Overall survival and cause-specific mortality in a hospital-based cohort of retinoblastoma patients in São Paulo, Brazil.

Studies are lacking on long-term effects among retinoblastoma patients in low- and middle-income countries. Therefore, we examined cause-specific mortality in a retrospective cohort of retinoblastoma patients treated at Antonio Candido de Camargo Cancer Center (ACCCC), São Paulo, Brazil from 1986 to 2003 and followed up through December 31, 2018. Vital status and cause of death were ascertained from medical records and multiple national databases. We estimated overall and cause-specific survival using the Kaplan-Meier survival method, and estimated standardized mortality ratios (SMRs) and absolute excess risk (AER) of death. This cohort study included 465 retinoblastoma patients (42% hereditary, 58% nonhereditary), with most (77%) patients diagnosed at advanced stages (IV or V). Over an 11-year average follow-up, 80 deaths occurred: 70% due to retinoblastoma, 22% due to subsequent malignant neoplasms (SMNs) and 5% to non-cancer causes. The overall 5-year survival rate was 88% consistent across hereditary and nonhereditary patients (p = .67). Hereditary retinoblastoma patients faced an 86-fold higher risk of SMN-related death compared to the general population (N = 16, SMR = 86.1, 95% CI 52.7-140.5), corresponding to 42.4 excess deaths per 10,000 person-years. This risk remained consistent for those treated with radiotherapy and chemotherapy (N = 10, SMR = 90.3, 95% CI 48.6-167.8) and chemotherapy alone (N = 6, SMR = 80.0, 95% CI 35.9-177.9). Nonhereditary patients had only two SMN-related deaths (SMR = 7.2, 95% CI 1.8-28.7). There was no excess risk of non-cancer-related deaths in either retinoblastoma form. Findings from this cohort with a high proportion of advanced-stage patients and extensive chemotherapy use may help guide policy and healthcare planning, emphasizing the need to enhance early diagnosis and treatment access in less developed countries.

Long-term cardiovascular disease risk after anthracycline and trastuzumab treatments in US breast cancer survivors.

BACKGROUND: Although breast cancer survivors are at risk for cardiovascular disease (CVD) from treatment late effects, evidence to inform long-term and age-specific cardiovascular surveillance recommendations is lacking. METHODS: We conducted a retrospective cohort study of 10 211 women diagnosed with first primary unilateral breast cancer in Kaiser Permanente Washington or Colorado (aged 20 years and older, survived ≥1 year). We estimated multivariable adjusted hazard ratios (HRs) for associations between initial chemotherapy regimen type (anthracycline and/or trastuzumab, other chemotherapies, no chemotherapy [referent]) and CVD risk, adjusted for patient characteristics, other treatments, and CVD risk factors. Cumulative incidence was calculated considering competing events. RESULTS: After 5.79 median years, 14.67% of women developed CVD (cardiomyopathy and/or heart failure [HF], ischemic heart disease, stroke). Women treated with anthracyclines and/or trastuzumab had a higher risk of CVD compared with no chemotherapy (adjusted HR = 1.53, 95% confidence interval [CI] = 1.31 to 1.79), persisting at least 5 years postdiagnosis (adjusted HR5-<10 years = 1.85, 95% CI = 1.44 to 2.39; adjusted HR≥10 years = 1.83, 95% CI = 1.34 to 2.49). Cardiomyopathy and/or HF risks were elevated among women treated with anthracyclines and/or trastuzumab compared with no chemotherapy, especially for those aged younger than 65 years (adjusted HR20-54years = 2.97, 95% CI = 1.72 to 5.12; adjusted HR55-64years = 2.21, 95% CI = 1.52 to 3.21), differing for older women (adjusted HR≥65 years = 1.32, 95% CI = 0.97 to 1.78), and at least 5 years postdiagnosis (adjusted HR5-<10years = 1.89, 95% CI = 1.35 to 2.64; adjusted HR≥10 years = 2.21, 95% CI = 1.52 to 3.20). Anthracyclines and/or trastuzumab receipt was associated with increased ischemic heart disease risks after 5 or more years (adjusted HR5-<10years = 1.51, 95% CI = 1.06 to 2.14; adjusted HR≥10 years = 1.86, 95% CI = 1.18 to 2.93) with no clear age effects, and stroke risk (adjusted HR = 1.33, 95% CI = 1.05 to 1.69), which did not vary by time or age. There was some evidence of long-term cardiomyopathy and/or HF and ischemic heart disease risks with other chemotherapies. Among women aged younger than 65 treated with anthracyclines and/or trastuzumab, up to 16% developed CVD by 10 years (20-54 years = 6.91%; 55-64 years = 16.00%), driven by cardiomyopathy and/or HF (20-54 years = 3.90%; 55-64 years = 9.78%). CONCLUSIONS: We found increased long-term risks of cardiomyopathy and/or HF and ischemic heart disease among breast cancer survivors treated with anthracyclines and/or trastuzumab and increased cardiomyopathy and/or HF risk among women aged younger than 65 years.

