi-rural areas. Results have implications for health education interventions. Navigation strategies that target individuals, families, and health care settings can promote improved prevention and early detection of melanoma in these communities.

Expanded Parameters in Active Surveillance for Low-risk Papillary Thyroid Carcinoma: A Nonrandomized Controlled Trial.

Importance: Unlike for prostate cancer, active surveillance for thyroid cancer has not achieved wide adoption. The parameters by which this approach is feasible are also not well defined, nor is the effect of patient anxiety. Objective: To determine if expanded size/growth parameters for patients with low-risk thyroid cancer are viable, as well as to assess for cohort differences in anxiety. Design, Setting, and Participants: This prospective nonrandomized controlled trial was conducted at a US academic medical center from 2014 to 2021, with mean [SD] 37.1 [23.3]-month follow-up. Of 257 patients with 20-mm or smaller Bethesda 5 to 6 thyroid nodules, 222 (86.3%) enrolled and selected treatment with either active surveillance or immediate surgery. Delayed surgery was recommended for size growth larger than 5 mm or more than 100% volume growth. Patients completed the 18-item Thyroid Cancer Modified Anxiety Scale over time. Interventions: Active surveillance. Main Outcomes and Measures: Cumulative incidence and rate of size/volume growth. Results: Of the 222 patients enrolled, the median (IQR) age for the study population was 46.8 (36.6-58) years, and 76.1% were female. Overall, 112 patients (50.5%) underwent treatment with active surveillance. Median tumor size was 11.0 mm (IQR, 9-15), and larger tumors (10.1-20.0 mm) comprised 67 cases (59.8%). One hundred one (90.1%) continued to receive treatment with active surveillance, 46 (41.0%) had their tumors shrink, and 0 developed regional/distant metastases. Size growth of more than 5 mm was observed in 3.6% of cases, with cumulative incidence of 1.2% at 2 years and 10.8% at 5 years. Volumetric growth of more than 100% was observed in 7.1% of cases, with cumulative incidence of 2.2% at 2 years and 13.7% at 5 years. Of 110 patients who elected to undergo immediate surgery, 21 (19.1%) had equivocal-risk features discovered on final pathology. Disease severity for all such patients remained classified as stage I. Disease-specific and overall survival rates in both cohorts were 100%. On multivariable analysis, immediate surgery patients exhibited significantly higher baseline anxiety levels compared with active surveillance patients (estimated difference in anxiety scores between groups at baseline, 0.39; 95% CI, 0.22-0.55; P < .001). This difference endured over time, even after intervention (estimated difference at 4-year follow-up, 0.50; 95% CI, 0.21-0.79; P = .001). Conclusions and Relevance: The results of this nonrandomized controlled trial suggest that a more permissive active surveillance strategy encompassing most diagnosed thyroid cancers appears viable. Equivocal-risk pathologic features exist in a subset of cases that can be safely treated, but suggest the need for more granular risk stratification. Surgery and surveillance cohorts possess oppositional levels of worry, elevating the importance of shared decision-making when patients face treatment equivalence. Trial Registration: ClinicalTrials.gov Identifier: NCT02609685.

Addressing Health Disparities Across the Cancer Continuum-a Los Angeles Approach to Achieving Equity.

