Association between diabetes and subsequent malignancy risk among older breast cancer survivors.

Type II diabetes is associated with cancer risk in the general population but has not been well studied as a risk factor for subsequent malignancies among cancer survivors. We investigated the association between diabetes and subsequent cancer risk among older (66-84 years), 1-year breast cancer survivors within the linked Surveillance Epidemiology and End Results (SEER)-Medicare database using Cox regression analyses to quantify hazard ratios (HR) and corresponding 95% confidence intervals (95% CI). Among 133 324 women, 29.3% were diagnosed with diabetes before or concurrent with their breast cancer diagnosis, and 10 452 women developed subsequent malignancies over a median follow-up of 4.3 years. Diabetes was statistically significantly associated with liver (HR = 2.35, 95% CI = 1.48 to 3.74), brain (HR = 1.94, 95% CI = 1.26 to 2.96), and thyroid cancer risks (HR = 1.38, 95% CI = 1.01 to 1.89). Future studies are needed to better understand the spectrum of subsequent cancers associated with diabetes and the role of diabetes medications in modifying subsequent cancer risk, alone or in combination with cancer treatments.

Survival of adult AML patients treated with chemotherapy in the U.S. population by age, race and ethnicity, sex, calendar-year period, and AML subgroup, 2001-2019.

Background: Population-based survival studies of adult acute myeloid leukemia (AML) have not simultaneously evaluated age at diagnosis, race and ethnicity, sex, calendar period or AML subtypes/subgroups among chemotherapy-treated patients. Methods: For 28,473 chemotherapy-treated AML patients diagnosed at ages ≥20 years in population-based cancer registry areas of the Surveillance, Epidemiology, and End Results Program (2001-2018, followed through 2019), we evaluated 1-month through 5-year relative survival (RS) and 95% confidence intervals (95% CI) using the actuarial method in the SEER∗Stat Survival Session and overall survival (OS) using multivariable Cox regression to estimate proportional hazard ratios (HR) and 95% CI. Findings: RS decreased with increasing age (20-39, 40-59, 60-74, 75-84, ≥85 years) at AML diagnosis. RS declined substantially within the first month and, except for acute promyelocytic leukemia, decreasing patterns continued thereafter for core binding factor AML, AML with antecedent condition/therapy, and all other AML. For all ages, acute promyelocytic leukemia RS stabilized after the first year. For total AML the hazard of death was significantly increased for non-Hispanic (NH)-Black (HR = 1.18, 95% CI = 1.12-1.24) and NH-Pacific Islander patients (HR = 1.31, 95% CI = 1.11-1.55) compared with NH-White patients. In contrast, NH-Asian and Hispanic patients had similar OS to NH-White patients across all ages and most AML subgroups. Males had significantly inferior survival to females with some exceptions. Compared to 2001-2006, in 2013-2018 OS improved for all age and AML subgroups. Interpretation: Chemotherapy-treated U.S. adults with AML have notable differences in survival by age, race and ethnicity, sex, calendar-year period, and AML subgroup. Despite survival gains over time, our findings highlight the need for improving early outcomes across all AML subgroups, older ages, and Black and Pacific Islander patients and long-term outcomes among most treated groups. Funding: Intramural Research Program of the U.S. National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, and the U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of Surveillance and Epidemiology.

Utilization of Autologous Hematopoietic Cell Transplantation Over Time in Multiple Myeloma: A Population-Based Study.

PURPOSE: Autologous hematopoietic cell transplantation (autoHCT) is associated with survival benefits in multiple myeloma (MM), but utilization remains low and differs by sociodemographic factors. Prior population-based studies have not fully captured autoHCT utilization or examined relationships between sociodemographic factors and autoHCT trends over time. PATIENTS AND METHODS: We used a novel data linkage between the California Cancer Registry, Center for International Blood and Marrow Transplant Research, and hospitalizations to capture autoHCT in a population-based MM cohort (n = 29, 109; 1991-2016). Due to interactions by treatment era, stratified multivariable Cox proportional hazards regression models determined factors associated with autoHCT. RESULTS: The frequency of MM patients who received autoHCT increased from 5.7% (1991-1995) to 27.4% (2011-2016). In models by treatment era, patients with public/no (vs. private) health insurance were less likely to receive autoHCT (2011-2016 Medicare hazard ratio (HR) 0.70, 95% confidence interval (CI): 0.63-0.78; Medicaid HR 0.81, CI: 0.72-0.91; no insurance HR 0.56, CI: 0.32-0.99). In each treatment era, Black/African American (vs. non-Hispanic White) patients were less likely to receive autoHCT (2011-2016 HR 0.83, CI: 0.72-0.95). Hispanic patients were less likely to undergo autoHCT, most prominently in the earliest treatment era (1991-1995 HR 0.58, 95% CI: 0.37-0.90; 2011-2016 HR 1.07, CI: 0.96-1.19). Patients in lower socioeconomic status neighborhoods were less likely to utilize autoHCT, but differences decreased over time. CONCLUSIONS: Despite increases in autoHCT utilization, sociodemographic disparities remain. Identifying and mitigating barriers to autoHCT is essential to ensuring more equitable access to this highly effective therapy.

