Modeling risks of cardiovascular and cancer mortality following a diagnosis of loco-regional breast cancer

Background Many women with breast cancer also have a high likelihood of cardiovascular mortality, and while there are several cardiovascular risk prediction models, none have been validated in a cohort of breast cancer patients. We first compared the performance of commonly-used cardiovascular models, and then derived a new model where breast cancer and cardiovascular mortality were modeled simultaneously, to account for the competing risk endpoints and commonality of risk factors between the two events. Methods We included 20,462 women diagnosed with stage I–III breast cancer between 2000 and 2010 in Kaiser Permanente Northern California (KPNC) with follow-up through April 30, 2015, and examined the performance of the Framingham, CORE and SCOREOP cardiovascular risk models by area under the receiver operating characteristic curve (AUC), and observed-to -expected (O/E) ratio. We developed a multi-state model based on cause-specific hazards (CSH) to jointly model the causes of mortality. Results The extended models including breast cancer characteristics (grade, tumor size, nodal involvement) with CVD risk factors had better discrimination at 5-years with AUCs of 0.85 (95% CI 0.83, 0.86) for cardiovascular death and 0.80 (95% CI 0.78, 0.87) for breast cancer death compared with the existing cardiovascular models evaluated at 5 years AUCs ranging 0.71–0.78. Five-year calibration for breast and cardiovascular mortality from our multi-state model was also excellent (O/E = 1.01, 95% CI 0.91–1.11). Conclusion A model incorporating cardiovascular risk factors, breast cancer characteristics, and competing events, outperformed traditional models of cardiovascular disease by simultaneously estimating cancer and cardiovascular mortality risks

Evidence-Based Interventions for Reducing Breast Cancer Disparities: What Works and Where the Gaps Are?

The National Cancer Institute (NCI) has established an online repository of evidence-based cancer control programs (EBCCP) and increasingly calls for the usage of these EBCCPs to reduce the cancer burden. To inventory existing EBCCPs and identify remaining gaps, we summarized NCI’s EBCCPs relevant to reducing breast cancer risk with an eye towards interventions that address multiple levels of influence in populations facing breast cancer disparities. For each program, the NCI EBCCP repository provides the following expert panel determined summary metrics: (a) program ratings (1–5 scale, 5 best) of research integrity, intervention impact, and dissemination capability, and (b) RE-AIM framework assessment (0–100%) of program reach, effectiveness, adoption, and implementation. We quantified the number of EBCCPs that met the quality criteria of receiving a score of ≥3 for research integrity, intervention impact, and dissemination capability, and receiving a score of ≥50% for available RE-AIM reach, effectiveness, adoption, and implementation. For breast cancer risk reduction, we assessed the presence and quality of EBCCPs related to physical activity (PA), obesity, alcohol, tobacco control in early life, breastfeeding, and environmental chemical exposures. Our review revealed several major gaps in EBCCPs for reducing the breast cancer burden: (1) there are no EBCCPs for key breast cancer risk factors including alcohol, breastfeeding, and environmental chemical exposures; (2) among the EBCPPs that exist for PA, obesity, and tobacco control in early life, only a small fraction (24%, 17% and 31%, respectively) met all the quality criteria (≥3 EBCCP scores and ≥50% RE-AIM scores) and; (3) of those that met the quality criteria, only two PA interventions, one obesity, and no tobacco control interventions addressed multiple levels of influence and were developed in populations facing breast cancer disparities. Thus, developing, evaluating, and disseminating interventions to address important risk factors and reduce breast cancer disparities are needed

COVID-19-Specific Mortality among World Trade Center Health Registry Enrollees Who Resided in New York City

