Spectrum of somatic mutational features of colorectal tumors in ancestrally diverse populations.

Ancestrally diverse and admixed populations, including the Hispanic/Latino/a/x/e community, are underrepresented in cancer genetic and genomic studies. Leveraging the Latino Colorectal Cancer Consortium, we analyzed whole exome sequencing data on tumor/normal pairs from 718 individuals with colorectal cancer (128 Latino, 469 non-Latino) to map somatic mutational features by ethnicity and genetic ancestry. Global proportions of African, East Asian, European, and Native American ancestries were estimated using ADMIXTURE. Associations between global genetic ancestry and somatic mutational features across genes were examined using logistic regression. TP53 , APC , and KRAS were the most recurrently mutated genes. Compared to non-Latino individuals, tumors from Latino individuals had fewer KRAS (OR=0.64, 95%CI=0.41-0.97, p=0.037) and PIK3CA mutations (OR=0.55, 95%CI=0.31-0.98, p=0.043). Genetic ancestry was associated with presence of somatic mutations in 39 genes (FDR-adjusted LRT p<0.05). Among these genes, a 10% increase in African ancestry was associated with significantly higher odds of mutation in KNCN (OR=1.34, 95%CI=1.09-1.66, p=5.74×10 -3 ) and TMEM184B (OR=1.53, 95%CI=1.10-2.12, p=0.011). Among RMGs, we found evidence of association between genetic ancestry and mutation status in CDC27 (LRT p=0.0084) and between SMAD2 mutation status and AFR ancestry (OR=1.14, 95%CI=1.00-1.30, p=0.046). Ancestry was not associated with tumor mutational burden. Individuals with above-average Native American ancestry had a lower frequency of microsatellite instable (MSI-H) vs microsatellite stable tumors (OR=0.45, 95%CI=0.21-0.99, p=0.048). Our findings provide new knowledge about the relationship between ancestral haplotypes and somatic mutational profiles that may be useful in developing precision medicine approaches and provide additional insight into genomic contributions to cancer disparities. Significance: Our data in ancestrally diverse populations adds essential information to characterize mutational features in the colorectal cancer genome. These results will help enhance equity in the development of precision medicine strategies.

Functional quality of life among newly diagnosed young adult colorectal cancer survivors compared to older adults: results from the ColoCare Study.

PURPOSE: Colorectal cancer (CRC) incidence and mortality are increasing among young adults (YAs) aged 18-39. This study compared quality of life (QOL) between YA and older adult CRC survivors in the ColoCare Study. METHODS: Participants were grouped by age (years) as follows: 18-39 (YA), 40-49, 50-64, and 65 + . Functional QOL (physical, social, role, emotional, cognitive) and global QOL were assessed with the EORTC-QLQ-C30 at enrollment, 3, 6, and 12 months. Average scores were compared between groups over time using longitudinal mixed-effect modeling. Proportions with clinically meaningful QOL impairment were calculated using age-relevant thresholds and compared between groups over time using logistic regression with mixed effects. RESULTS: Participants (N = 1590) were n = 81 YAs, n = 196 aged 40-49, n = 627 aged 50-64, and n = 686 aged 65 + . Average physical function was better among YAs than participants aged 50-64 (p = 0.010) and 65 + (p < 0.001), and average social function was worse among YAs than aged 65 + (p = 0.046). Relative to YAs, all age groups were less likely to report clinically meaningful social dysfunction (aged 40-49 OR = 0.13, 95%CI = 0.06-0.29; aged 50-64 OR = 0.10, 95%CI = 0.05-0.21; aged 65 + OR = 0.07, 95%CI = 0.04-0.15) and role dysfunction (aged 40-49 OR = 0.36, 95%CI = 0.18-0.75; aged 50-64 OR = 0.41, 95%CI = 0.22-0.78; aged 65 + OR = 0.32, 95%CI = 0.17-0.61). Participants aged 40-49 were also less likely to report physical dysfunction (OR = 0.42, 95%CI = 0.19-0.93). CONCLUSION: YA CRC survivors reported better physical and worse social function compared to older CRC survivors, and YA CRC survivors were more likely to report clinically meaningful social, role, and physical disfunction. Future work should further investigate QOL using age-relevant benchmarks to inform best practices for CRC survivorship care. TRIAL REGISTRATION: NCT02328677, registered December 2014.

