Identifying potential targets for prevention and treatment of amyotrophic lateral sclerosis based on a screen of medicare prescription drugs.

Background: Few well-established factors are associated with risk of amyotrophic lateral sclerosis (ALS). We comprehensively evaluate prescription drugs use in administrative health claims from U.S. Medicare beneficiaries in relation to ALS risk to generate hypotheses for further research. Methods: This is a population-based case-control study of 10,450 U.S. Medicare participants (ages 66-89 years) diagnosed with ALS, based on Medicare Parts A and B fee-for-service claims, between 1 January 2008, and 31 December 2014, and 104,500 controls (1:10 ratio) frequency-matched on age, sex, and selection year. Odds ratios (ORs) for the ALS association with 685 prescription drugs were estimated using logistic regression models for both a one- and three-year lag period. Covariates included demographic characteristics and key comorbidities, among other factors. Prescription drug use was based on Medicare Part D claims. We adjusted for multiple comparisons using a Bonferroni correction. Additional a priori analyses of sex hormone drugs were also undertaken. Results: In the large drug screen, we found 10 drugs significantly associated with lower ALS risk after the multiple-testing correction in a one-year and three-year lag analysis. These included several drugs for hypertension, diabetes, and cardiovascular disease. In a separate a priori inquiry of sex hormone drugs, tamoxifen was related to lower ALS risk, and testosterone to a higher risk in women. Conclusions: These associations warrant replication in databases that include information on the severity and duration of medical conditions underlying drug use, and drug use over a longer portion of individuals' lifespans, to further help evaluate confounding by indication.

Lifetime exposure to ultraviolet radiation and the risk of multiple sclerosis in the US radiologic technologists cohort study.

BACKGROUND: Low exposure to ultraviolet radiation (UVR) from sunlight may be a risk factor for developing multiple sclerosis (MS). Possible pathways may be related to effects on immune system function or vitamin D insufficiency, as UVR plays a role in the production of the active form of vitamin D in the body. OBJECTIVE: This study examined whether lower levels of residential UVR exposure from sunlight were associated with increased MS risk in a cohort of radiologic technologists. METHODS: Participants in the third and fourth surveys of the US Radiologic Technologists (USRT) Cohort Study eligible (N = 39,801) for analysis provided complete residential histories and reported MS diagnoses. MS-specialized neurologists conducted medical record reviews and confirmed 148 cases. Residential locations throughout life were matched to satellite data from NASA's Total Ozone Mapping Spectrometer (TOMS) project to estimate UVR dose. RESULTS: Findings indicate that MS risk increased as average lifetime levels of UVR exposures in winter decreased. The effects were consistent across age groups <40 years. There was little indication that low exposures during summer or at older ages were related to MS risk. CONCLUSION: Our findings are consistent with the hypothesis that UVR exposure reduces MS risk and may ultimately suggest prevention strategies.

Ultraviolet radiation and incidence of cataracts in a nationwide US cohort.

PURPOSE: We examine the risk of cataract and cataract surgery with measures of ultraviolet radiation (UVR) exposure and UVR sensitivity in a large, nationwide population of indoor workers. METHODS: Participants from the US Radiologic Technologists Study were followed from age at baseline survey (2003-2005) to age at earliest of cataract diagnosis, cataract surgery, or completion of last survey (2012-2013). UVR-related factors included satellite-based ambient UVR linked to lifetime residences, time spent outdoors across various age periods, history of blistering sunburns, prior diagnosis of keratinocyte carcinoma, and iris color. We used Cox proportional hazards models with age as timescale to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for cataract and cataract surgery. RESULTS: Participants had a median age of entry of 54.0 years, were 80.0% female, and 95.7% white. Of the 44, 891 eligible participants, 9399 cases of cataract and 3826 cases of cataract surgery were reported. Ambient UVR (quintile 5 vs. 1) was associated with an increased risk of cataract (HR = 1.08; 95% CI: 1.01-1.16) and cataract surgery (HR = 1.16; 95% CI: 1.05-1.29). Lifetime average time spent outdoors was not associated with cataract risk. History of blistering sunburns before and after age 15, but not previous keratinocyte carcinoma diagnosis was associated with both cataract and cataract surgery. CONCLUSION: Our results suggest a modest role for residence-based ambient UVR and cataract risk among indoor workers in the United States.

Prediagnostic body size and risk of amyotrophic lateral sclerosis death in 10 studies.