Introduction: Different models have been developed to address inequities across the cancer care continuum. However, there remains a scarcity of best practices on understanding and responding to the burden of cancer in a defined catchment area.As such, the National Cancer Institute (NCI) recently provided a framework to maximize the impact on cancer burden, including a greater focus on community outreach and engagement. In this paper, we describe how Cedars Sinai Cancer (CSC), a health system that serves one of the most diverse counties in the US, implemented the framework to define its catchment area, characterize its population, identify high risk priority groups, and make decisions to address health disparities. Methods: We provide a review of the methods used to assess socio-ecological levels of influence. Data were reviewed from numerous national, statewide, and county sources and supplemented by locally administered questionnaires, heat maps, and community profile summaries to gain more localized snapshots of cancer disparities in Los Angeles County. Lastly, feedback was solicited from external peer groups, community stakeholders, and key decision-makers, and the proposed catchment area was aligned with the State's Cancer Plan and the NCI Catchment Area and Community Outreach and Engagement Mandate. Results: The selected CSC catchment area meets NCI criteria and has potential to demonstrate impact both at the population level and within specialty populations. As a result, strategies are being developed to organize community outreach and engagement, as well as research across basic, clinical, and population sciences to guide cancer control and prevention efforts. Discussion: To maintain a high level of cultural inclusion and sensitivity, multiple layers of data are needed to understand localized pictures of cancer disparities and underlying causes. Community engagement remains essential to implementing policy, best practice, and translational science for broader impact. Impact: The clinical and translation work conducted at any cancer center requires an understanding of the determinants of health that contribute to the differences in cancer incidence and mortality among different groups. The NCI-aligned approach that we highlight is critical to support the design of future cancer control strategies that address and possibly reduce local health inequities.

Rare Variants in the DNA Repair Pathway and the Risk of Colorectal Cancer.

BACKGROUND: Inherited susceptibility is an important contributor to colorectal cancer risk, and rare variants in key genes or pathways could account in part for the missing proportion of colorectal cancer heritability. METHODS: We conducted an exome-wide association study including 2,327 cases and 2,966 controls of European ancestry from three large epidemiologic studies. Single variant associations were tested using logistic regression models, adjusting for appropriate study-specific covariates. In addition, we examined the aggregate effects of rare coding variation at the gene and pathway levels using Bayesian model uncertainty techniques. RESULTS: In an exome-wide gene-level analysis, we identified ST6GALNAC2 as the top associated gene based on the Bayesian risk index (BRI) method [summary Bayes factor (BF)BRI = 2604.23]. A rare coding variant in this gene, rs139401613, was the top associated variant (P = 1.01 × 10-6) in an exome-wide single variant analysis. Pathway-level association analyses based on the integrative BRI (iBRI) method found extreme evidence of association with the DNA repair pathway (BFiBRI = 17852.4), specifically with the nonhomologous end joining (BFiBRI = 437.95) and nucleotide excision repair (BFiBRI = 36.96) subpathways. The iBRI method also identified RPA2, PRKDC, ERCC5, and ERCC8 as the top associated DNA repair genes (summary BFiBRI ≥ 10), with rs28988897, rs8178232, rs141369732, and rs201642761 being the most likely associated variants in these genes, respectively. CONCLUSIONS: We identified novel variants and genes associated with colorectal cancer risk and provided additional evidence for a role of DNA repair in colorectal cancer tumorigenesis. IMPACT: This study provides new insights into the genetic predisposition to colorectal cancer, which has potential for translation into improved risk prediction.

Development of a DNA Methylation-Based Diagnostic Signature to Distinguish Benign Oncocytoma From Renal Cell Carcinoma.

PURPOSE: A challenge in the diagnosis of renal cell carcinoma (RCC) is to distinguish chromophobe RCC (chRCC) from benign renal oncocytoma, because these tumor types are histologically and morphologically similar, yet they require different clinical management. Molecular biomarkers could provide a way of distinguishing oncocytoma from chRCC, which could prevent unnecessary treatment of oncocytoma. Such biomarkers could also be applied to preoperative biopsy specimens such as needle core biopsy specimens, to avoid unnecessary surgery of oncocytoma. METHODS: We profiled DNA methylation in fresh-frozen oncocytoma and chRCC tumors and adjacent normal tissue and used machine learning to identify a signature of differentially methylated cytosine-phosphate-guanine sites (CpGs) that robustly distinguish oncocytoma from chRCC. RESULTS: Unsupervised clustering of Stanford and preexisting RCC data from The Cancer Genome Atlas (TCGA) revealed that of all RCC subtypes, oncocytoma is most similar to chRCC. Unexpectedly, however, oncocytoma features more extensive, overall abnormal methylation than does chRCC. We identified 79 CpGs with large methylation differences between oncocytoma and chRCC. A diagnostic model trained on 30 CpGs could distinguish oncocytoma from chRCC in 10-fold cross-validation (area under the receiver operating curve [AUC], 0.96 (95% CI, 0.88 to 1.00)) and could distinguish TCGA chRCCs from an independent set of oncocytomas from a previous study (AUC, 0.87). This signature also separated oncocytoma from other RCC subtypes and normal tissue, revealing it as a standalone diagnostic biomarker for oncocytoma. CONCLUSION: This CpG signature could be developed as a clinical biomarker to support differential diagnosis of oncocytoma and chRCC in surgical samples. With improved biopsy techniques, this signature could be applied to preoperative biopsy specimens.