Cancer mortality in chrysotile miners and millers, Russian Federation: main results (Asbest Chrysotile Cohort-Study).

BACKGROUND: We investigated mortality in workers of the world's largest chrysotile mine and enrichment factories located in the town of Asbest, Russian Federation. METHODS: This historical cohort study included all workers employed for at least 1 year between 1975 and 2010 and follow-up until the end of 2015. Cumulative exposure to dust was estimated based on workers' complete occupational history linked to dust measurements systematically collected from the 1950s. Exposure to chrysotile fibers was estimated using dust-to-fiber conversion factors. Relative risks (RRs) and 95% confidence intervals (CIs) were estimated as mortality rate ratios in Poisson regression models. RESULTS: A total of 30 445 (32% women) workers accumulated 721 312 person-years at risk and 11 110 (36%) died. Of the workers, 54% had more than 30 years since their first exposure. We found an exposure-response between cumulative dust and lung cancer mortality in men. No clear association with dust exposure but a modest increase in the highest category of fiber exposure was seen for lung cancer in women. Mesothelioma mortality was increased (RR = 7.64, 95% CI = 1.18 to 49.5, to at least 80 fibers per cm3 years and RR = 4.56, 95% CI = 0.94 to 22.1, to at least 150 mg/m3 years [dust]), based on 13 deaths. For colorectal and stomach cancer, there were inconsistent associations. No associations were seen for laryngeal or ovarian cancer. CONCLUSION: In this large-scale epidemiological study in the world's largest active asbestos mine, we confirmed an increased risk of mesothelioma with high fiber exposure and an increasing mortality for lung cancer in men with increasing dust exposure. Less clear-cut increased lung cancer mortality was seen in the women. Continued mortality follow-up is warranted.

Comparison of Vital Status, Cause of Death, and Follow-Up after Hematopoietic Cell Transplantation in Linked Center for International Blood and Marrow Transplant Research and California Cancer Registry Data, 1991 to 2018.

Assessing outcomes following hematopoietic cell transplantation (HCT) poses challenges due to the necessity for systematic and often prolonged patient follow-up. Linking the HCT database of the Center for International Blood and Marrow Transplant Research (CIBMTR) with cancer registry data may improve long-term outcome ascertainment, but the reliability of mortality data in death certificates from cancer registries among HCT recipients remains unknown. We compared the classification of vital status and primary cause of death (COD), as well as the length of follow-up between the CIBMTR and California Cancer Registry (CCR) to assess the possibility of supplementing the CIBMTR with cancer registry data. This retrospective study leveraged a linked CIBMTR-CCR dataset. We included patients who were California residents at the time of HCT and received a first allogeneic (allo) or autologous (auto) HCT for a hematologic malignancy diagnosed during 1991-2016. Follow-up was through 2018. We analyzed 18,450 patients (alloHCT, n = 8232; autoHCT, n = 10,218). The Vital status agreement was 97.7% for alloHCT and 97.2% for autoHCT. Unknown COD was higher in CIBMTR (12.9%) than in CCR (1.6%). After excluding patients with unknown COD information, the overall agreement of primary COD (cancer versus noncancer) was 53.7% for alloHCT and 83.2% for autoHCT. This agreement was lower within the first 100 days post-HCT (alloHCT, 31.0%; autoHCT, 54.6%). Compared with CIBMTR, deaths due to cancer were higher in CCR (alloHCT, 90.0%; autoHCT, 90.1% versus alloHCT, 47.3%; autoHCT, 82.5% in CIBMTR). CIBMTR reports more frequently noncancer-related deaths, including graft-versus-host disease and infections. The cumulative incidence of cancer-specific mortality at 20 years differed, particularly for alloHCT (CCR, 53.7%; CIBMTR, 27.6%). The median follow-up among alive patients was longer in CCR (alloHCT, 6.0 years; autoHCT, 4.7 years) than in CIBMTR (alloHCT, 5.0 years; autoHCT, 3.8 years). Our findings highlight the completeness of vital status data in CIBMTR but reveal substantial disagreement in primary COD. Consequently, caution is required when interpreting HCT studies that use only death certificates to estimate cause-specific mortality outcomes. Improving the accuracy of COD registration and follow-up completeness by developing communication pathways between cancer registries and hospital-based cohorts may enhance our understanding of late effects and long-term outcomes among HCT survivors.

