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Background Breast cancer survivors are living longer due to early detection and advances in treatment and are at increased risk for second primary cancers. Comprehensive evaluation of second cancer risk among patients treated in recent decades is lacking. Methods We identified 16,004 females diagnosed with a first primary stage I-III breast cancer between 1990 and 2016 (followed through 2017) and survived ≥ 1 year at Kaiser Permanente (KP) Colorado, Northwest, and Washington. Second cancer was defined as an invasive primary cancer diagnosed ≥ 12 months after the first primary breast cancer. Second cancer risk was evaluated for all cancers (excluding ipsilateral breast cancer) using standardized incidence ratios (SIRs), and a competing risk approach for cumulative incidence and hazard ratios (HRs) adjusted for KP center, treatment, age, and year of first cancer diagnosis. Results Over a median follow-up of 6.2 years, 1,562 women developed second cancer. Breast cancer survivors had a 70% higher risk of any cancer (95%CI = 1.62–1.79) and 45% higher risk of non-breast cancer (95%CI = 1.37–1.54) compared with the general population. SIRs were highest for malignancies of the peritoneum (SIR = 3.44, 95%CI = 1.65–6.33), soft tissue (SIR = 3.32, 95%CI = 2.51–4.30), contralateral breast (SIR = 3.10, 95%CI = 2.82–3.40), and acute myeloid leukemia (SIR = 2.11, 95%CI = 1.18–3.48)/myelodysplastic syndrome (SIR = 3.25, 95%CI = 1.89–5.20). Women also had elevated risks for oral, colon, pancreas, lung, and uterine corpus cancer, melanoma, and non-Hodgkin lymphoma (SIR range = 1.31–1.97). Radiotherapy was associated with increased risk for all second cancers (HR = 1.13, 95%CI = 1.01–1.25) and soft tissue sarcoma (HR = 2.36, 95%CI = 1.17–4.78), chemotherapy with decreased risk for all second cancers (HR = 0.87, 95%CI = 0.78–0.98) and increased myelodysplastic syndrome risk (HR = 3.01, 95%CI = 1.01–8.94), and endocrine therapy with lower contralateral breast cancer risk (HR = 0.48, 95%CI = 0.38–0.60). Approximately 1 in 9 women who survived ≥ 1 year developed second cancer, 1 in 13 developed second non-breast cancer, and 1 in 30 developed contralateral breast cancer by 10 years. Trends in cumulative incidence declined for contralateral breast cancer but not for second non-breast cancers. Conclusions Elevated risks of second cancer among breast cancer survivors treated in recent decades suggests that heightened surveillance is warranted and continued efforts to reduce second cancers are needed.

Low-dose computed tomography (LDCT) of the chest for lung cancer screening of heavy smokers was given a 'B' rating by the U.S. Preventive Services Task Force (USPSTF) in 2013, and gained widespread insurance coverage in the U.S. in 2015. Lung cancer screening has since had low uptake. However, for those that do choose to screen, little is known about patient motivations for completing screening in real-world practice. To explore the motivations for screening-eligible patients to screen for lung cancer. Semi-structured qualitative interviews were conducted with 20 LDCT screen-completed men and women who were members of an integrated mixed-model healthcare system in Washington State. From June to September 2015, participants were recruited and individual interviews performed about motivations to screen for lung cancer. Audio-recorded interviews were transcribed and analyzed using inductive content analysis by three investigators. Four primary themes emerged as motivations for completing LDCT lung cancer screening: 1) trust in the referring clinician; 2) early-detection benefit; 3) low or limited harm perception; and 4) friends or family with advanced cancer. Participants in our study were primarily motivated to screen for lung cancer based on perceived benefit of early-detection, absence of safety concerns, and personal relationships. Our findings provide new insights about patient motivations to screen, and can potentially be used to improve lung cancer screening uptake and shared decision-making processes.