Exploratory Genome-Wide Interaction Analysis of Nonsteroidal Anti-inflammatory Drugs and Predicted Gene Expression on Colorectal Cancer Risk.

BACKGROUND: Regular use of nonsteroidal anti-inflammatory drugs (NSAID) is associated with lower risk of colorectal cancer. Genome-wide interaction analysis on single variants (G × E) has identified several SNPs that may interact with NSAIDs to confer colorectal cancer risk, but variations in gene expression levels may also modify the effect of NSAID use. Therefore, we tested interactions between NSAID use and predicted gene expression levels in relation to colorectal cancer risk. METHODS: Genetically predicted gene expressions were tested for interaction with NSAID use on colorectal cancer risk among 19,258 colorectal cancer cases and 18,597 controls from 21 observational studies. A Mixed Score Test for Interactions (MiSTi) approach was used to jointly assess G × E effects which are modeled via fixed interaction effects of the weighted burden within each gene set (burden) and residual G × E effects (variance). A false discovery rate (FDR) at 0.2 was applied to correct for multiple testing. RESULTS: Among the 4,840 genes tested, genetically predicted expression levels of four genes modified the effect of any NSAID use on colorectal cancer risk, including DPP10 (PG×E = 1.96 × 10-4), KRT16 (PG×E = 2.3 × 10-4), CD14 (PG×E = 9.38 × 10-4), and CYP27A1 (PG×E = 1.44 × 10-3). There was a significant interaction between expression level of RP11-89N17 and regular use of aspirin only on colorectal cancer risk (PG×E = 3.23 × 10-5). No interactions were observed between predicted gene expression and nonaspirin NSAID use at FDR < 0.2. CONCLUSIONS: By incorporating functional information, we discovered several novel genes that interacted with NSAID use. IMPACT: These findings provide preliminary support that could help understand the chemopreventive mechanisms of NSAIDs on colorectal cancer.

Correction: Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Endoscopic History and Provider Characteristics Influence Gastric Cancer Survival in Asian Americans.

Gastric carcinoma (GC) disproportionately affects Asian Americans. We examined whether history of upper gastrointestinal (GI) endoscopy was associated with lower stage at GC diagnosis among Asian Americans and whether origin of providers influenced referral for endoscopy. We employed Surveillance Epidemiology and End Results-Medicare data on Asian Americans diagnosed with GC in 2004-2013 (n = 1,554). Stage distribution, GI conditions at diagnosis, and history of endoscopy were compared between Asian ethnic groups. Multivariate logistic regression adjusting for age, sex, poverty level, tumor location, and histology was used to examine the association of ethnicity and endoscopic history with stage I disease at diagnosis of GC. Koreans were more likely to be diagnosed with stage I, T1a GC and have prior history of endoscopy, compared with other Asian ethnicities (24% vs. 8% for stage I, T1a; 40% vs. 15% for endoscopy). Patients with primary care providers of concordant ethnic origin were more likely to have history of endoscopy. Asian American patients with GC with history of endoscopy were more likely to be diagnosed with GC at stage I disease (adjusted OR, 3.07; 95% confidence interval, 2.34-4.02). Compared with other Asian Americans, Koreans were diagnosed with GC at earlier stages owing to common history of endoscopy, which was more often undergone by patients with primary care providers of concordant ethnic origin. Overall, upper GI endoscopy was associated with early detection of GC in Asian Americans. Novelty and Impact. It is well-established that Asian Americans in the United States are disproportionately affected by gastric cancer. In our study we found that Asian American patients treated by physicians of similar ethnic background are more likely to undergo upper GI endoscopy in the United States, leading to early detection of gastric cancer and longer survival. Given this, targeted endoscopic screening in Asian Americans should be considered for early detection of GC.