All-Cause and Cause-Specific Mortality Among Low-Risk Differentiated Thyroid Cancer Survivors in the United States.

Background: Despite the excellent disease-specific survival associated with low-risk differentiated thyroid cancer (DTC), its diagnosis and management have been linked to patient concerns about cancer recurrence, treatment-related health risks, and mortality. Lack of information regarding long-term health outcomes can perpetuate these concerns. Therefore, we assessed all-cause and cause-specific mortality in a large cohort of individuals diagnosed with low-risk DTC. Methods: From the U.S. Surveillance, Epidemiology, and End Results-12 cancer registry database (1992-2019), we identified 51,854 individuals (81.8% female) diagnosed with first primary DTC at low risk of recurrence (≤4 cm, localized). We estimated cause-specific cumulative mortality by time since diagnosis, accounting for competing risks. Standardized mortality ratios (SMRs) and CIs were used to compare observed mortality rates in DTC patients with expected rates in the matched U.S. general population, overall and by time since DTC diagnosis. We used Cox proportional hazards models to examine associations between radioactive iodine (RAI) treatment and cause-specific mortality. Results: During follow-up (median = 8.8, range 0-28 years), 3467 (6.7%) deaths were recorded. Thyroid cancer accounted for only 4.3% of deaths (n = 148). The most common causes of death were malignancies (other than thyroid cancer) (n = 1031, 29.7%) and cardiovascular disease (CVD; n = 912, 26.3%). The 20-year cumulative mortality rate from thyroid cancer, malignancies (other than thyroid or nonmelanoma skin cancer), and CVD was 0.6%, 4.6%, and 3.9%, respectively. Lower than expected mortality was observed for all causes excluding thyroid cancer (SMR = 0.69 [CI 0.67-0.71]) and most specific causes, including all malignancies combined (other than thyroid cancer; SMR = 0.80 [CI 0.75-0.85]) and CVD (SMR = 0.64 [CI 0.60-0.69]). However, mortality rates were elevated for specific cancers, including pancreas (SMR = 1.58 [CI 1.18-2.06]), kidney and renal pelvis (SMR = 1.85 [CI 1.10-2.93]), and brain and other nervous system (SMR = 1.62 [CI 0.99-2.51]), and myeloma (SMR = 2.35 [CI 1.46-3.60]) and leukemia (SMR = 1.62 [CI 1.07-2.36]); these associations were stronger ≥10 years after diagnosis. RAI was not associated with risk of cause-specific death, but numbers of events were small and the range of administered activities was likely narrow. Conclusions: Overall, our findings provide reassurance regarding low overall and cause-specific mortality rates in individuals with low-risk DTC. Additional research is necessary to confirm and understand the increased mortality from certain subsequent cancers.

Trends in risk for therapy-related myelodysplastic syndrome/acute myeloid leukemia after initial chemo/immunotherapy for common and rare lymphoid neoplasms, 2000-2018.