Second primary cancer risks according to race and ethnicity among U.S. breast cancer survivors.

Breast cancer survivors have an increased risk of developing second primary cancers, yet risks by race and ethnicity have not been comprehensively described. We evaluated second primary cancer risks among 717,335 women diagnosed with first primary breast cancer (aged 20-84 years and survived ≥1-year) in the SEER registries using standardized incidence ratios (SIRs; observed/expected). SIRs were estimated by race and ethnicity compared with the racial- and ethnic-matched general population, and further stratified by clinical characteristics of the index breast cancer. Poisson regression was used to test for heterogeneity by race and ethnicity. SIRs for second primary cancer differed by race and ethnicity with the highest risks observed among non-Hispanic/Latina Asian American, Native Hawaiian, or other Pacific Islander (AANHPI), non-Hispanic/Latina Black (Black), and Hispanic/Latina (Latina) survivors and attenuated risk among non-Hispanic/Latina White (White) survivors (SIRAANHPI = 1.49, 95% CI = 1.44-1.54; SIRBlack = 1.41, 95% CI = 1.37-1.45; SIRLatina = 1.45, 95% CI = 1.41-1.49; SIRWhite = 1.09, 95% CI = 1.08-1.10; p-heterogeneity<.001). SIRs were particularly elevated among AANHPI, Black, and Latina survivors diagnosed with an index breast cancer before age 50 (SIRs range = 1.88-2.19) or with estrogen receptor-negative tumors (SIRs range = 1.60-1.94). Heterogeneity by race and ethnicity was observed for 16/27 site-specific second cancers (all p-heterogeneity's < .05) with markedly elevated risks among AANHPI, Black, and Latina survivors for acute myeloid and acute non-lymphocytic leukemia (SIRs range = 2.68-3.15) and cancers of the contralateral breast (SIRs range = 2.60-3.01) and salivary gland (SIRs range = 2.03-3.96). We observed striking racial and ethnic differences in second cancer risk among breast cancer survivors. Additional research is needed to inform targeted approaches for early detection strategies and treatment to reduce these racial and ethnic disparities.

Latin America and the Caribbean Code Against cancer 1st edition: Environment, occupation, and cancer.

Within the framework of the Latin America and Caribbean region (LAC) Code Against Cancer 1st edition, the current work presents recommendations to reduce exposure to environmental and occupational carcinogenic agents relevant for LAC. Using the methodology established by the International Agency for Research on Cancer (IARC) in the World Code Against Cancer Framework and experience from developing the European Code Against Cancer 4th edition, a working group of LAC cancer-prevention experts reviewed the list of Group I IARC carcinogenic agents, identified prevalent environmental and occupational exposures in the region, and proposed evidence-based cancer prevention recommendations suited to the epidemiological, socioeconomic, and cultural conditions of LAC countries. Two sets of recommendations were drafted: those targeting the general public and a second set for policymakers. Outdoor and indoor air pollution, ultra-violet radiation and occupational exposures to silica dust, asbestos, benzene, diesel, and welding fumes were identified as prevalent carcinogens in LAC and as agents that could be reduced or eliminated to prevent cancers. Recommendations for additional risk factors were not included due to insufficient data of their attributable burden in LAC (sunbeds, radon, aflatoxin), or lack of a clear preventive action to be taken by the individual (arsenic in drinking water, medical radiation), or lack of evidence of carcinogenicity effect (bisphenol A, phthalates, and pesticides). A broad consensus was reached on environmental and occupational carcinogenic exposures present throughout the LAC region and on individual-level and public policy-level recommendations to reduce or eliminate these exposures. Key educational content for the dissemination of these recommendations was also developed as part of LAC Code Against Cancer 1st Edition.