Potential impact of family history-based screening guidelines on the detection of early-onset colorectal cancer.

BACKGROUND: Initiating screening at an earlier age based on cancer family history is one of the primary recommended strategies for the prevention and detection of early-onset colorectal cancer (EOCRC), but data supporting the effectiveness of this approach are limited. The authors assessed the performance of family history-based guidelines for identifying individuals with EOCRC. METHODS: The authors conducted a population-based, case-control study of individuals aged 40 to 49 years with (2473 individuals) and without (772 individuals) incident CRC in the Colon Cancer Family Registry from 1998 through 2007. They estimated the sensitivity and specificity of family history-based criteria jointly recommended by the American Cancer Society, the US Multi-Society Task Force on CRC, and the American College of Radiology in 2008 for early screening, and the age at which each participant could have been recommended screening initiation if these criteria had been applied. RESULTS: Family history-based early screening criteria were met by approximately 25% of cases (614 of 2473 cases) and 10% of controls (74 of 772 controls), with a sensitivity of 25% and a specificity of 90% for identifying EOCRC cases aged 40 to 49 years. Among 614 individuals meeting early screening criteria, 98.4% could have been recommended screening initiation at an age younger than the observed age of diagnosis. CONCLUSIONS: Of CRC cases aged 40 to 49 years, 1 in 4 met family history-based early screening criteria, and nearly all cases who met these criteria could have had CRC diagnosed earlier (or possibly even prevented) if earlier screening had been implemented as per family history-based guidelines. Additional strategies are needed to improve the detection and prevention of EOCRC for individuals not meeting family history criteria for early screening.

Impaired Immune Health in Survivors of Diffuse Large B-Cell Lymphoma.

PURPOSE: Therapeutic advances for diffuse large B-cell lymphoma (DLBCL) have led to an increasing number of survivors. Both DLBCL and its treatments perturb the immune system, yet little is known about immune health during extended survivorship. METHODS: In this retrospective cohort study, we compared 21,690 survivors of DLBCL from the California Cancer Registry (CCR) to survivors of breast, prostate, head and neck, and melanoma cancers. We linked their CCR records to a statewide database documenting hospital, emergency room, and ambulatory surgery visits and investigated the incidence of autoimmune conditions, immune deficiencies, and infections 1-10 years after cancer diagnosis. RESULTS: We found elevated incidence rate ratios (IRRs) for many immune-related conditions in survivors of DLBCL compared with other cancer survivors, including significantly and consistently elevated IRRs for viral and fungal pneumonias (up to 10.8-fold), meningitis (up to 5.3-fold), as well as humoral deficiency (up to 17.6-fold) and autoimmune cytopenias (up to 12-fold). IRRs for most conditions remained high even in the late survivorship period (5-10 years after cancer diagnosis). The elevated risks could not be explained by exposure to chemotherapy, stem-cell transplantation, or rituximab, except for IRRs for humoral deficiency, which were consistently higher after the incorporation of rituximab into DLBCL treatments. CONCLUSION: To our knowledge, this is the largest cohort study with extended follow-up to demonstrate impaired immune health in survivors of DLBCL. The observed persistent, elevated risks for autoimmune diseases, immune deficiencies, and infectious conditions may reflect persistent immune dysregulation caused by lymphoma or treatment and may lead to excess morbidity and mortality during survivorship. Improved understanding of these risks could meaningfully improve long-term care of patients with DLBCL.

Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.

PURPOSE: Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer. METHODS: We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years. RESULTS: There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer. CONCLUSION: Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.

DNA repair and cancer in colon and rectum: Novel players in genetic susceptibility.

Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p-value = 3.5 × 10-6 ) and rs2189517 (in RAD51B) with rectal cancer risk (p-value = 5.7 × 10-6 ). The results had statistical significance close to the Bonferroni corrected p-value of 5.8 × 10-6 . Ninety-four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g., rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis-eQTL suggesting possible mechanisms of carcinogenesis.