Background: Historically, survivors of common lymphoid neoplasms (LNs) had increased risks for therapy-related myelodysplastic syndrome/acute myeloid leukemia (tMDS/AML). Despite major treatment advances in the treatment of LNs over the last two decades, a comprehensive evaluation of tMDS/AML trends following both common and rare LNs treated in this contemporary period is lacking. Methods: In US cancer registries during 2000-2018, we identified 1496 tMDS/AML cases among 186,503 adults who were treated with initial chemo/immunotherapy for first primary LN and survived ≥1 year. We quantified tMDS/AML standardized incidence ratios (SIRs), excess absolute risks (EARs, per 10,000 person-years), and cumulative incidence. Findings: The highest tMDS/AML risks occurred after precursor leukemia/lymphoma (SIR = 39, EAR = 30), Burkitt leukemia/lymphoma (SIR = 20, EAR = 24), peripheral T-cell lymphoma (SIR = 12, EAR = 23), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; SIR = 9.0, EAR = 27), and mantle cell lymphoma (SIR = 8.5, EAR = 25). Elevated risks (SIRs = 4.2-6.9, EARs = 4.9-15) also were observed after all other LN subtypes except hairy cell leukemia and mycosis fungoides/Sézary syndrome. Among patients treated more recently, tMDS/AML risks were significantly higher after CLL/SLL (SIR2000-2005 = 4.8, SIR2012-2017 = 10, Ptrend = 0.0043), significantly lower after Hodgkin (SIR2000-2005 = 15, SIR2012-2017 = 6.3, Ptrend = 0.024) and marginal zone (SIR2000-2005 = 7.5, SIR2012-2017 = 2.3, Ptrend = 0.015) lymphomas, and non-significantly lower after mantle cell lymphoma (SIR2000-2005 = 10, SIR2012-2017 = 3.2, Ptrend = 0.054), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (SIR2000-2005 = 6.9, SIR2012-2017 = 1.0, Ptrend = 0.067), and plasma cell neoplasms (SIR2000-2005 = 5.4, SIR2012-2017 = 3.1, Ptrend = 0.051). EAR and cumulative incidence trends generally were similar to SIR trends. Median survival after tMDS/AML was 8.0 months (interquartile range, 3.0-22.0). Interpretation: Although tMDS/AML risks are significantly elevated after initial chemo/immunotherapy for most LNs, patients treated more recently have lower tMDS/AML risks, except after CLL/SLL. Though rare, the poor prognosis following tMDS/AML emphasizes the importance of continued efforts to reduce treatment-associated toxicity. Funding: This research was supported in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. LMM, GMD, REC, and CBS verified the data, and all authors had access to the data and made the decision to submit for publication.

Comparing Risk for Second Primary Cancers After Intensity-Modulated vs 3-Dimensional Conformal Radiation Therapy for Prostate Cancer, 2002-2015.

Importance: Compared with 3-dimensional conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT) can spare nearby tissue but may result in increased scatter radiation to distant normal tissue, including red bone marrow. It is unclear whether second primary cancer risk varies by radiotherapy type. Objective: To evaluate whether radiotherapy type (IMRT vs 3DCRT) is associated with second primary cancer risk among older men treated for prostate cancer. Design, Setting, and Participants: In this retrospective cohort study of a linked database of Medicare claims and Surveillance, Epidemiology, and End Results (SEER) Program population-based cancer registries (2002-2015), male patients aged 66 to 84 diagnosed with a first primary nonmetastatic prostate cancer from 2002 to 2013, as reported to SEER, and who received radiotherapy (IMRT and/or 3DCRT without proton therapy) within the first year following prostate cancer were identified. The data were analyzed from January 2022 through June 2022. Exposure: Receipt of IMRT and 3DCRT, based on Medicare claims. Main Outcomes and Measures: The association between radiotherapy type and development of a subsequent hematologic cancer at least 2 years after prostate cancer diagnosis or a subsequent solid cancer at least 5 years after prostate cancer diagnosis. Hazard ratios (HRs) and 95% CIs were estimated using multivariable Cox proportional regression. Results: The study included 65 235 2-year first primary prostate cancer survivors (median [range] age, 72 [66-82] years; 82.2% White patients) and 45 811 5-year survivors with similar demographic characteristics (median [range] age, 72 [66-79] years; 82.4% White patients). Among 2-year prostate cancer survivors (median [range] follow-up, 4.6 [0.003-12.0] years), 1107 second hematologic cancers were diagnosed (IMRT, 603; 3DCRT, 504). Radiotherapy type was not associated with second hematologic cancers overall or any specific types evaluated. Among 5-year survivors (median [range] follow-up, 3.1 [0.003-9.0] years), 2688 men were diagnosed with a second primary solid cancer (IMRT, 1306; 3DCRT, 1382). The overall HR for IMRT vs 3DCRT was 0.91 (95% CI, 0.83-0.99). This inverse association was restricted to the earlier calendar year period of prostate cancer diagnosis (HR2002-2005 = 0.85; 95% CI, 0.76-0.94; HR2006-2010 = 1.14; 95% CI, 0.96-1.36), with a similar pattern observed for colon cancer (HR2002-2005 = 0.66; 95% CI, 0.46-0.94; HR2006-2010 = 1.06; 95% CI, 0.59-1.88). Conclusions and Relevance: The results of this large, population-based cohort study suggest that IMRT for prostate cancer is not associated with an increased risk of second primary cancers, either solid or hematologic, and any inverse associations may be associated with calendar year of treatment.