We examined the all-cause and COVID-19-specific mortality among World Trade Center Health Registry (WTCHR) enrollees. We also examined the socioeconomic factors associated with COVID-19-specific death. Mortality data from the NYC Bureau of Vital Statistics between 2015–2020 were linked to the WTCHR. COVID-19-specific death was defined as having positive COVID-19 tests that match to a death certificate or COVID-19 mentioned on the death certificate via text searching. We conducted step change and pulse regression to assess excess deaths. Limiting to those who died in 2019 (n = 210) and 2020 (n = 286), we examined factors associated with COVID-19-specific deaths using multinomial logistic regression. Death rate among WTCHR enrollees increased during the pandemic (RR: 1.70, 95% CL: 1.25–2.32), driven by the pulse in March–April 2020 (RR: 3.38, 95% CL: 2.62–4.30). No significantly increased death rate was observed during May–December 2020. Being non-Hispanic Black and having at least one co-morbidity had a higher likelihood of COVID-19-associated mortality than being non-Hispanic White and not having any co-morbidity (AOR: 2.43, 95% CL: 1.23–4.77; AOR: 2.86, 95% CL: 1.19–6.88, respectively). The racial disparity in COVID-19-specific deaths attenuated after including neighborhood proportion of essential workers in the model (AOR:1.98, 95% CL: 0.98–4.01). Racial disparities continue to impact mortality by differential occupational exposure and structural inequality in neighborhood representation. The WTC-exposed population are no exception. Continued efforts to reduce transmission risk in communities of color is crucial for addressing health inequities

Mortality after the 9/11 terrorist attacks among world trade center health registry enrollees with cancer

Abstract Background While several studies have reported the association between 9/11 exposure and cancer risk, cancer survival has not been well studied in the World Trade Center (WTC) exposed population. We examined associations of 9/11‐related exposures with mortality in WTC Health Registry enrollees diagnosed with cancer before and after 9/11/2001. Patients and Methods This is a longitudinal cohort study of 5061 enrollees with a first‐ever primary invasive cancer diagnosis between 1995 and 2015 and followed through 2016. Based on the timing of first cancer diagnosis, pre‐9/11 (n = 634) and post‐9/11 (n = 4427) cancer groups were examined separately. 9/11‐related exposures included witnessing traumatic events, injury on 9/11, and 9/11‐related post‐traumatic stress disorder (PTSD). Associations of exposures with all‐cause mortality were examined using Cox proportional hazards regression. In the post‐9/11 group, cancer‐specific mortality was evaluated by enrollee group (WTC rescue/recovery workers vs. non‐workers) using Fine and Gray's proportional sub‐distribution hazard models, adjusting for baseline covariates, tumor characteristics, and treatment. Results In the pre‐9/11 group, 9/11‐related exposures were not associated with all‐cause mortality. In the post‐9/11 group, increased risk of all‐cause mortality was associated with PTSD (adjusted HR = 1.35; 95% CI = 1.11–1.65), but not with injury or witnessing traumatic events. Cancer‐specific mortality was not statistically significantly associated with 9/11‐related exposures. In rescue/recovery workers, increased non‐cancer mortality risk was associated with PTSD (aHR = 2.13, 95% CI = 1.13–4.00) and witnessing ≥3 traumatic events (aHR = 2.00, 95% CI = 1.13–3.55). Conclusions We did not observe associations between 9/11‐related exposures and cancer‐specific mortality. Similar to findings in the non‐cancer WTC exposed population, PTSD was associated with increased risk of all‐cause mortality in cancer patients

Exposure to polycyclic aromatic hydrocarbons during pregnancy and breast tissue composition in adolescent daughters and their mothers: a prospective cohort study