Risk of second primary cancer among women in the Kaiser Permanente Breast Cancer Survivors Cohort.

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.

Racial and ethnic disparities in treatment-related heart disease mortality among US breast cancer survivors.

BACKGROUND: Racial and ethnic disparities in heart disease mortality by initial treatment type among breast cancer survivors have not been well described. METHODS: We included 739 557 women diagnosed with first primary invasive breast cancer between 2000 and 2017 (aged 18-84 years, received surgery, survived ≥1 year, followed through 2018) in the Surveillance, Epidemiology, and End Results-18 database. Standardized mortality ratios (SMRs; observed over expected) were calculated by race and ethnicity (non-Hispanic/Latina Asian American, Native Hawaiians, and other Pacific Islanders [AANHPI]; non-Hispanic/Latina Black [Black]; Hispanic/Latina [Latina]; and non-Hispanic/Latina White [White]) and initial treatment (surgery only; chemotherapy with surgery; chemotherapy, radiotherapy, with surgery; and radiotherapy with surgery) compared with the racial- and ethnic-matched general population, and by clinical characteristics. Cumulative heart disease mortality was estimated accounting for competing risks. RESULTS: SMRs were elevated for Black and Latina women treated with surgery only and chemotherapy with surgery (SMR range = 1.15-1.21) and AANHPI women treated with chemotherapy, radiotherapy, with surgery (SMR = 1.29; 95% confidence interval [CI] = 1.11 to 1.48), whereas SMRs were less than 1 for White women (SMR range = 0.70-0.96). SMRs were especially high for women with advanced (regional or distant) stage among Black women for all treatment (range = 1.15-2.89) and for AANHPI and Latina women treated with chemotherapy with surgery (range = 1.28-3.61). Non-White women diagnosed at younger than age 60 years had higher SMRs, as did Black and AANHPI women diagnosed with estrogen receptor-positive breast cancers. Black women had the highest 10-year cumulative risk of heart disease mortality: aged younger than 60 years (Black: 1.78%, 95% CI = 1.63% to 1.94%) compared with White, AANHPI, and Latina women (<1%) and aged 60 years and older (Black: 7.92%, 95% CI = 7.53% to 8.33%) compared with White, AANHPI, and Latina women (range = 3.90%-6.48%). CONCLUSIONS: Our findings illuminated striking racial and ethnic disparities in heart disease mortality among Black, AANHPI, and Latina breast cancer survivors, especially after initial chemotherapy receipt.

Ionising radiation and cardiovascular disease: systematic review and meta-analysis.

OBJECTIVE: To systematically review and perform a meta-analysis of radiation associated risks of cardiovascular disease in all groups exposed to radiation with individual radiation dose estimates. DESIGN: Systematic review and meta-analysis. MAIN OUTCOME MEASURES: Excess relative risk per unit dose (Gy), estimated by restricted maximum likelihood methods. DATA SOURCES: PubMed and Medline, Embase, Scopus, Web of Science Core collection databases. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Databases were searched on 6 October 2022, with no limits on date of publication or language. Animal studies and studies without an abstract were excluded. RESULTS: The meta-analysis yielded 93 relevant studies. Relative risk per Gy increased for all cardiovascular disease (excess relative risk per Gy of 0.11 (95% confidence interval 0.08 to 0.14)) and for the four major subtypes of cardiovascular disease (ischaemic heart disease, other heart disease, cerebrovascular disease, all other cardiovascular disease). However, interstudy heterogeneity was noted (P<0.05 for all endpoints except for other heart disease), possibly resulting from interstudy variation in unmeasured confounders or effect modifiers, which is markedly reduced if attention is restricted to higher quality studies or those at moderate doses (<0.5 Gy) or low dose rates (<5 mGy/h). For ischaemic heart disease and all cardiovascular disease, risks were larger per unit dose for lower dose (inverse dose effect) and for fractionated exposures (inverse dose fractionation effect). Population based excess absolute risks are estimated for a number of national populations (Canada, England and Wales, France, Germany, Japan, USA) and range from 2.33% per Gy (95% confidence interval 1.69% to 2.98%) for England and Wales to 3.66% per Gy (2.65% to 4.68%) for Germany, largely reflecting the underlying rates of cardiovascular disease mortality in these populations. Estimated risk of mortality from cardiovascular disease are generally dominated by cerebrovascular disease (around 0.94-1.26% per Gy), with the next largest contribution from ischaemic heart disease (around 0.30-1.20% per Gy). CONCLUSIONS: Results provide evidence supporting a causal association between radiation exposure and cardiovascular disease at high dose, and to a lesser extent at low dose, with some indications of differences in risk between acute and chronic exposures, which require further investigation. The observed heterogeneity complicates a causal interpretation of these findings, although this heterogeneity is much reduced if only higher quality studies or those at moderate doses or low dose rates are considered. Studies are needed to assess in more detail modifications of radiation effect by lifestyle and medical risk factors. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020202036.