Linking the Center for International Blood and Marrow Transplant Research Registry to the California Cancer Registry and California Hospital Patient Discharge Data.

Advances in hematopoietic cell transplantation (HCT) have substantially improved patient survival, increasing the importance of studying outcomes and long-term adverse effects in the rapidly growing population of HCT survivors. Large-scale registry data from the Center for International Blood and Marrow Transplant Research (CIBMTR) are a valuable resource for studying mortality and late effects after HCT, providing detailed data reported by HCT centers on transplantation-related factors and key outcomes. This study was conducted to evaluate the robustness of CIBMTR outcome data and assess health-related outcomes and healthcare utilization among HCT recipients. We linked data from the CIBMTR for California residents with data from the population-based California Cancer Registry (CCR) and hospitalization information from the California Patient Discharge Database (PDD). In this retrospective cohort study, probabilistic and deterministic record linkage used key patient identifiers, such as Social Security number, ZIP code, sex, birth date, hematologic malignancy type and diagnosis date, and HCT type and date. Among 22,733 patients registered with the CIBMTR who underwent autologous or allogeneic HCT for hematologic malignancy between 1991 and 2016, 89.0% were matched to the CCR and/or PDD (n = 17,707 [77.9%] for both, n = 1179 [5.2%] for the CCR only, and n = 1342 [5.9%] for the PDD only). Unmatched patients were slightly more likely to have undergone a first autologous HCT than an allogeneic HCT (12.6% versus 9.0%), to have a larger number of missing linkage identifiers, and to have undergone HCT prior to 2010. Among the patients reported to the CIBMTR who matched to the CCR, 85.7% demonstrated concordance of both hematologic malignancy type and diagnosis date across data sources. This linkage presents unparalleled opportunities to advance our understanding of HCT practices and patient outcomes.

Immune-Related Adverse Events After Immune Checkpoint Inhibitors for Melanoma Among Older Adults.

Importance: Immune checkpoint inhibitors (ICIs) have improved survival in patients with advanced melanoma but can be associated with a spectrum of immune-related adverse events (AEs), including both autoimmune-related AEs and other immune-related inflammatory AEs. These associations have primarily been evaluated in clinical trials that include highly selected patients, with older adults often underrepresented. Objective: To evaluate the association between use of ICIs and immune-related AEs (autoimmune and other immune related) among older patients with cutaneous melanoma. Design, Setting, and Participants: A population-based cohort study was conducted from January 1, 2011, to December 31, 2015. Data were analyzed from January 31 to May 31, 2021. With use of a linked database of Medicare claims and Surveillance, Epidemiology, and End Results (SEER) Program population-based cancer registries, patients of White race diagnosed with stages II-IV or unknown (American Joint Committee on Cancer, AJCC Cancer Staging Manual 6th edition) first primary cutaneous melanoma during 2011-2015, as reported to SEER, and followed up through December 31, 2015, were identified. Exposures: Immune checkpoint inhibitors for treatment of melanoma. Main Outcomes and Measures: The association between ICIs and immune-related AEs ascertained from Medicare claims data was estimated using multivariable Cox regression with hazard ratios (HRs) and 95% CIs and with cumulative incidence accounting for competing risk of death. Results: The study included 4489 patients of White race with first primary melanoma (3002 men [66.9%]; median age, 74.9 [range, 66.0-84.9] years). During follow-up (median, 1.4 [range, 0-5.0] years), 1576 patients (35.1%) had an immune-related AE on a Medicare claim. Use of ICIs (reported for 418 patients) was associated with autoimmune-related AEs (HR, 2.5; 95% CI, 1.6-4.0), including primary adrenal insufficiency (HR, 9.9; 95% CI, 4.5-21.5) and ulcerative colitis (HR, 8.6; 95% CI, 2.8-26.3). Immune checkpoint inhibitors also were associated with other immune-related AEs (HR, 2.2; 95% CI, 1.7-2.8), including Cushing syndrome (HR, 11.8; 95% CI, 1.4-97.2), hyperthyroidism (HR, 6.3; 95% CI, 2.0-19.5), hypothyroidism (HR, 3.8; 95% CI, 2.4-6.1), hypopituitarism (HR, 19.8; 95% CI, 5.4-72.9), other pituitary gland disorders (HR, 6.0; 95% CI, 1.2-30.2), diarrhea (HR, 3.5; 95% CI, 2.5-4.9), and sepsis or septicemia (HR, 2.2; 95% CI, 1.4-3.3). Most associations were pronounced within 6 months following the first ICI claim and comparable with or without a baseline history of autoimmune disease. The cumulative incidence at 6 months following the first ICI claim was 13.7% (95% CI, 9.7%-18.3%) for autoimmune-related AEs and 46.8% (95% CI, 40.7%-52.7%) for other immune-related AEs. Conclusions and Relevance: In this cohort study of older adults with melanoma, ICIs were associated with autoimmune-related AEs and other immune-related AEs. Although some findings were consistent with clinical trials of ICIs, others warrant further investigation. As ICI use continues to expand rapidly, ongoing investigation of the spectrum of immune-related AEs may optimize management of disease in patients.