Abstract Background Polycyclic aromatic hydrocarbons (PAH), which are found in air pollution, have carcinogenic and endocrine disrupting properties that might increase breast cancer risk. PAH exposure might be particularly detrimental during pregnancy, as this is a time when the breast tissue of both the mother and daughter is undergoing structural and functional changes. In this study, we tested the hypothesis that ambient PAH exposure during pregnancy is associated with breast tissue composition, measured one to two decades later, in adolescent daughters and their mothers. Methods We conducted a prospective analysis using data from a New York City cohort of non-Hispanic Black and Hispanic mother–daughter dyads (recruited 1998–2006). During the third trimester of pregnancy, women wore backpacks containing a continuously operating air sampling pump for two consecutive days that measured ambient exposure to eight carcinogenic higher molecular weight nonvolatile PAH compounds (Σ8 PAH) and pyrene. When daughters (n = 186) and mothers (n = 175) reached ages 11–20 and 29–55 years, respectively, optical spectroscopy (OS) was used to evaluate measures of breast tissue composition (BTC) that positively (water content, collagen content, optical index) and negatively (lipid content) correlate with mammographic breast density, a recognized risk factor for breast cancer. Multivariable linear regression was used to evaluate associations between ambient PAH exposure and BTC, overall and by exposure to household tobacco smoke during pregnancy (yes/no). Models were adjusted for race/ethnicity, age, and percent body fat at OS. Results No overall associations were found between ambient PAH exposure (Σ8 PAH or pyrene) and BTC, but statistically significant additive interactions between Σ8 PAH and household tobacco smoke exposure were identified for water content and optical index in both daughters and mothers (interaction p values < 0.05). Σ8 PAH exposure was associated with higher water content (β daughters = 0.42, 95% CI = 0.15–0.68; β mothers = 0.32, 95% CI = 0.05–0.61) and higher optical index (β daughters = 0.38, 95% CI = 0.12–0.64; β mothers = 0.38, 95% CI = 0.12–0.65) in those exposed to household tobacco smoke during pregnancy; no associations were found in non-smoking households (interaction p values < 0.05). Conclusions Exposure to ambient Σ8 PAH and tobacco smoke during pregnancy might interact synergistically to impact BTC in mothers and daughters. If replicated in other cohorts, these findings might have important implications for breast cancer risk across generations

Prepubertal Internalizing Symptoms and Timing of Puberty Onset in Girls

Stressful environments have been associated with earlier menarche. We hypothesized that anxiety, and possibly other internalizing symptoms, are also associated with earlier puberty in girls. The Lessons in Epidemiology and Genetics of Adult Cancer From Youth (LEGACY) Girls Study (2011-2016) included 1,040 girls aged 6-13 years at recruitment whose growth and development were assessed every 6 months. Prepubertal maternal reports of daughter's internalizing symptoms were available for breast onset (n&nbsp;=&nbsp;447), pubic hair onset (n&nbsp;=&nbsp;456), and menarche (n&nbsp;=&nbsp;681). Using Cox proportional hazard regression, we estimated prospective hazard ratios and 95% confidence intervals for the relationship between 1 standard deviation of the percentiles of prepubertal anxiety, depression, and somatization symptoms and the timing of each pubertal outcome. Multivariable models included age, race/ethnicity, study center, maternal education, body mass index percentile, and family history of breast cancer. Additional models included maternal self-reported anxiety. A 1-standard deviation increase in maternally reported anxiety in girls at baseline was associated with earlier subsequent onset of breast (hazard ratio (HR)&nbsp;=&nbsp;1.22, 95% confidence interval (CI): 1.09, 1.36) and pubic hair (HR&nbsp;=&nbsp;1.15, 95% CI: 1.01, 1.30) development, but not menarche (HR&nbsp;=&nbsp;0.94, 95% CI: 0.83, 1.07). The association of anxiety with earlier breast development persisted after adjustment for maternal anxiety. Increased anxiety in young girls may indicate risk for earlier pubertal onset

Alcohol consumption, cigarette smoking, and familial breast cancer risk: findings from the Prospective Family Study Cohort (ProF-SC)