Type 2 diabetes mellitus, blood cholesterol, triglyceride and colorectal cancer risk in Lynch syndrome.

BACKGROUND: Type 2 diabetes mellitus and high total cholesterol and triglycerides are known to be associated with increased colorectal cancer risk for the general population. These associations are unknown for people with a germline DNA mismatch repair gene mutation (Lynch syndrome), who are at high risk of colorectal cancer. METHODS: This study included 2023 (56.4% female) carriers with a mismatch repair gene mutation (737 in MLH1, 928 in MSH2, 230 in MSH6, 106 in PMS2, 22 in EPCAM) recruited by the Colon Cancer Family Registry between 1998 and 2012. Weighted Cox regression was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for the associations between self-reported type 2 diabetes, high cholesterol, triglyceride and colorectal cancer risk. RESULTS: Overall, 802 carriers were diagnosed with colorectal cancer at a median age of 42 years. A higher risk of colorectal cancer was observed in those with self-reported type-2 diabetes (HR 1.92; 95% CI, 1.03-3.58) and high cholesterol (HR 1.76; CI 1.23-2.52) compared with those without these conditions. There was no evidence of high triglyceride being associated with colorectal cancer risk. CONCLUSION: For people with Lynch syndrome, self-reported type-2 diabetes mellitus and high cholesterol were associated with increased colorectal cancer risk.

Association of a Pathway-Specific Genetic Risk Score With Risk of Radiation-Associated Contralateral Breast Cancer.

Importance: Radiation therapy for breast cancer is associated with increased risk of a second primary contralateral breast cancer, but the genetic factors modifying this association are not well understood. Objective: To determine whether a genetic risk score comprising single nucleotide polymorphisms in the nonhomologous end-joining DNA repair pathway is associated with radiation-associated contralateral breast cancer. Design, Setting, and Participants: This case-control study included a case group of women with contralateral breast cancer that was diagnosed at least 1 year after a first primary breast cancer who were individually matched to a control group of women with unilateral breast cancer. Inclusion criteria were receiving a first invasive breast cancer diagnosis prior to age 55 years between 1985 and 2008. Women were recruited through 8 population-based cancer registries in the United States, Canada, and Denmark as part of the Women's Environment, Cancer, and Radiation Epidemiology Studies I (November 2000 to August 2004) and II (March 2010 to December 2012). Data analysis was conducted from July 2017 to August 2019. Exposures: Stray radiation dose to the contralateral breast during radiation therapy for the first breast cancer. A novel genetic risk score comprised of genetic variants in the nonhomologous end-joining DNA repair pathway was considered the potential effect modifier, dichotomized as high risk if the score was above the median of 74 and low risk if the score was at or below the median. Main Outcomes and Measures: The main outcome was risk of contralateral breast cancer associated with stray radiation dose stratified by genetic risk score, age, and latency. Results: A total of 5953 women were approached for study participation, and 3732 women (62.7%) agreed to participate. The median (range) age at first diagnosis was 46 (23-54) years. After 5 years of latency or more, among women who received the first diagnosis when they were younger than 40 years, exposure to 1.0 Gy (to convert to rad, multiply by 100) or more of stray radiation was associated with a 2-fold increased risk of contralateral breast cancer compared with women who were not exposed (rate ratio, 2.0 [95% CI, 1.1-3.6]). The risk was higher among women with a genetic risk score above the median (rate ratio, 3.0 [95% CI, 1.1-8.1]), and there was no association among women with a genetic risk score below the median (rate ratio, 1.3 [95% CI, 0.5-3.7]). Among younger women with a high genetic risk score, the attributable increased risk for contralateral breast cancer associated with stray radiation dose was 28%. Conclusions and Relevance: This study found an increased risk of contralateral breast cancer that was attributable to stray radiation exposure among women with a high genetic risk score and who received a first breast cancer diagnosis when they were younger than 40 years after 5 years or more of latency. This genetic risk score may help guide treatment and surveillance for women with breast cancer.

Folic acid supplementation and risk of colorectal neoplasia during long-term follow-up of a randomized clinical trial.