Breast cancer tends to occur in an older age group of women also burdened with comorbidities such as cardiovascular disease (CVD). Numerous medications used to manage CVD (e.g., statins and antihypertensives) are hypothesized to alter breast cancer risk, but there are few studies on breast cancer outcomes. The CO mmonly used M edications and B reast Cancer O utcomes (COMBO) cohort was developed to study how medications and co-morbidities influence breast cancer prognosis. Cohort study among adult women, diagnosed with incident early stage breast cancer, and enrolled in an integrated health plan. Data sources included health plan administrative databases, Surveillance, Epidemiology, and End Results tumor registry, and medical records. Statins, angiotensin-converting enzyme inhibitors (ACEI), beta blockers (BB), calcium blockers, and diuretics were the exposures of interest. The outcome was second breast cancer events (SBCE) defined as recurrence or second primary breast cancer. We used multivariable Cox proportional hazards models to estimate hazard ratios (HR) and 95 % confidence intervals (CI) for SBCE, and components of SBCE. 4,216 women were followed for a median of 6.3 years, and 13.2 % experienced a SBCE (first of: n  = 415 recurrences and n  = 143 s primary breast cancers). Compared to non-users, we observed an increased risk of second primary breast cancer with ACEI use (HR = 1.66; 95 % CI, 1.06–2.58) and an increased risk of recurrence with BB use (HR = 1.29; 95 % CI, 1.01–1.64). There was suggestion of a reduced risk of SBCE with statin use (HR = 0.82; 95 % CI, 0.62–1.08) and second primary breast cancer with BB use (HR = 0.77; 95 % CI, 0.50–1.19). No differences in outcomes were observed by duration of medication use. A majority of CVD medications evaluated in this study appear safe with respect to SBCE, but ACEI and BB use warrant further evaluation. The study presented is one example of the questions that can be addressed using the COMBO cohort.

Background Women with dense breasts have an increased risk of breast cancer. However, breast density is measured with variability, which may reduce the reliability and accuracy of its association with breast cancer risk. This is particularly relevant when visually assessing breast density due to variation in inter- and intra-reader assessments. To address this issue, we developed a longitudinal breast density measure which uses an individual woman’s entire history of mammographic density, and we evaluated its association with breast cancer risk as well as its predictive ability. Methods In total, 132,439 women, aged 40–73 yr, who were enrolled in Kaiser Permanente Washington and had multiple screening mammograms taken between 1996 and 2013 were followed up for invasive breast cancer through 2014. Breast Imaging Reporting and Data System (BI-RADS) density was assessed at each screen. Continuous and derived categorical longitudinal density measures were developed using a linear mixed model that allowed for longitudinal density to be updated at each screen. Predictive ability was assessed using (1) age and body mass index-adjusted hazard ratios (HR) for breast density (time-varying covariate), (2) likelihood-ratio statistics (ΔLR- χ 2 ) and (3) concordance indices. Results In total, 2704 invasive breast cancers were diagnosed during follow-up (median = 5.2 yr; median mammograms per woman = 3). When compared with an age- and body mass index-only model, the gain in statistical information provided by the continuous longitudinal density measure was 23% greater than that provided by BI-RADS density (follow-up after baseline mammogram: ΔLR- χ 2  = 379.6 (degrees of freedom ( df ) = 2) vs. 307.7 ( df  = 3)), which increased to 35% (ΔLR- χ 2  = 251.2 vs. 186.7) for follow-up after three mammograms ( n  = 76,313, 2169 cancers). There was a sixfold difference in observed risk between densest and fattiest eight-category longitudinal density (HR = 6.3, 95% CI 4.7–8.7), versus a fourfold difference with BI-RADS density (HR = 4.3, 95% CI 3.4–5.5). Discriminatory accuracy was marginally greater for longitudinal versus BI-RADS density (c-index = 0.64 vs. 0.63, mean difference = 0.008, 95% CI 0.003–0.012). Conclusions Estimating mammographic density using a woman’s history of breast density is likely to be more reliable than using the most recent observation only, which may lead to more reliable and accurate estimates of individual breast cancer risk. Longitudinal breast density has the potential to improve personal breast cancer risk estimation in women attending mammography screening.

Purpose: Many studies suggest increased body mass index (BMI) is associated with worse breast cancer outcomes, but few account for variability in screening, access to treatment, and tumor differences. We examined the association between BMI and risk of breast cancer recurrence, breast cancer-specific mortality, and all-cause mortality, and evaluated whether tumor characteristics differ by BMI among a mammographically screened population with access to treatment. Methods: Using a retrospective cohort study design, we followed 485 women aged ≥40 years diagnosed with stage I/II breast cancer within 24 months of a screening mammogram occurring between 1988 and 1993 for 10-year outcomes. BMI before diagnosis was categorized as normal (<25 kg/m²), overweight (25–29.9 kg/m²), and obese (≥30 kg/m²). Tumor marker expression was assessed via immunohistochemistry using tissue collected before adjuvant treatment. Medical records were abstracted to identify treatment, recurrence, and mortality. We used Cox proportional hazards to separately model the hazard ratios (HR) of our three outcomes by BMI while adjusting for age, stage, and tamoxifen use. Results: Relative to normal-weight women, obese women experienced increased risk of recurrence (HR 2.43; 95 % CI 1.34–4.41) and breast cancer death (HR 2.41; 95 % CI 1.00–5.81) within 10 years of diagnosis. There was no association between BMI and all-cause mortality. Obese women had significantly faster growing tumors, as measured by Ki-67. Conclusions: Our findings add to the growing evidence that obesity may contribute to poorer breast cancer outcomes, and also suggest that increased tumor proliferation among obese women is a pathway that explains part of their excess risk of adverse outcomes.