OBJECTIVES AND METHODS: Using pooled multivariable-adjusted rate ratios (RR), we explored relationships between prediagnostic body-mass-index (BMI), waist-to-hip-ratio (WHR), and weight-gain during adulthood, and ALS in 419,894 women and 148,166 men from 10 community-based cohorts in USA, Europe, and Australia; 428 ALS deaths were documented in women and 204 in men. RESULTS: Higher mid-to-later adulthood BMI was associated with lower ALS mortality. For 5 kg/m2 increased BMI, the rate was 15% lower (95% confidence interval [CI]: 4-24%; p = 0.005). Although a clear linear trend was not evident for WHR at enrollment (p = 0.099) individuals in the highest cohort-specific quartile had 27% (95% CI: 0-47%; p = 0.053) lower ALS compared to those in the lowest. BMI in early adulthood did not predict ALS; fewer than 10% of participants had early adulthood BMI >25 kg/m2, limiting power. Weight-gain during adulthood was strongly associated with lower ALS; for an additional 1kg gain in weight/year, the RR = 0.43 (95% CI: 0.28-0.65; p < 0.001). Associations persisted when adjusted for diabetes at enrollment, restricted to never-smokers, and ALS deaths in the 5 years after enrollment were excluded (accounting for recent weight loss). CONCLUSIONS: These findings confirm somewhat conflicting, underpowered evidence that adiposity is inversely associated with ALS. We newly demonstrate that weight-gain during adulthood is strongly predictive of lower ALS risk.

Lipid-lowering drugs, dyslipidemia, and breast cancer risk in a Medicare population.

PURPOSE: We sought to disentangle the effects of statins and other lipid-lowering drugs and the underlying dyslipidemia for which they are prescribed on breast cancer risk. METHODS: We conducted a case-control study within the linked Surveillance, Epidemiology, and End results (SEER)-Medicare data. Cases were women with invasive breast cancer aged 66 + years (N = 30,004) identified by SEER registries (years 2007-2011). Controls were women (N = 198,969) identified from a 5% random sample of Medicare recipients alive and breast cancer free in year of selection. Participants had a minimum of 13 months of Part A, Part B non-health maintenance organization Medicare and Part D Medicare coverage at least 13 months preceding cancer diagnosis/selection. Exposures were assessed until 12 months before diagnosis/control selection. Odds ratios (OR) and 99.9% confidence intervals (CI) were estimated using adjusted unconditional and multinomial logistic regression. RESULTS: ORs of invasive breast cancer associated with dyslipidemia, statins, and non-statin lipid-lowering drugs were 0.86 (99.9% CI 0.81-0.90), 1.07 (99.9% CI 1.03-1.13) and 1.03 (99.9% CI 0.95-1.11), respectively. Risk reductions with dyslipidemia were slightly greater when untreated than treated and did not vary much by time between dyslipidemia and breast cancer diagnosis. Whether treated or untreated, dyslipidemia was associated with greater reductions in risk for later stage than earlier stage breast cancer (p-heterogeneity < 0.0001). CONCLUSIONS: Lipid-lowering drugs did not account for the lower breast cancer risk associated with dyslipidemia. Our data do not support using statins or other lipid-lowering drugs to prevent breast cancer.

Relationship of statins and other cholesterol-lowering medications and risk of amyotrophic lateral sclerosis in the US elderly.

OBJECTIVE: Statins are commonly prescribed drugs that have been inconsistently associated with amyotrophic lateral sclerosis (ALS) risk. We examined associations between ALS risk and overall statin use, statin categories based on lipophilicity and other cholesterol-lowering medications, in Medicare beneficiaries. METHODS: In this nation-wide population-based case-control study, 10,450 Medicare participants (ages 66-89 years) diagnosed with ALS, using Medicare Parts A and B claims, between 1 January 2008 and 31 December 2014, were frequency-matched to 104,500 controls on age, sex, and selection year. Odds ratios (ORs) for the association between statins and ALS were estimated using logistic regression models. Covariates included dyslipidemia, other comorbidities, age, sex, race, proxies for smoking and obesity, Medicare use, and indicators of socioeconomic status. Statin use derived from Medicare Part D claims. Non-statin cholesterol-lowering drugs were evaluated as comparison drugs. RESULTS: ALS risk was reduced with statin use (OR = 0.87 (95% confidence interval (CI) = 0.83-0.91)). While risk was unrelated to three cholesterol-lowering medications (nitrates, bile acid sequestrants, and ezetimibe), it was associated with fibrates (OR = 0.88 (95% CI = 0.80-0.97)). Risk for lipophilic statins was slightly lower than for other statins. ALS risk was lower in all statin categories for dyslipidemic individuals, but only lipophilic statins were associated with lower risk in non-dyslipidemic individuals and demonstrated an inverse trend with duration. CONCLUSIONS: Our findings suggest that statins are associated with lower ALS risk and offer new evidence that fibrates may be related to lower risk. However, we were unable to fully adjust for smoking and body mass index.