County-level geographic disparities in cardiovascular disease mortality among US breast cancer survivors, 2000-2018.

BACKGROUND: Disparities in cardiovascular disease mortality among breast cancer survivors are documented, but geographic factors by county-level socioeconomic status (SES) and rurality are not well described. METHODS: We analyzed 724 518 women diagnosed with localized or regional stage breast cancer between 2000 and 2017 within Surveillance, Epidemiology, and End Results Program-18 with follow-up until 2018. We calculated relative risks (RRs) of cardiovascular disease mortality using Poisson regression, accounting for age- and race-specific rates in the general population, according to county-level quintiles of SES (measured by Yost index), median income, and rurality at breast cancer diagnosis. We also calculated 10-year cumulative mortality risk of cardiovascular disease accounting for competing risks. RESULTS: Cardiovascular disease mortality was 41% higher among breast cancer survivors living in the lowest SES (RR = 1.41, 95% confidence interval [CI] = 1.36 to 1.46, Ptrend < .001) and poorest (RR = 1.41, 95% CI = 1.36 to 1.47, Ptrend < .001) counties compared with the highest SES and wealthiest counties, and 24% higher for most rural relative to most urban counties (RR = 1.24, 95% CI = 1.17 to 1.30, Ptrend < .001). Disparities for the lowest SES relative to highest SES counties were greatest among younger women aged 18-49 years (RR = 2.32, 95% CI = 1.90 to 2.83) and aged 50-59 years (RR = 2.01, 95% CI = 1.77 to 2.28) and within the first 5 years of breast cancer diagnosis (RR = 1.53, 95% CI = 1.44 to 1.64). In absolute terms, however, disparities were widest for women aged 60+ years, with approximately 2% higher 10-year cumulative cardiovascular disease mortality risk in the poorest compared with wealthiest counties. CONCLUSIONS: Geographic factors at breast cancer diagnosis were associated with increased cardiovascular disease mortality risk. Studies with individual- and county-level information are needed to inform public health interventions and reduce disparities among breast cancer survivors.

Treatment-related thoracic soft tissue sarcomas in US breast cancer survivors: a retrospective cohort study.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: US National Cancer Institute and National Institutes of Health.

Pooled Analysis of Meningioma Risk Following Treatment for Childhood Cancer.