Abstract Background Alcohol consumption and cigarette smoking are associated with an increased risk of breast cancer (BC), but it is unclear whether these associations vary by a woman’s familial BC risk. Methods Using the Prospective Family Study Cohort, we evaluated associations between alcohol consumption, cigarette smoking, and BC risk. We used multivariable Cox proportional hazard models to estimate hazard ratios (HR) and 95% confidence intervals (CI). We examined whether associations were modified by familial risk profile (FRP), defined as the 1-year incidence of BC predicted by Breast Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA), a pedigree-based algorithm. Results We observed 1009 incident BC cases in 17,435 women during a median follow-up of 10.4 years. We found no overall association of smoking or alcohol consumption with BC risk (current smokers compared with never smokers HR 1.02, 95% CI 0.85–1.23; consuming ≥ 7 drinks/week compared with non-regular drinkers HR 1.10, 95% CI 0.92–1.32), but we did observe differences in associations based on FRP and by estrogen receptor (ER) status. Women with lower FRP had an increased risk of ER-positive BC associated with consuming ≥ 7 drinks/week (compared to non-regular drinkers), whereas there was no association for women with higher FRP. For example, women at the 10th percentile of FRP (5-year BOADICEA = 0.15%) had an estimated HR of 1.46 (95% CI 1.07–1.99), whereas there was no association for women at the 90th percentile (5-year BOADICEA = 4.2%) (HR 1.07, 95% CI 0.80–1.44). While the associations with smoking were not modified by FRP, we observed a positive multiplicative interaction by FRP (pinteraction = 0.01) for smoking status in women who also consumed alcohol, but not in women who were non-regular drinkers. Conclusions Moderate alcohol intake was associated with increased BC risk, particularly for women with ER-positive BC, but only for those at lower predicted familial BC risk (5-year BOADICEA < 1.25). For women with a high FRP (5-year BOADICEA ≥ 6.5%) who also consumed alcohol, being a current smoker was associated with increased BC risk

Alcohol consumption, cigarette smoking, and familial breast cancer risk: findings from the Prospective Family Study Cohort (ProF-SC)

Background Alcohol consumption and cigarette smoking are associated with an increased risk of breast cancer (BC), but it is unclear whether these associations vary by a woman’s familial BC risk. Methods Using the Prospective Family Study Cohort, we evaluated associations between alcohol consumption, cigarette smoking, and BC risk. We used multivariable Cox proportional hazard models to estimate hazard ratios (HR) and 95% confidence intervals (CI). We examined whether associations were modified by familial risk profile (FRP), defined as the 1-year incidence of BC predicted by Breast Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA), a pedigree-based algorithm. Results We observed 1009 incident BC cases in 17,435 women during a median follow-up of 10.4 years. We found no overall association of smoking or alcohol consumption with BC risk (current smokers compared with never smokers HR 1.02, 95% CI 0.85–1.23; consuming ≥ 7 drinks/week compared with non-regular drinkers HR 1.10, 95% CI 0.92–1.32), but we did observe differences in associations based on FRP and by estrogen receptor (ER) status. Women with lower FRP had an increased risk of ER-positive BC associated with consuming ≥ 7 drinks/week (compared to non-regular drinkers), whereas there was no association for women with higher FRP. For example, women at the 10th percentile of FRP (5-year BOADICEA = 0.15%) had an estimated HR of 1.46 (95% CI 1.07–1.99), whereas there was no association for women at the 90th percentile (5-year BOADICEA = 4.2%) (HR 1.07, 95% CI 0.80–1.44). While the associations with smoking were not modified by FRP, we observed a positive multiplicative interaction by FRP (pinteraction = 0.01) for smoking status in women who also consumed alcohol, but not in women who were non-regular drinkers. Conclusions Moderate alcohol intake was associated with increased BC risk, particularly for women with ER-positive BC, but only for those at lower predicted familial BC risk (5-year BOADICEA < 1.25). For women with a high FRP (5-year BOADICEA ≥ 6.5%) who also consumed alcohol, being a current smoker was associated with increased BC risk

Regular use of aspirin and other non-steroidal anti-inflammatory drugs and breast cancer risk for women at familial or genetic risk: a cohort study