Soft tissue sarcoma is a rare but serious side-effect of radiotherapy to treat breast cancer, and rates are increasing in the USA. We evaluated potential co-factors in two complimentary cohorts of US breast cancer survivors. In this retrospective cohort study, we sourced data from the Kaiser Permanente (KP) cohort and the Surveillance, Epidemiology, and End Results (SEER) 13 registries cohort, both in the USA. The KP cohort included 15 940 women diagnosed with breast cancer from Jan 1, 1990, to Dec 31, 2016, in KP Colorado, KP Northwest (which serves Oregon and Southwest Washington state), or KP Washington, with detailed treatment data and comorbidities (including hypertension and diabetes at or before breast cancer diagnosis) from electronic medical records. The SEER cohort included 457 300 women diagnosed with breast cancer from Jan 1, 1992, to Dec 31, 2016, within the 13 SEER registries across the USA, with initial treatment data (yes vs no or unknown). Eligibility criteria in both cohorts were female breast cancer survivors (stage I–III) aged 20–84 years at diagnosis who had breast cancer surgery, and had survived at least 1 year after breast cancer diagnosis. The outcome of interest was any second thoracic soft tissue sarcoma (angiosarcomas and other subtypes) that developed at least 1 year after breast cancer diagnosis. Risk factors for thoracic soft tissue sarcoma were assessed using multivariable Poisson regression models. In the KP cohort, median follow-up was 9·3 years (IQR 5·7–13·9) and 19 (0·1%) of 15 940 eligible, evaluable women developed a thoracic soft tissue sarcoma (11 angiosarcomas, eight other subtypes). Most (94·7%; 18 of 19) thoracic soft tissue sarcomas occurred in women treated with radiotherapy; thus, radiotherapy was associated with a significantly increased risk of developing a thoracic soft tissue sarcoma (relative risk [RR] 8·1 [95% CI 1·1–60·4]; p=0·0052), but there was no association with prescribed dose, fractionation, or boost. The RR of angiosarcoma after anthracyclines was 3·6 (95% CI 1·0–13·3; p=0·058). Alkylating agents were associated with an increased risk of developing other sarcomas (RR 7·7 [95% CI 1·2–150·8]; p=0·026). History of hypertension (RR 4·8 [95% CI 1·3–17·6]; p=0·017) and diabetes (5·3 [1·4–20·8]; p=0·036) were each associated with around a five-times increased risk of angiosarcoma. In the SEER cohort, 430 (0·1%) of 457 300 patients had subsequent thoracic soft tissue sarcomas (268 angiosarcomas and 162 other subtypes) after a median follow-up of 8·3 years (IQR 4·3–13·9). Most (77·9%; 335 of 430) cases occurred after radiotherapy; thus, radiotherapy was associated with a significantly increased risk of developing a thoracic soft tissue sarcoma (RR 3·0 [95% CI 2·4–3·8]; p<0·0001) and, for angiosarcomas, the RR for breast-conserving surgery plus radiotherapy versus mastectomy plus radiotherapy was 1·9 (1·1–3·3; p=0·012). By 10 years after radiotherapy, the cumulative incidence of thoracic soft tissue sarcoma was 0·21% (95% CI 0·12–0·34) in the KP cohort and 0·15% (95% CI 0·13–0·17) in SEER. Radiotherapy was the strongest risk factor for thoracic soft tissue sarcoma in both cohorts. This finding, along with the novel findings for diabetes and hypertension as potential risk factors for angiosarcomas, warrant further investigation as potential targets for prevention strategies and increased surveillance. US National Cancer Institute and National Institutes of Health.

Purpose This retrospective cohort study examined patterns of endocrine therapy initiation over time and by demographic, tumor, and treatment characteristics. Methods We included 7777 women from three U.S. integrated healthcare systems diagnosed with incident stage I–III hormone receptor-positive breast cancer between 2001 and 2016. We extracted endocrine therapy from pharmacy dispensings, defining initiation as dispensings within 12 months of diagnosis. Demographic, tumor, and treatment characteristics were collected from electronic health records. Using generalized linear models with a log link and Poisson distribution, we estimated initiation of any endocrine therapy, tamoxifen, and aromatase inhibitors (AI) over time with relative risks (RR) and 95% confidence intervals (CI) adjusted for age, tumor characteristics, diagnosis year, other treatment, and study site. Results Among women aged 20+ (mean 62 years), 6329 (81.4%) initiated any endocrine therapy, and 1448 (18.6%) did not initiate endocrine therapy. Tamoxifen initiation declined from 67 to 15% between 2001 and 2016. AI initiation increased from 6 to 69% between 2001 and 2016 in women aged ≥ 55 years. The proportion of women who did not initiate endocrine therapy decreased from 19 to 12% between 2002 and 2014 then increased to 17% by 2016. After adjustment, women least likely to initiate endocrine therapy were older (RR = 0.81, 95% CI 0.77–0.85 for age 75+ vs. 55–64), Black (RR = 0.93, 95% CI 0.87–1.00 vs. white), and had stage I disease (RR = 0.88, 95% CI 0.85–0.91 vs. stage III). Conclusions Despite an increase in AI use over time, at least one in six eligible women did not initiate endocrine therapy, highlighting opportunities for improving endocrine therapy uptake in breast cancer survivors.