Importance: Meningioma is the most common subsequent neoplasm following cranial irradiation among survivors of childhood cancer, but there are still uncertainties regarding the magnitude of the radiation dose-response association, potential modifiers of radiation risks, and the role of chemotherapy. Objective: To evaluate meningioma risk in survivors of childhood cancer following radiotherapy and chemotherapy and identify possible modifying factors of radiation-associated risk. Design, Setting, and Participants: This international case-control study pooled data from 4 nested case-control studies of survivors of childhood cancer diagnosed between 1942 and 2000, followed through 2016. Cases were defined as participants diagnosed with a subsequent meningioma. Controls were matched to cases based on sex, age at first cancer diagnosis, and duration of follow-up. Data were analyzed from July 2019 to June 2022. Exposures: Radiation dose (Gy) to the meningioma site and cumulative chemotherapy doses, including intrathecal and systemic methotrexate doses. Main Outcomes and Measures: The main outcome was subsequent meningioma, assessed using odds ratios (ORs) and excess odds ratios per gray (EOR/Gy). Results: The analysis included 273 survivors of childhood cancer who developed meningioma (cases) and 738 survivors who did not (controls), with a total of 1011 individuals (median [IQR] age at first cancer diagnosis 5.0 [3.0-9.2] years; 599 [59.2%] female). Median (IQR) time since first cancer was 21.5 (15.0-27.0) years. Increasing radiation dose was associated with increased risk of meningioma (EOR/Gy, 1.44; 95% CI, 0.62-3.61), and there was no evidence of departure from linearity (P = .90). Compared with survivors who were not exposed to radiation therapy, those who received doses of 24 Gy or more had more than 30-fold higher odds of meningioma (OR, 33.66; 95% CI, 14.10-80.31). The radiation dose-response association was significantly lower among patients treated at age 10 years or older compared with those treated before age 10 years (EOR/Gy, 0.57; 95% CI, 0.18-1.91 vs 2.20; 95% CI, 0.87-6.31; P for heterogeneity = .03). Risk associated with radiation remained significantly elevated 30 years after exposure (EOR/Gy, 3.76; 95% CI, 0.77-29.15). We found an increased risk of meningioma among children who had received methotrexate (OR, 3.43; 95% CI, 1.56-7.57), but no evidence of a dose-response association or interaction with radiation dose. Conclusions and Relevance: These findings suggest that the meninges are highly radiosensitive, especially for children treated before age 10 years. These results support the reduction in whole-brain irradiation over recent decades and the prioritization of approaches that limit radiation exposure in healthy tissue for children. The persistence of elevated risks of meningiomas for 30 years after cranial radiotherapy could help inform surveillance guidelines.

The influence of treatment on hormone receptor subgroups and breast cancer-specific mortality within US integrated healthcare systems.

PURPOSE: Estrogen receptor (ER) + /progesterone receptor (PR) - or ER-/PR + breast cancer prognosis has not been well-described outside of clinical trials. We evaluated the relationship between ER/PR (ER + /PR-, ER-/PR + , ER + /PR + , ER-/PR-) subgroups and breast cancer-specific mortality within a general community setting in the US. METHODS: A Retrospective cohort of 11,737 women diagnosed with breast cancer between 1990 and 2016 within US integrated healthcare systems (median follow-up = 7 years; 1,104 breast cancer-specific deaths) were included in this analysis. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) adjusting for site, demographic and clinicopathological characteristics, and treatment (surgery/radiotherapy, chemotherapy, endocrine therapy). RESULTS: Breast cancer-specific mortality was higher for those with ER + /PR- (n = 1,233) compared with ER + /PR + tumors (n = 8,439) before (HR = 1.43; 95% CI = 1.17-1.75) and after treatment adjustment (HR = 1.58; 95% CI = 1.27-1.97). ER + /PR- breast cancer-specific mortality remained higher than ER + /PR + tumors when stratified by treatment received. Breast cancer-specific mortality was similar in ER-/PR + (n = 161) compared with ER + /PR + tumors. CONCLUSION: Our findings suggest that ER + /PR- tumors may have worse breast cancer-specific mortality than ER + /PR + tumors in a community setting.

Endocrine therapy initiation among women with stage I-III invasive, hormone receptor-positive breast cancer from 2001-2016.

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.

Trends in heart disease mortality among breast cancer survivors in the US, 1975-2017.

PURPOSE: Heart disease is a significant concern among breast cancer survivors, in part due to cardiotoxic treatments including chemotherapy and radiotherapy. Long-term trends in heart disease mortality have not been well characterized. We examined heart disease mortality trends among US breast cancer survivors by treatment type. METHODS: We included first primary invasive breast cancer survivors diagnosed between 1975 and 2016 (aged 18-84; survived 12 + months; received initial chemotherapy, radiotherapy, or surgery) in the SEER-9 Database. Standardized mortality ratios (SMRs) and 10-year cumulative heart disease mortality estimates accounting for competing events were calculated by calendar year of diagnosis and initial treatment regimen. Ptrends were assessed using Poisson regression. All statistical tests were 2-sided. RESULTS: Of 516,916 breast cancer survivors, 40,812 died of heart disease through 2017. Heart disease SMRs declined overall from 1975-1979 to 2010-2016 (SMR 1.01 [95%CI: 0.98, 1.03] to 0.74 [0.69, 0.79], ptrend < 0.001). This decline was also observed for survivors treated with radiotherapy alone and chemotherapy plus radiotherapy. A sharper decline in heart disease SMRs was observed from 1975 to 1989 for left-sided radiotherapy, compared to right-sided. In contrast, there was a non-significant increasing trend in SMRs for chemotherapy alone, and significant by regional stage (ptrend = 0.036). Largest declines in 10-year cumulative mortality were observed from 1975-1984 to 2005-2016 among surgery only: 7.02% (95%CI: 6.80%, 7.23%) to 4.68% (95%CI: 4.39%, 4.99%) and radiotherapy alone: 6.35% (95%CI: 5.95%, 6.77%) to 2.94% (95%CI: 2.73%, 3.16%). CONCLUSIONS: We observed declining heart disease mortality trends by most treatment types yet increasing for regional stage patients treated with chemotherapy alone, highlighting a need for additional studies with detailed treatment data and cardiovascular management throughout cancer survivorship.