Trends in the Management of Localized Papillary Thyroid Carcinoma in the United States (2000-2018).

Background: In response to evidence of overdiagnosis and overtreatment of papillary thyroid carcinoma (PTC), the 2009 and 2015 American Thyroid Association (ATA) adult guidelines recommended less extensive surgery (lobectomy vs. total thyroidectomy) and more restricted use of postsurgical radioactive iodine (RAI) in management of PTC at low risk of recurrence. In 2015, active surveillance was suggested as a viable option for some <1-cm PTCs, or microcarcinomas. The 2015 ATA pediatric guidelines similarly shifted toward more restricted use of RAI for low-risk PTCs. The impact of these recommendations on low-risk adult and pediatric PTC management remains unclear, particularly after 2015. Methods: Using data from 18 Surveillance, Epidemiology, and End Results (SEER) U.S. registries (2000-2018), we described time trends in reported first-course treatment (total thyroidectomy alone, total thyroidectomy+RAI, lobectomy, no surgery, and other/unknown) for 105,483 patients diagnosed with first primary localized PTC (without nodal/distant metastases), overall and by demographic and tumor characteristics. Results: The declining use of RAI represented the most pronounced change in management of PTCs <4 cm (44-18% during the period 2006-2018), including microcarcinomas (26-6% during the period 2007-2018). In parallel, an increasing proportion of PTCs were managed with total thyroidectomy alone (35-54% during the period 2000-2018), while more subtle changes were observed for lobectomy (declining from 23% to 17% during the period 2000-2006, stabilizing, and then rising from 17% to 24% during the period 2015-2018). Use of nonsurgical management did not meaningfully change over time, impacting <1% of microcarcinomas annually during the period 2000-2018. Similar treatment trends were observed by sex, age, race/ethnicity, metropolitan vs. nonmetropolitan residence, and insurance status. For pediatric patients (<20 years), use of RAI peaked in 2009 (59%), then decreased markedly to 11% (2018), while use of total thyroidectomy alone and, to a lesser extent, lobectomy increased. No changing treatment trends were observed for ≥4-cm PTCs. Conclusions: The declining use of RAI in management of low-risk adult and pediatric PTC is consistent with changing recommendations from the ATA practice guidelines. Post-2015 trends in use of lobectomy and nonsurgical management of low-risk PTCs, particularly microcarcinomas, were more subtle than expected; however, these trends may change as evidence regarding their safety continues to emerge.

Developing a company-specific job exposure matrix for the Asbest Chrysotile Cohort Study.