To evaluate the effectiveness of methods that control for confounding by indication, we compared breast cancer recurrence rates among women receiving adjuvant chemotherapy with those who did not. In a medical record review-based study of breast cancer treatment in older women ( n = 1798) diagnosed between 1990 and 1994, our crude analysis suggested that adjuvant chemotherapy was positively associated with recurrence (hazard ratio [HR] = 2.6; 95% confidence interval [CI] = 1.9, 3.5). We expected a protective effect, so postulated that the crude association was confounded by indications for chemotherapy. We attempted to adjust for this confounding by restriction, multivariable regression, propensity scores (PSs), and instrumental variable (IV) methods. After restricting to women at high risk for recurrence ( n = 946), chemotherapy was not associated with recurrence (HR = 1.1; 95% CI = 0.7, 1.6) using multivariable regression. PS adjustment yielded similar results (HR = 1.3; 95% CI = 0.8, 2.0). The IV-like method yielded a protective estimate (HR = 0.9; 95% CI = 0.2, 4.3); however, imbalances of measured factors across levels of the IV suggested residual confounding. Conventional methods do not control for unmeasured factors, which often remain important when addressing confounding by indication. PS and IV analysis methods can be useful under specific situations, but neither method adequately controlled confounding by indication in this study.

Breast cancer subtypes defined by estrogen receptor (ER), progesterone receptor (PR), and HER2 expression are biologically distinct and thus, may have distinct etiologies. In particular, it is plausible that risk factors operating through hormonal mechanisms are differentially related to risk of such tumor subtypes. Using data from the Breast Cancer Surveillance Consortium, we explored associations between reproductive history and three breast cancer subtypes. Data on parity and age at first birth were collected from 743,623 women, 10,896 of whom were subsequently diagnosed with breast cancer. Cases were classified into three subtypes based on tumor maker expression: (1) ER positive (ER+, N = 8,203), (2) ER negative/PR negative/HER2 positive (ER−/PR−/HER2+, N = 288), or (3) ER-, PR-, and HER2-negative (triple-negative, N = 645). Associations with reproductive history, evaluated using Cox regression, differed significantly across tumor subtypes. Nulliparity was most strongly associated with risk of ER+ breast cancer [hazard ratio (HR) = 1.31, 95% confidence interval (CI): 1.23-1.39]; late age at first birth was most strongly associated with risk of ER-/PR-/HER2+ disease (HR = 1.83, 95% CI: 1.31-2.56). Neither parity nor age at first birth was associated with triple-negative breast cancer. In contrast to ER+ and ER−/PR−/HER2+ subtypes, reproductive history does not appear to be a risk factor for triple-negative breast cancer.

Objective We provide new information about how the risk of adverse events following colonoscopy varies by age and indication (screening vs. follow-up performed to evaluate a positive result from another screening modality). Methods We constructed a retrospective cohort comprised of 43,456 individuals aged 40-85 years enrolled in a large integrated healthcare organization in Washington State who underwent outpatient colonoscopy between 1994 and 2009. We calculated rates of serious adverse events (perforation, hemorrhage, and acute diverticulitis) in the 30 days following colonoscopy and compared rates using log-binomial regression models. Results We observed 4.7 serious adverse events per 1,000 screening colonoscopies and 6.8 per 1,000 follow-up colonoscopies. Polypectomy increased the rate of serious adverse events (relative rate [RR], 2.64; 95% confidence interval [CI], 1.97-3.56). Older age was associated with increased risk of serious adverse events, after adjusting for polypectomy, gender, and indication. Compared to individuals aged 50-64 years, risk was elevated for those aged 65-74 (RR, 1.93; 95% CI, 1.40-2.65) and 75-85 (RR, 3.21; 95% CI 2.14-4.86). We observed similar age effects in individuals with and without significant comorbid conditions. Conclusions The risks of serious adverse events following colonoscopy performed as part of screening are low but increase with age and are more likely after polypectomy.