Epidemiological studies of CT scans and cancer risk: the state of the science.

20 years ago, 3 manuscripts describing doses and potential cancer risks from CT scans in children raised awareness of a growing public health problem. We reviewed the epidemiological studies that were initiated in response to these concerns that assessed cancer risks from CT scans using medical record linkage. We evaluated the study methodology and findings and provide recommendations for optimal study design for new efforts. We identified 17 eligible studies; 13 with published risk estimates, and 4 in progress. There was wide variability in the study methodology, however, which made comparison of findings challenging. Key differences included whether the study focused on childhood or adulthood exposure, radiosensitive outcomes (e.g. leukemia, brain tumors) or all cancers, the exposure metrics (e.g. organ doses, effective dose or number of CTs) and control for biases (e.g. latency and exclusion periods and confounding by indication). We were able to compare results for the subset of studies that evaluated leukemia or brain tumors. There were eight studies of leukemia risk in relation to red bone marrow (RBM) dose, effective dose or number of CTs; seven reported a positive dose-response, which was statistically significant (p < 0.05) in four studies. Six of the seven studies of brain tumors also found a positive dose-response and in five, this was statistically significant. Mean RBM dose ranged from 6 to 12 mGy and mean brain dose from 18 to 43 mGy. In a meta-analysis of the studies of childhood exposure the summary ERR/100 mGy was 1.78 (95%CI: 0.01-3.53) for leukemia/myelodisplastic syndrome (n = 5 studies) and 0.80 (95%CI: 0.48-1.12) for brain tumors (n = 4 studies) (p-heterogeneity >0.4). Confounding by cancer pre-disposing conditions was unlikely in these five studies of leukemia. The summary risk estimate for brain tumors could be over estimated, however, due to reverse causation. In conclusion, there is growing evidence from epidemiological data that CT scans can cause cancer. The absolute risks to individual patients are, however, likely to be small. Ongoing large multicenter cohorts and future pooling efforts will provide more precise risk quantification.

Body Mass Index and Risk of Second Cancer Among Women With Breast Cancer.

BACKGROUND: Breast cancer survivors are at increased risk for developing second primary cancers compared with the general population. Little is known about whether body mass index (BMI) increases this risk. We examined the association between BMI and second cancers among women with incident invasive breast cancer. METHODS: This retrospective cohort included 6481 patients from Kaiser Permanente Colorado and Washington of whom 822 (12.7%) developed a second cancer (mean follow-up was 88.0 months). BMI at the first cancer was extracted from the medical record. Outcomes included: 1) all second cancers, 2) obesity-related second cancers, 3) any second breast cancer, and 4) estrogen receptor-positive second breast cancers. Multivariable Poisson regression models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for second cancers associated with BMI adjusted for site, diagnosis year, treatment, demographic, and tumor characteristics. RESULTS: The mean age at initial breast cancer diagnosis was 61.2 (SD = 11.8) years. Most cases were overweight (33.4%) or obese (33.8%) and diagnosed at stage I (62.0%). In multivariable models, for every 5 kg/m2 increase in BMI, the risk of any second cancer diagnosis increased by 7% (RR = 1.07, 95% CI = 1.01 to 1.14); 13% (RR = 1.13, 95% CI = 1.05 to 1.21) for obesity-related cancers, 11% (RR = 1.11, 95% CI = 1.02 to 1.21) for a second breast cancer, and 15% (RR = 1.15, 95% CI = 1.04 to 1.27) for a second estrogen receptor-positive breast cancer. CONCLUSIONS: We observed a statistically significant increased risk of second cancers associated with increasing BMI. These findings have important public health implications given the prevalence of overweight and obesity in breast cancer survivors and underscore the need for effective prevention strategies.