OBJECTIVES: Exposure assessment for retrospective industrial cohorts are often hampered by limited availability of historical measurements. This study describes the development of company-specific job-exposure matrices (JEMs) based on measurements collected over five decades for a cohort study of 35 837 workers (Asbest Chrysotile Cohort Study) in the Russian Federation to estimate their cumulative exposure to chrysotile containing dust and fibres. METHODS: Almost 100 000 recorded stationary dust measurements were available from 1951-2001 (factories) and 1964-2001 (mine). Linear mixed models were used to extrapolate for years where measurements were not available or missing. Fibre concentrations were estimated using conversion factors based on side-by-side comparisons. Dust and fibre JEMs were developed and exposures were allocated by linking them to individual workers' detailed occupational histories. RESULTS: The cohort covered a total of 515 355 employment-years from 1930 to 2010. Of these individuals, 15% worked in jobs not considered professionally exposed to chrysotile. The median cumulative dust exposure was 26 mg/m3 years for the entire cohort and 37.2 mg/m3 years for those professionally exposed. Median cumulative fibre exposure was 16.4 fibre/cm3 years for the entire cohort and 23.4 fibre/cm3 years for those professionally exposed. Cumulative exposure was highly dependent on birth cohort and gender. Of those professionally exposed, women had higher cumulative exposures than men as they were more often employed in factories with higher exposure concentrations rather than in the mine. CONCLUSIONS: Unique company-specific JEMs were derived using a rich measurement database that overlapped with most employment-years of cohort members and will enable estimation of quantitative exposure-response.

Assessment of surveillance versus etiologic factors in the reciprocal association between papillary thyroid cancer and breast cancer.

BACKGROUND: Mutually increased risks for thyroid and breast cancer have been reported, but the contribution of etiologic factors versus increased medical surveillance to these associations is unknown. METHODS: Leveraging large-scale US population-based cancer registry data, we used standardized incidence ratios (SIRs) to investigate the reciprocal risks of thyroid and breast cancers among adult females diagnosed with a first primary invasive, non-metastatic breast cancer (N = 652,627) or papillary thyroid cancer (PTC) (N = 92,318) during 2000-2017 who survived ≥1-year. RESULTS: PTC risk was increased 1.3-fold [N = 1434; SIR = 1.32; 95 % confidence interval (CI) = 1.25-1.39] after breast cancer compared to the general population. PTC risk declined significantly with time since breast cancer (Poisson regression = Ptrend <0.001) and was evident only for tumors ≤2 cm in size. The SIRs for PTC were higher after hormone-receptor (HR)+ (versus HR-) and stage II or III (versus stage 0-I) breast tumors. Breast cancer risk was increased 1.2-fold (N = 2038; SIR = 1.21; CI = 1.16-1.26) after PTC and was constant over time since PTC but was only increased for stage 0-II and HR + breast cancers. CONCLUSION: Although some of the patterns by latency, stage and size are consistent with heightened surveillance contributing to the breast-thyroid association, we cannot exclude a role of shared etiology or treatment effects.

Increased Risk of Skin Cancer in 1,851 Long-Term Retinoblastoma Survivors.

Patients with hereditary retinoblastoma are at risk for developing cutaneous melanoma, but little is known about the role of sun exposure or other factors, and the incidence of nonmelanoma skin cancer (NMSC) is poorly understood. We investigated the incidence of melanoma and NMSC in a cohort of 1,851 White, long-term retinoblastoma survivors (1,020 hereditary and 831 nonhereditary) diagnosed during 1914‒2006. During follow-up through 2016, 33 hereditary and 7 nonhereditary survivors developed melanoma, and 26 hereditary and 9 nonhereditary survivors developed NMSC. Most NMSCs were on the head/neck, whereas melanomas were more broadly distributed with patterns similar to melanoma-prone families. For both outcomes, the median age at diagnosis was ~20 years younger among hereditary survivors than among nonhereditary survivors. At 50 years after retinoblastoma diagnosis, the cumulative incidence in hereditary survivors was 4.5% for melanoma and 3.7% for NMSC; for nonhereditary survivors, it was 0.7% and 1.5%, respectively. Sun sensitivity and phenotypic characteristics generally did not vary by skin cancer status. Hereditary retinoblastoma survivors have an increased risk for melanoma and NMSC that occurred earlier than that observed among nonhereditary survivors, likely reflecting genetic factors. These findings among White retinoblastoma survivors support consensus-based recommendations for skin cancer screening and sun protection starting at young ages and continuing long term.