Traditional Mexican dietary pattern and cancer risk among women of Mexican descent.

PURPOSE: To examine the association of a traditional Mexican diet score with risk of total, breast, and colorectal cancer among women of Mexican ethnic descent in the Women's Health Initiative (WHI). METHODS: Participants were WHI enrollees who self-identified as being of Mexican descent. Data from food frequency questionnaires self-administered at study baseline were used to calculate the MexD score, with higher scores indicating greater adherence to an a priori-defined traditional Mexican diet (high in dietary fiber, vegetables, and legumes). Incident cancers were self-reported by participants from 1993 to 2020 and adjudicated by trained physicians. We used multivariable-adjusted Cox proportional hazards models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Among 2,343 Mexican descent women (median baseline age: 59 years), a total of 270 cancers (88 breast, 37 colorectal) occurred during a mean follow-up of 14.4 years. The highest tertile of MexD score was associated with a lower risk of all-cancer incidence (HR: 0.67; 95% CI 0.49-0.91; p-trend: 0.01) and colorectal cancer (HR: 0.38; 95% CI 0.14-0.998; p-trend < 0.05), with each unit increase in the MexD score associated with a 6% lower risk of all-cancer incidence (HR: 0.94; 95% CI 0.88-0.99). There was no statistically significant association with risk of breast cancer. CONCLUSION: Consumption of a traditional Mexican diet was associated with a significantly lower risk of all-cancer incidence and colorectal cancer. Confirmation of these findings in future studies is important, given the prevalence of colorectal cancer and a growing U.S. population of women of Mexican descent.

Alcohol, Smoking, and Risks of Breast Cancer Recurrence and Mortality among Women with Luminal, Triple-Negative, and HER2-Overexpressing Breast Cancer.

BACKGROUND: This study evaluates the relationship between smoking, alcohol, and breast cancer outcomes according to molecular subtype. METHODS: This population-based prospective cohort consisted of 3,876 women ages 20 to 69 diagnosed with a first primary invasive breast cancer from 2004 to 2015 in the Seattle-Puget Sound region. Breast cancer was categorized into three subtypes based on estrogen receptor (ER), progesterone receptor (PR), and HER2 expressions: luminal (ER+), triple-negative (TN; ER-/PR-/HER2-), and HER2-overexpressing (H2E; ER-/HER2+). We fit Cox proportional hazards models to assess the association between alcohol consumption and smoking status at diagnosis and risks of recurrence, breast cancer-specific mortality, and all-cause mortality. RESULTS: Histories of ever smoking [HR, 1.33; 95% confidence interval (CI), 1.01-1.74] and current smoking (HR, 1.59; 95% CI, 1.07-2.35) were associated with greater risk of breast cancer recurrence among TN cases. Smoking was also associated with greater risk of recurrence to bone among all cases and among luminal cases. Elevated risks of breast cancer-specific and all-cause mortality were observed among current smokers across all subtypes. Alcohol use was not positively associated with risk of recurrence or mortality overall; however, TN patients who drank four or more drinks per week had a decreased risk of recurrence (HR, 0.71; 95% CI, 0.51-0.98) and breast cancer-specific mortality (HR, 0.73; 95% CI, 0.55-0.97) compared with non-current drinkers. CONCLUSIONS: Patients with breast cancer with a history of smoking at diagnosis have elevated risks of recurrence and mortality. IMPACT: These findings underscore the need to prioritize smoking cessation among women diagnosed with breast cancer.

Trajectories and risk factors of fatigue following colorectal cancer diagnosis.