Spectrum of Immune-Related Conditions Associated with Risk of Keratinocyte Cancers among Elderly Adults in the United States.

Background: Elevated keratinocyte carcinoma risk is present with several immune-related conditions, e.g., solid organ transplantation and non-Hodgkin lymphoma. Because many immune-related conditions are rare, their relationships with keratinocyte carcinoma have not been studied.Methods: We used Medicare claims to identify cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) cases in 2012, and controls matched on sex and age. All subjects were aged 65 to 95 years, of white race, and had attended ≥1 dermatologist visit in 2010-2011. Immune-related conditions were identified during 1999-2011 using Medicare claims. Associations were estimated with logistic regression, with statistical significance determined after Bonferroni correction for multiple comparisons.Results: We included 258,683 SCC and 304,903 BCC cases. Of 47 immune-related conditions, 21 and 9 were associated with increased SCC and BCC risk, respectively. We identified strongly elevated keratinocyte carcinoma risk with solid organ transplantation (SCC OR = 5.35; BCC OR = 1.94) and non-Hodgkin lymphoma (SCC OR = 1.62; BCC OR = 1.25). We identified associations with common conditions, e.g., rheumatoid arthritis [SCC OR = 1.06, 95% confidence interval (95% CI), 1.04-1.09] and Crohn's disease (SCC OR = 1.33, 95% CI, 1.27-1.39; BCC OR = 1.10, 95% CI, 1.05-1.15), and rare or poorly characterized conditions, e.g., granulomatosis with polyangiitis (SCC OR = 1.88; 95% CI, 1.61-2.19), autoimmune hepatitis (SCC OR = 1.81; 95% CI, 1.52-2.16), and deficiency of humoral immunity (SCC OR = 1.51, 95% CI, 1.41-1.61; BCC OR = 1.22, 95% CI, 1.14-1.31). Most conditions were more positively associated with SCC than BCC. Associations were generally consistent regardless of prior keratinocyte carcinoma history.Conclusions: Many immune-related conditions are associated with elevated keratinocyte carcinoma risk and appear more tightly linked to SCC.Impact: Immunosuppression or immunosuppressive treatment may increase keratinocyte carcinoma risk, particularly SCC. Cancer Epidemiol Biomarkers Prev; 26(7); 998-1007. ©2017 AACR.

Ultraviolet Radiation and Kaposi Sarcoma Incidence in a Nationwide US Cohort of HIV-Infected Men.

Background: Although ultraviolet radiation (UVR) is established as both an inducer of herpes simplex virus reactivation and as the primary risk factor for many common skin cancers, its relationship with human herpes virus 8 (HHV8) infection or risk of Kaposi sarcoma (KS) is unknown. Methods: Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for the association between ambient UVR, history of nonmelanoma skin cancer (NMSC; as a biomarker of personal cumulative UVR dose), and incidence of first primary KS in a nationwide US cohort of white and African American male veterans infected with HIV between 1986 and 1996 (prior to the widespread availability of treatment) using Cox regression. All statistical tests were two-sided. Results: Based on discharge records, there were 422 newly diagnosed KS cases among 17 597 HIV-infected veterans. Cohort members with prior NMSC had a statistically significantly increased risk of KS (HR = 8.64, 95% CI = 6.23 to 11.96) in the total population. Risk of KS was higher for quartile 4 vs 1 among the total population (HR = 1.49, 95% CI = 1.02 to 2.16, Ptrend UVR quartile [coded 1 to 4] = .02) and among whites (HR = 1.75, 95% CI = 1.11 to 2.78, Ptrend = .009), but not among African Americans (HR = 1.23, 95% CI = 0.71 to 2.15, Ptrend = .23). Conclusions: KS risk was elevated among HIV-infected men with NMSC diagnosis and in those living in locations with high ambient UVR at time of HIV diagnosis. Our novel findings suggesting that UVR exposure may increase KS risk warrant further investigation.

Prospective Study of Ultraviolet Radiation Exposure and Thyroid Cancer Risk in the United States.