Association of Breast Cancer Risk After Childhood Cancer With Radiation Dose to the Breast and Anthracycline Use: A Report From the Childhood Cancer Survivor Study.

Importance: Chest irradiation for childhood cancer is associated with increases in breast cancer risk. Growing evidence suggests that anthracyclines increase this risk, but the outcome of combined anthracycline use and radiotherapy has not been studied. Objectives: To evaluate breast cancer risk in childhood cancer survivors following radiotherapy and chemotherapy and assess whether risks varied by estrogen receptor (ER) status. Design, Setting, and Participants: In a North American hospital-based nested case-control study, a retrospective cohort of 14 358 five-year survivors of childhood cancer, diagnosed from 1970 to 1986 and followed up through December 31, 2016, was analyzed. Cases (n = 271) were defined as women with subsequent breast cancer. Controls (n = 1044) were matched 4:1 to cases by age at first cancer and duration of follow-up (± 2 years). Data analysis was conducted from September 2017 to July 2018. Exposures: Radiation dose to breast tumor site and ovaries and cumulative chemotherapy doses, including anthracyclines and alkylating agents. Main Outcomes and Measures: Odds ratios (ORs) for subsequent breast cancer by ER status. Results: A total of 271 women served as breast cancer cases (median age at first cancer diagnosis, 15 years [range, 3-20]; median age at breast cancer diagnosis, 39 years [range, 20-57]): 201 invasive (113 ER positive [ER+], 41 ER negative [ER-], and 47 unknown) and 70 in situ breast cancers. The OR for breast cancer increased with increasing radiation dose to the breast (OR per 10 Gy, 3.9; 95% CI, 2.5-6.5) and was similar for ER+ (OR per 10 Gy, 5.5; 95% CI, 2.8-12.6) and ER- (OR per 10 Gy, 4.8; 95% CI, 1.7-22.3) cancers. For women who received ovarian doses less than 1 Gy, the OR per 10 Gy to the breast was higher (OR, 6.8; 95% CI, 3.9-12.5) than for women who received ovarian doses greater than or equal to 15 Gy (OR, 1.4; 95% CI, 1.0-6.4). The OR for breast cancer increased with cumulative anthracycline dose (OR per 100 mg/m2, 1.23; 95% CI, 1.09-1.39; P < .01 for trend), and was 1.49 (95% CI, 1.21-1.83) for ER+ cancer vs 1.10 (95% CI, 0.84-1.45) for ER- cancers (P value for heterogeneity = .47). There was an additive interaction between radiotherapy and anthracycline treatment (P = .04) with the OR for the combined association between anthracycline therapy and breast radiation dose of 10 Gy or more (compared with 0 to less than 1 Gy) of 19.1 (95% CI, 7.6-48.0) vs 9.6 (95% CI, 4.4-20.7) without anthracycline use. Conclusions and Relevance: This study provides the first evidence to date that the combination of anthracyclines and radiotherapy may increase breast cancer risks compared with use of neither treatment with a similar radiation dose response for ER+ and ER- cancers and possibly higher anthracycline risks for ER+ cancers. These results might help inform surveillance guidelines for childhood cancer survivors.

Hyperthyroidism After Radiation Therapy for Childhood Cancer: A Report from the Childhood Cancer Survivor Study.