AIM: This study sought to identify groups of colorectal cancer patients based upon trajectories of fatigue and examine how demographic, clinical and behavioural risk factors differentiate these groups. METHOD: Patients were from six cancer centres in the United States and Germany. Fatigue was measured using the fatigue subscale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) at five time points (baseline/enrolment and 3, 6, 12 and 24 months after diagnosis). Piecewise growth mixture models identified latent trajectories of fatigue. Logistic regression models examined differences in demographic, clinical and behavioural characteristics between fatigue trajectory groups. RESULTS: Among 1615 participants (57% men, 86% non-Hispanic White, mean age 61 ± 13 years at diagnosis), three distinct groups were identified. In the high fatigue group (36%), fatigue significantly increased in the first 6 months after diagnosis and then showed statistically and clinically significant improvement from 6 to 24 months (P values < 0.01). Throughout the study period, average fatigue met or exceeded cutoffs for clinical significance. In the moderate (34%) and low (30%) fatigue groups, fatigue levels remained below or near population norms across the study period. Patients who were diagnosed with Stage II-IV disease and/or current smokers were more likely to be in the high fatigue than in the moderate fatigue group (P values < 0.05). CONCLUSION: A large proportion of colorectal cancer patients experienced sustained fatigue after initiation of cancer treatment. Patients with high fatigue at the time of diagnosis may benefit from early supportive care.

Association between antidepressant use and second breast cancer event after ductal carcinoma in situ diagnosis: a nested case-control study.

PURPOSE: Controversy exists regarding the potential relationship between antidepressant use and risk of breast cancer. No previous studies have evaluated the relationship between antidepressant use after diagnosis of ductal carcinoma in situ (DCIS) and risk of a subsequent breast cancer restricted to women with a history of DCIS. METHODS: We conducted a population-based, nested case-control study in western Washington State. Cases included 337 women diagnosed with DCIS and a subsequent breast cancer and they were compared to 592 individually matched controls (on age, year of DCIS diagnosis, primary treatment, histology, grade, and disease-free survival time) who were diagnosed with DCIS but not a subsequent breast cancer. Information on antidepressant use after DCIS diagnosis was obtained from comprehensive medical records reviews. Antidepressant use was defined as greater or equal to 3 months of duration. RESULTS: Antidepressant use after initial DCIS was associated with a 1.4-fold increased risk of a subsequent breast cancer event (adjusted OR 1.41, 95% CI 1.02, 1.95). Similar risks were observed when assessing individual antidepressant classes, however, there was no sufficient power across specific classes of antidepressants. CONCLUSIONS: Antidepressant use after DCIS diagnosis was associated with an increased risk of subsequent breast cancer in women. Further studies are needed to confirm the associations observed.

Racial/ethnic disparities in risk of breast cancer mortality by molecular subtype and stage at diagnosis.

PURPOSE: Previous research has found significant survival disparities between Black and White women among select stages and subtypes of breast cancer, however other racial/ethnic groups have been less well-studied. This study expands on previous research, examining differences in breast cancer-specific mortality across multiple racial and ethnic groups. METHODS: Women diagnosed with a first primary invasive breast cancer between 2010 and 2016 who were 20-85 years of age at diagnosis were identified from 18 Surveillance, Epidemiology, and End Results (SEER) registries. Subtypes were defined by joint hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status. Cox proportional hazards models for each stage and subtype were fit, with non-Hispanic white women as the reference group. Effect modification by age at diagnosis (< 50, ≥ 50) was found and thus analyses were age-stratified. RESULTS: After multivariable adjustment, younger Black women had greater risks of breast cancer-specific death for all stages of HR+/HER2-, and certain stages of HR+/HER2+ , TN, and HR-/HER2 + breast cancer. Asian/Pacific Islander women generally had a lower hazard of breast cancer-specific death. Older Hispanic White women had a lower hazard of breast cancer-specific death for stages I-III HR + /HER2- and stage II TN breast cancer. CONCLUSIONS: These findings demonstrate that different racial/ethnic groups experience different risks of breast cancer-specific mortality by stage and subtype. Efforts to address survival disparities should place additional focus on young Black women, as they experience meaningful disparities in breast cancer-specific mortality.

Antihypertensive medications and risks of recurrence and mortality in luminal, triple-negative, and HER2-overexpressing breast cancer.