Background: Thyroid cancer incidence has tripled in the past three decades, yet relatively few risk factors have been identified. Some studies have suggested that ultraviolet radiation (UVR) may affect thyroid cancer risk.Methods: We conducted a prospective analysis of 44,039 participants in the United States Radiologic Technologists Study (153 thyroid cancer cases) from all 50 states. We examined the association between risk of thyroid cancer and exposure to UVR, estimated by ambient UVR, time outdoors, and a combined variable. Participants reported location of residence and time outdoors during five age periods starting in childhood. Ambient UVR was estimated by linking satellite-based UVR measurements to geocoded residences. We assessed the association of UVR by age and average lifetime UVR with thyroid cancer risk using Cox proportional hazards models, starting at the time of the baseline questionnaire (2003-2005) through 2012-2013.Results: Combined UVR from the latest age period (age 40+) was associated with a decreased risk of thyroid cancer (HR for 4th vs. 1st quartile = 0.56; 95% CI, 0.31-1.02, Ptrend = 0.04). This was limited to participants with benign thyroid disease and to those with darker complexions, although we found no evidence of effect modification. Thyroid cancer risk was unrelated to all metrics of UVR in earlier age periods and for average lifetime exposure.Conclusions: Recent UVR exposure was associated with a decreased risk of thyroid cancer. This association appeared to be modified by benign thyroid disease and skin complexion.Impact: UVR exposure may be associated with a decreased risk of thyroid cancer. Cancer Epidemiol Biomarkers Prev; 26(5); 684-91. ©2016 AACR.

Relationship between plasma 25-hydroxyvitamin D and leucocyte telomere length by sex and race in a US study.

A few studies have examined the association between vitamin D and telomere length, and fewer still have examined the relationship in black or male populations. We investigated the cross-sectional association between the vitamin D metabolite 25-hydroxyvitamin D (25(OH)D) concentration in plasma and relative leucocyte telomere length (LTL) in 1154 US radiologic technologists who were 48-93 years old (373 white females, 278 white males, 338 black females, 165 black males). Plasma 25(OH)D concentration was measured by the chemiluminescence immunoassay, and relative LTL was measured by quantitative PCR. Logistic regression was used to obtain OR and 95 % CI for long v. short (based on median) LTL in relation to continuous 25(OH)D, quartiles of 25(OH)D and 25(OH)D deficiency. We found no significant association between continuous 25(OH)D and long LTL in all participants (P trend=0·440), nor in white females (P trend=0·845), white males (P trend=0·636), black females (P trend=0·967) or black males (P trend=0·484). Vitamin D deficiency (defined as 25(OH)D<30 nmol/l), however, was significantly associated with short LTL in whites (P=0·024), but not in other groups. In this population, we found little evidence to support associations between 25(OH)D and long LTL over the entire range of 25(OH)D in the overall study population or by sex and race.

Prospective study of ultraviolet radiation exposure and risk of breast cancer in the United States.

Although there are few environmental risk factors for breast cancer, some epidemiologic studies found that exposure to solar UV radiation (UVR) may lower risk. Prior epidemiologic studies are limited by narrow ambient UVR ranges and lack lifetime exposure assessment. To address these issues, we studied a cohort with residences representing a wide range of ambient UVR. Using the nationwide U.S. Radiologic Technologists study (USRT), we examined the association between breast cancer risk and UVR based on ambient UVR, time outdoors, a combined variable of ambient UVR and time outdoors (combined UVR), and sun susceptibility factors. Participants reported location of residence and hours spent outdoors during five age periods. Ambient UVR was derived by linking satellite-based annual UVR estimates to self-reported residences. Lifetime values were calculated by averaging these measures accounting for years spent in that location. We examined the risk of breast cancer among 36,725 participants (n=716 cases) from baseline questionnaire completion (2003-2005) through 2012-2013 using Cox proportional hazards models. Breast cancer risk was unrelated to ambient UVR (HR for lifetime 5th vs 1st quintile=1.22, 95% CI: 0.95-1.56, p-trend=0.36), time outdoors (HR for lifetime 5th vs 1st quintile=0.87, 95% confidence interval (CI): 0.68-1.10, p-trend=0.46), or combined UVR (HR lifetime 5th vs 1st quintile =0.85, 95% CI: 0.67-1.08, p-trend=0.46). Breast cancer risk was not associated with skin complexion, eye or hair color, or sunburn history. This study does not support the hypothesis that UVR exposure lowers breast cancer risk.

Associations between cancer and Parkinson's disease in U.S. elderly adults.