Abstract Background The use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced breast cancer risk, but it is not known if this association extends to women at familial or genetic risk. We examined the association between regular NSAID use and breast cancer risk using a large cohort of women selected for breast cancer family history, including 1054 BRCA1 or BRCA2 mutation carriers. Methods We analyzed a prospective cohort (N = 5606) and a larger combined, retrospective and prospective, cohort (N = 8233) of women who were aged 18 to 79 years, enrolled before June 30, 2011, with follow-up questionnaire data on medication history. The prospective cohort was further restricted to women without breast cancer when medication history was asked by questionnaire. Women were recruited from seven study centers in the United States, Canada, and Australia. Associations were estimated using multivariable Cox proportional hazards regression models adjusted for demographics, lifestyle factors, family history, and other medication use. Women were classified as regular or non-regular users of aspirin, COX-2 inhibitors, ibuprofen and other NSAIDs, and acetaminophen (control) based on self-report at follow-up of ever using the medication for at least twice a week for ≥1 month prior to breast cancer diagnosis. The main outcome was incident invasive breast cancer, based on self- or relative-report (81% confirmed pathologically). Results From fully adjusted analyses, regular aspirin use was associated with a 39% and 37% reduced risk of breast cancer in the prospective (HR = 0.61; 95% CI = 0.33–1.14) and combined cohorts (HR = 0.63; 95% CI = 0.57–0.71), respectively. Regular use of COX-2 inhibitors was associated with a 61% and 71% reduced risk of breast cancer (prospective HR = 0.39; 95% CI = 0.15–0.97; combined HR = 0.29; 95% CI = 0.23–0.38). Other NSAIDs and acetaminophen were not associated with breast cancer risk in either cohort. Associations were not modified by familial risk, and consistent patterns were found by BRCA1 and BRCA2 carrier status, estrogen receptor status, and attained age. Conclusion Regular use of aspirin and COX-2 inhibitors might reduce breast cancer risk for women at familial or genetic risk

Regular use of aspirin and other non-steroidal anti-inflammatory drugs and breast cancer risk for women at familial or genetic risk: a cohort study

Background The use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced breast cancer risk, but it is not known if this association extends to women at familial or genetic risk. We examined the association between regular NSAID use and breast cancer risk using a large cohort of women selected for breast cancer family history, including 1054 BRCA1 or BRCA2 mutation carriers. Methods We analyzed a prospective cohort (N = 5606) and a larger combined, retrospective and prospective, cohort (N = 8233) of women who were aged 18 to 79 years, enrolled before June 30, 2011, with follow-up questionnaire data on medication history. The prospective cohort was further restricted to women without breast cancer when medication history was asked by questionnaire. Women were recruited from seven study centers in the United States, Canada, and Australia. Associations were estimated using multivariable Cox proportional hazards regression models adjusted for demographics, lifestyle factors, family history, and other medication use. Women were classified as regular or non-regular users of aspirin, COX-2 inhibitors, ibuprofen and other NSAIDs, and acetaminophen (control) based on self-report at follow-up of ever using the medication for at least twice a week for ≥1 month prior to breast cancer diagnosis. The main outcome was incident invasive breast cancer, based on self- or relative-report (81% confirmed pathologically). Results From fully adjusted analyses, regular aspirin use was associated with a 39% and 37% reduced risk of breast cancer in the prospective (HR = 0.61; 95% CI = 0.33–1.14) and combined cohorts (HR = 0.63; 95% CI = 0.57–0.71), respectively. Regular use of COX-2 inhibitors was associated with a 61% and 71% reduced risk of breast cancer (prospective HR = 0.39; 95% CI = 0.15–0.97; combined HR = 0.29; 95% CI = 0.23–0.38). Other NSAIDs and acetaminophen were not associated with breast cancer risk in either cohort. Associations were not modified by familial risk, and consistent patterns were found by BRCA1 and BRCA2 carrier status, estrogen receptor status, and attained age. Conclusion Regular use of aspirin and COX-2 inhibitors might reduce breast cancer risk for women at familial or genetic risk