PURPOSE: Antihypertensives are commonly prescribed medications and their effect on breast cancer recurrence and mortality is not clear, particularly among specific molecular subtypes of breast cancer: luminal, triple-negative (TN), and HER2-overexpressing (H2E). METHODS: A population-based prospective cohort study of women aged 20-69 diagnosed with a first primary invasive breast cancer between 2004 and 2015 was conducted in the Seattle, Washington and Albuquerque, New Mexico greater metropolitan areas. Multivariable-adjusted Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for risks of breast cancer recurrence, breast cancer-specific mortality, and all-cause mortality associated with hypertension and antihypertensives. RESULTS: In this sample of 2,383 luminal, 1,559 TN, and 615 H2E breast cancer patients, overall median age was 52 (interquartile range, 44-60). Hypertension and current use of antihypertensives were associated with increased risks of all-cause mortality in each subtype. Current use of angiotensin-converting enzyme inhibitors was associated with increased risks of both recurrence and breast cancer-specific mortality among luminal patients (HR: 2.5; 95% CI: 1.5, 4.3 and HR: 1.9; 95% CI: 1.2, 3.0, respectively). Among H2E patients, current use of calcium channel blockers was associated with an increased risk of breast cancer-specific mortality (HR: 1.8; 95% CI: 0.6, 5.4). CONCLUSION: Our findings suggest that some antihypertensive medications may be associated with adverse breast cancer outcomes among women with certain molecular subtypes. Additional studies are needed to confirm these findings.

Risks of preterm birth and growth restriction in second births after a first-born male infant.

PURPOSE: A first-born male infant may lead to an exaggerated immune response in the mother in subsequent pregnancies, increasing the risk of preterm birth (PTB) and growth restriction. This study investigated whether risks of PTB and growth restriction are greater among infants preceded by a first-born male infant and evaluated if the associations differ by paternity change or the second-born's sex. METHODS: We conducted a population-based cohort study using 2003-2014 Washington State birth certificate data and included mothers and birth year frequency-matched second live-born infants preceded by a first-born male (n = 58,704) or by a first-born female infant (n = 58,704). Using stratified analyses, we estimated adjusted relative risks (RRs) of PTB, low birthweight (LBW), and small for gestational age (SGA). RESULTS: Second-born infants preceded by a first-born male had greater risks of PTB (RR = 1.14; 95% CI: 1.09-1.19), LBW (RR = 1.17; 1.10-1.24), and SGA (RR = 1.13; 1.08-1.18). The RR was elevated for indicated PTB (RR = 1.19; 1.10-1.29), preterm premature rupture of membranes (RR = 1.15; 1.01-1.32), and spontaneous PTB (RR = 1.12; 1.05-1.20). Associations did not differ by second-born infant's sex or paternity change. CONCLUSION: Having a first-born male infant was associated with a greater risk of PTB, LBW, and SGA in the second-born infant.

Recent Use of Oral Contraceptives and Risk of Luminal B, Triple-Negative, and HER2-Overexpressing Breast Cancer.

Oral contraceptive use is a well-established risk factor for breast cancer and is common among reproductive-aged women in the USA. Its relationship with less common, more aggressive, molecular subtypes is less clear. A population-based case-case analysis was conducted comparing three less common molecular subtypes to luminal A breast cancer among 1701 premenopausal cases aged 21-49 diagnosed with a first primary invasive breast cancer between 2004 and 2015. Medical record reviews and structured interviewer-administered questionnaires were used to collect data on oral contraceptive use. Multinomial logistic regression was used to estimate odds ratios (OR) and corresponding 95% confidence intervals (95% CI) for recency of oral contraceptive use for each subtype of breast cancer. Current use of oral contraceptives and use within 5 years before diagnosis was associated with lower odds of H2E tumors compared with luminal A tumors [OR = 0.5, 95% CI: 0.3, 0.9 and OR = 0.5, 95% CI: 0.4, 0.8, respectively] with increasing duration associated with decreasing odds (p for trend < 0.05). Oral contraceptive use was not associated with risks of TN or luminal B breast cancer. Oral contraceptive use may be more strongly positively associated with risks of luminal A, luminal B, and TN breast cancer than with risk of H2E tumors. These findings contribute to the etiological understanding of different molecular subtypes of breast cancer.