BACKGROUND: The Aspirin/Folate Polyp Prevention Study previously found folic acid increased risk of advanced and multiple colorectal adenomas during a surveillance colonoscopy interval starting about 3 y after randomization. OBJECTIVE: We conducted secondary analyses to evaluate folic acid effects with additional follow-up after treatment was stopped. METHODS: In total, 1021 participants recently diagnosed with colorectal adenomas were randomly assigned to 1 mg/d of folic acid (n = 516) or placebo (n = 505), with or without aspirin, beginning 6 July 1994. The original 3-y treatment period was extended into a subsequent colonoscopy interval, but eventually stopped prematurely on 1 October 2004. With additional post-treatment follow-up, a total of 663 participants who extended treatment completed a second colonoscopic surveillance interval after the initial 3-y follow-up. In addition, 490 participants provided information regarding a subsequent surveillance colonoscopy occurring before completion of follow-up on 31 May 2012, including 325 who had agreed to extended treatment. Study endpoints included conventional adenomas, sessile serrated adenomas/polyps (SSA/Ps), or colorectal cancer, and RRs with 95% CIs were adjusted for baseline characteristics associated with availability of follow-up. RESULTS: Among those who extended treatment, any colorectal neoplasia was found in 118 (36%) participants assigned to placebo and 146 (43%) assigned to folic acid during the second surveillance interval (RR: 1.21; 95% CI: 0.99, 1.47; P = 0.06). Increased risk of SSA/P with extended folic acid supplementation was statistically significant during the second surveillance interval (RR: 1.94; 95% CI: 1.02, 3.68; P = 0.04). There was no evidence of post-treatment effects for any colorectal neoplasia (RR: 1.01; 95% CI: 0.80, 1.28; P = 0.94), and the post-treatment effect for SSA/P was no longer statistically significant (RR: 1.38; 95% CI: 0.59, 3.19; P = 0.46). CONCLUSIONS: Delayed treatment effects were not observed, but folic acid may increase SSA/P risk. This trial was registered at clinicaltrials.gov as NCT00272324.

Methylated SEPTIN9 plasma test for colorectal cancer detection may be applicable to Lynch syndrome.

OBJECTIVE: The plasma-based methylated SEPTIN9 (mSEPT9) is a colorectal cancer (CRC) screening test for adults aged 50-75 years who are at average risk for CRC and have refused colonoscopy or faecal-based screening tests. The applicability of mSEPT9 for high-risk persons with Lynch syndrome (LS), the most common hereditary CRC condition, has not been assessed. This study sought preliminary evidence for the utility of mSEPT9 for CRC detection in LS. DESIGN: Firstly, SEPT9 methylation was measured in LS-associated CRC, advanced adenoma, and subject-matched normal colorectal mucosa tissues by pyrosequencing. Secondly, to detect mSEPT9 as circulating tumor DNA, the plasma-based mSEPT9 test was retrospectively evaluated in LS subjects using the Epi proColon 2.0 CE assay adapted for 1mL plasma using the "1/1 algorithm". LS case groups included 20 peri-surgical cases with acolonoscopy-based diagnosis of CRC (stages I-IV), 13 post-surgical metastatic CRC, and 17 pre-diagnosis cases. The control group comprised 31 cancer-free LS subjects. RESULTS: Differential hypermethylation was found in 97.3% (36/37) of primary CRC and 90.0% (18/20) of advanced adenomas, showing LS-associated neoplasia frequently produce the mSEPT9 biomarker. Sensitivity of plasma mSEPT9 to detect CRC was 70.0% (95% CI, 48%-88%)in cases with a colonoscopy-based CRC diagnosis and 92.3% (95% CI, 64%-100%) inpost-surgical metastatic cases. In pre-diagnosis cases, plasma mSEPT9 was detected within two months prior to colonoscopy-based CRC diagnosis in 3/5 cases. Specificity in controls was 100% (95% CI 89%-100%). CONCLUSION: These preliminary findings suggest mSEPT9 may demonstrate similar diagnostic performance characteristics in LS as in the average-risk population, warranting a well-powered prospective case-control study.