BACKGROUND: Several studies suggest that cancer is reduced before and after a Parkinson's disease (PD) diagnosis. However, determining relationships among diseases of ageing is challenging due to possible biases in ascertaining disease. This study evaluates the PD and cancer relationship, addressing potential biases. METHODS: Using Surveillance, Epidemiology, and End Results-Medicare linked data (1992-2005) of adults ≥ 65 years, we assessed PD risk after cancer comparing PD in 743 779 cancer patients with PD in a non-cancer group (n = 419 432) in prospective cohort analyses. We also conducted a case-control study of 836 947 cancer cases and 142 869 controls to assess cancer following PD. We applied Cox proportional hazards models to estimate hazards ratios (HRs) for PD after cancer and unconditional logistic regression to estimate odds ratios (ORs) for PD preceding cancer, controlling for physician visits and other factors. To explore biases in ascertaining cancer, we examined relationships between cancer and automobile accident injuries, which we expected to be null. RESULTS: No association was observed between cancer and subsequent PD [HR = 0.97; 95% confidence interval (CI) = 0.92-1.01] nor between cancer and subsequent automobile injuries (HR = 1.03; 95% CI = 0.98-1.07). One site, lung cancer, was associated with subsequent reduced PD, which may reflect confounding by smoking. In the case-control analysis, PD was associated with reduced subsequent cancer, overall (OR = 0.77; 95% CI = 0.71-0.82) and for several cancer sites. However, the automobile injury/ subsequent cancer association was similar (OR = 0.83; 95% CI = 0.78-0.88), suggesting a cancer detection bias after serious health outcomes. CONCLUSIONS: In totality, our data do not support a biological relationship between PD and cancer.

Cancer Risks in U.S. Radiologic Technologists Working With Fluoroscopically Guided Interventional Procedures, 1994-2008.

OBJECTIVE: The purpose of this study was to examine risks of cancer incidence and mortality among U.S. radiation technologists performing or assisting with fluoroscopically guided interventional procedures. SUBJECTS AND METHODS: A nationwide prospective cohort of 90,957 radiologic technologists, who responded to a 1994-1998 survey that collected information on whether they had ever worked with fluoroscopically guided interventional procedures, was followed through completion of a subsequent cohort survey during 2003-2005 (for cancer incidence) or December 31, 2008 (for cancer mortality). Sex-adjusted hazard ratios (HRs) and 95% CIs were calculated by use of Cox proportional hazards models for incidence and mortality from all cancers other than nonmelanoma skin cancer and for specific cancer outcomes in participants who reported ever performing fluoroscopically guided interventional procedures compared with technologists who never performed these procedures. RESULTS: The analysis showed an approximately twofold increased risk of brain cancer mortality (HR, 2.55; 95% CI, 1.48-4.40) and modest elevations in incidence of melanoma (HR, 1.30; 95% CI, 1.05-1.61) and in breast cancer incidence (HR, 1.16; 95% CI, 1.02-1.32) but not mortality (HR, 1.07; 95% CI, 0.69-1.66) among technologists who performed fluoroscopically guided interventional procedures compared with those who never performed these procedures. Although there was a small suggestive increase in incidence of all cancers combined, excluding nonmelanoma skin cancers (HR, 1.08; 95% CI, 1.00-1.17), mortality from all cancers combined, excluding nonmelanoma skin cancers, was not elevated (HR, 1.00; 95% CI, 0.88-1.14). We similarly observed no elevated risk of cancers of the thyroid, skin other than melanoma, prostate, lung, or colon and rectum or of leukemia that was not chronic lymphocytic leukemia among workers who performed fluoroscopically guided interventional procedures. CONCLUSION: We observed elevated risks of brain cancer, breast cancer, and melanoma among technologists who performed fluoroscopically guided interventional procedures. Although exposure to low-dose radiation is one possible explanation for these increased risks, these results may also be due to chance or unmeasured confounding by nonradiation risk factors. Our results must be confirmed in other studies, preferably with individual radiation dose data.

Relationship between ambient ultraviolet radiation and Hodgkin lymphoma subtypes in the United States.