PURPOSE: The association of hyperthyroidism with exposure to ionizing radiation is poorly understood. This study addresses the risk of hyperthyroidism in relation to incidental therapeutic radiation dose to the thyroid and pituitary glands in a large cohort of survivors of childhood cancer. METHODS AND MATERIALS: Using the Childhood Cancer Survivor Study's cohort of 5-year survivors of childhood cancer diagnosed at hospitals in the United States and Canada between 1970 and 1986, the occurrence of hyperthyroidism through 2009 was ascertained among 12,183 survivors who responded to serial questionnaires. Radiation doses to the thyroid and pituitary glands were estimated from radiation therapy records, and chemotherapy exposures were abstracted from medical records. Binary outcome regression was used to estimate prevalence odds ratios (ORs) for hyperthyroidism at 5 years from diagnosis of childhood cancer and Poisson regression to estimate incidence rate ratios (RRs) after the first 5 years. RESULTS: Survivors reported 179 cases of hyperthyroidism, of which 148 were diagnosed 5 or more years after their cancer diagnosis. The cumulative proportion of survivors diagnosed with hyperthyroidism by 30 years after the cancer diagnosis was 2.5% (95% confidence interval [CI], 2.0%-2.9%) among those who received radiation therapy. A linear relation adequately described the thyroid radiation dose response for prevalence of self-reported hyperthyroidism 5 years after cancer diagnosis (excess OR/Gy, 0.24; 95% CI, 0.06-0.95) and incidence rate thereafter (excess RR/Gy, 0.06; 95% CI, 0.03-0.14) over the dose range of 0 to 63 Gy. Neither radiation dose to the pituitary gland nor chemotherapy was associated significantly with hyperthyroidism. Radiation-associated risk remained elevated >25 years after exposure. CONCLUSIONS: Risk of hyperthyroidism after radiation therapy during childhood is positively associated with external radiation dose to the thyroid gland, with radiation-related excess risk persisting for >25 years. Neither radiation dose to the pituitary gland nor chemotherapy exposures were associated with hyperthyroidism among childhood cancer survivors through early adulthood.

Hypothyroidism after Radiation Therapy for Childhood Cancer: A Report from the Childhood Cancer Survivor Study.

While thyroid cancer risks from exposure to ionizing radiation early in life are well characterized quantitatively, the association of radiation with nonmalignant, functional thyroid disorders has been less studied. Here, we report on a risk analysis study of hypothyroidism with radiation dose to the thyroid gland and the hypothalamic-pituitary axis among survivors of childhood cancer. Utilizing data from the Childhood Cancer Survivor Study, a cohort of 14,364 five-year survivors of childhood cancer diagnosed at 26 hospitals in the U.S. and Canada between 1970 and 1986 and followed through 2009, the occurrence of hypothyroidism was ascertained among 12,015 survivors through serial questionnaires. Radiation doses to the thyroid gland and pituitary gland were estimated from radiotherapy records. Binary outcome regression was used to estimate prevalence odds ratios for hypothyroidism at five years from diagnosis of childhood cancer and Poisson regression to model incidence rate ratios (RR) after the first five years. A total of 1,193 cases of hypothyroidism were observed, 777 (65%) of which occurred five or more years after cancer diagnosis. The cumulative proportion affected with hypothyroidism (prevalence at five years after cancer diagnosis plus incidence through 30 years after cancer diagnosis) was highest among five-year survivors of Hodgkin lymphoma (32.3%; 95% CI: 29.5-34.9) and cancers of the central nervous system (17.7%; 95% CI: 15.2-20.4). The incidence rate was significantly associated with radiation dose to the thyroid and pituitary. The joint association of hypothyroidism with thyroid and pituitary dose was sub-additive for pituitary doses greater than 16 Gy. In particular, a very strong thyroid radiation dose dependence at low-to-moderate pituitary/hypothalamic doses was diminished at high pituitary doses. Radiation-related risks were higher in males than females and inversely associated with age at exposure and time since exposure but remained elevated more than 25 years after exposure. Our findings indicated that hypothyroidism was significantly associated with treatment with bleomycin (RR = 3.4; 95% CI: 1.6-7.3) and the alkylating agents cyclohexyl-chloroethyl-nitrosourea (CCNU) (RR = 3.0; 95% CI: 1.5-5.3) and cyclophosphamide (RR = 1.3; 95% CI: 1.0-1.8), with a significant dose response for CCNU ( P < 0.01). The risk of hypothyroidism among childhood cancer survivors treated with radiation depends both on direct, dose-dependent radiation-induced damage to the thyroid gland and on dose-dependent indirect effects secondary to irradiation of the hypothalamic-pituitary axis. The dose-response relationship for each site depends on dose to the other. Radiation-related risk persists for more than 25 years after treatment. Treatment with certain chemotherapy agents may increase the risk of hypothyroidism.