BACKGROUND: There are few modifiable risk factors for Hodgkin lymphoma (HL), the most common cancer among young adults in Western populations. Some studies have found a reduced risk with exposure to ultraviolet radiation (UVR), but findings have been inconsistent and limited to HL as a group or the most common subtypes. METHODS: We evaluated UVR and incidence of HL subtypes using data from 15 population-based cancer registries in the United States from 2001 to 2010 (n=20 021). Ground-based ambient UVR estimates were linked to county of diagnosis. Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were calculated for UVR quintiles using Poisson regression models adjusted for age, sex, race/ethnicity, diagnosis year, and registry. RESULTS: Hodgkin lymphoma incidence was lower in the highest UVR quintile for nodular sclerosis (IRR=0.84, 95% CI=0.75-0.96, P-trend<0.01), mixed cellularity/lymphocyte-depleted (IRR=0.66, 95% CI=0.51-0.86, P-trend=0.11), lymphocyte-rich (IRR=0.71, 95% CI=0.57-0.88, P-trend<0.01), and nodular lymphocyte predominant HL (IRR=0.74, 95% CI=0.56-0.97, P-trend<0.01), but 'not otherwise specified' HL (IRR=1.19, 95% CI=0.96-1.47, P-trend=0.11). CONCLUSIONS: This is the largest study of UVR and HL subtypes covering a wide range of UVR levels; however, we lack information on personal UVR and other individual risk factors. These findings support an inverse association between UVR and HL.

Incidence and mortality risks for circulatory diseases in US radiologic technologists who worked with fluoroscopically guided interventional procedures, 1994-2008.

OBJECTIVES: Although fluoroscopically guided interventional procedures (FGIP) have provided major advances in the treatment of various common diseases, radiation exposures associated with these procedures may cause adverse health effects in workers. We assess risk of circulatory disease incidence and mortality in medical radiation workers performing FGIP. METHODS: A US nationwide prospective cohort study of 90,957 radiologic technologists who completed a cohort survey during 1994-1998 was followed until completion of a subsequent survey during 2003-2005 for circulatory disease incidence, or until 31 December 2008 for mortality. Incidence analyses were restricted to the 63,482 technologists who completed both the second survey (1994-1998) and the third survey (2003-2005). Cox proportional hazards models were used to assess adjusted HR and 95% CIs for mortality from all causes, all circulatory diseases, all heart diseases, ischaemic heart disease, stroke, acute myocardial infarction and hypertension in participants who reported ever performing FGIP compared to technologists who never performed FGIP procedures. Adjusted HRs were calculated for self-reported hypertension, stroke and myocardial infarction. RESULTS: We observed a 34% increase in stroke incidence (HR=1.34, 95% CI 1.10 to 1.64) in technologists who performed FGIP compared to those who never performed these procedures. Mortality from stroke was also modestly elevated, although not statistically significant (HR=1.22, 95% CI 0.85 to 1.73). We observed no statistically significant excess risks of incidence or mortality from any other outcome evaluated. CONCLUSIONS: Our finding of elevated risk of stroke in workers performing FGIP needs to be confirmed in studies with individual radiation dose data, but nonetheless underlines the need to keep radiation exposure as low as reasonably achievable without compromising key diagnostic information.

Female Estrogen-Related Factors and Incidence of Basal Cell Carcinoma in a Nationwide US Cohort.

PURPOSE: UV radiation exposure is the primary risk factor for basal cell carcinoma (BCC), the most common human malignancy. Although the photosensitizing properties of estrogens have been recognized for decades, few studies have examined the relationship between reproductive factors or exogenous estrogen use and BCC. METHODS: Using data from the US Radiologic Technologists Study, a large, nationwide, prospective cohort, we assessed the relationship between reproductive factors, exogenous estrogen use, and first primary BCC while accounting for sun exposure, personal sun sensitivity, and lifestyle factors for geographically dispersed women exposed to a wide range of ambient UV radiation. RESULTS: Elevated risk of BCC was associated with late age at natural menopause (hazard ratio [HR] for ≥ 55 years v 50 to 54 years, 1.50; 95% CI, 1.04 to 2.17) and any use of menopausal hormone therapy (MHT; HR, 1.16; 95% CI, 1.03 to 1.30; P for trend for duration = .001). BCC risk was most increased among women reporting natural menopause who used MHT for 10 or more years versus women who never used MHT (HR, 1.97; 95% CI, 1.35 to 2.87). Risk of BCC was not associated with age at menarche, parity, age at first birth, infertility, use of diethylstilbestrol by participant's mother, age at hysterectomy, or use of oral contraceptives. CONCLUSION: These analyses confirm a previous finding of increased risk of BCC associated with MHT. Novel findings of increased BCC risk associated with MHT in women experiencing natural menopause and for late age at natural menopause warrant further investigation. Users of MHT may constitute an additional high-risk group in need of more frequent skin cancer screening.