Radiation-related genomic profile of papillary thyroid carcinoma after the Chernobyl accident.

The 1986 Chernobyl nuclear power plant accident increased papillary thyroid carcinoma (PTC) incidence in surrounding regions, particularly for radioactive iodine (131I)-exposed children. We analyzed genomic, transcriptomic, and epigenomic characteristics of 440 PTCs from Ukraine (from 359 individuals with estimated childhood 131I exposure and 81 unexposed children born after 1986). PTCs displayed radiation dose-dependent enrichment of fusion drivers, nearly all in the mitogen-activated protein kinase pathway, and increases in small deletions and simple/balanced structural variants that were clonal and bore hallmarks of nonhomologous end-joining repair. Radiation-related genomic alterations were more pronounced for individuals who were younger at exposure. Transcriptomic and epigenomic features were strongly associated with driver events but not radiation dose. Our results point to DNA double-strand breaks as early carcinogenic events that subsequently enable PTC growth after environmental radiation exposure.

Risk factors for contralateral breast cancer in postmenopausal breast cancer survivors in the NIH-AARP Diet and Health Study.

PURPOSE: The role of established breast cancer risk factors and clinical characteristics of the first breast cancer in the development of contralateral breast cancer (CBC) among postmenopausal women is unclear. METHODS: We identified 10,934 postmenopausal women diagnosed with a first primary breast cancer between 1995 and 2011 in the NIH-AARP Diet and Health Study. CBC was defined as a second primary breast cancer diagnosed in the contralateral breast ≥ 3 months after the first breast cancer. Exposures included pre-diagnosis risk factors (lifestyle, reproductive, family history) and clinical characteristics of the first breast cancer. We used multivariable Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Over a median follow-up of 6.8 years, 436 women developed CBC. We observed an increasing trend in CBC risk by age (p-trend = 0.002) and decreasing trend by year of diagnosis (p-trend = 0.001) of the first breast cancer. Additional risk factor associations were most pronounced for endocrine therapy (HR 0.68, 95% CI 0.53-0.87) and family history of breast cancer (HR 1.38, 95% CI 1.06-1.80, restricted to invasive first breast cancer). No associations were found for lifestyle (body mass index, physical activity, smoking, alcohol) or reproductive factors (age at menarche, parity, age at first birth, age at menopause). CONCLUSIONS: This study suggests that clinical characteristics of the first breast cancer and family history of breast cancer, but not pre-diagnosis lifestyle and reproductive factors, are strongly associated with CBC risk among postmenopausal women. Future studies are needed to understand how these factors contribute to CBC etiology and to identify further opportunities for prevention.

Benign Tumors in Long-Term Survivors of Retinoblastoma.

Hereditary retinoblastoma survivors have substantially increased risk of subsequent malignant neoplasms (SMNs). The risk of benign neoplasms, a substantial cause of morbidity, is unclear. We calculated the cumulative incidence of developing benign tumors at 60 years following retinoblastoma diagnosis among 1128 hereditary (i.e., bilateral retinoblastoma or unilateral with family history, mutation testing was not available) and 924 nonhereditary retinoblastoma survivors diagnosed during 1914-2006 at two US medical centers with follow-up through 2016. Using Cox proportional hazards regression, we compared benign tumor risk by hereditary status and evaluated the association between benign tumors and SMNs. There were 100 benign tumors among 73 hereditary survivors (cumulative incidence = 17.6%; 95% confidence interval [CI] = 12.9-22.8%) and 22 benign tumors among 16 nonhereditary survivors (cumulative incidence = 3.9%; 95%CI = 2.2-6.4%), corresponding to 4.9-fold (95%CI = 2.8-8.4) increased risk for hereditary survivors. The cumulative incidence after hereditary retinoblastoma was highest for lipoma among males (14.0%; 95%CI = 7.7-22.1%) and leiomyoma among females (8.9%; 95%CI = 5.2-13.8%). Among hereditary survivors, having a prior SMN was associated with 3.5-fold (95%CI = 2.0-6.1) increased risk of developing a benign tumor; the reciprocal risk for developing an SMN after a benign tumor was 1.8 (95%CI = 1.1-2.9). These large-scale, long-term data demonstrate an increased risk for benign tumors after hereditary versus nonhereditary retinoblastoma. If confirmed, the association between benign tumors and SMNs among hereditary patients may have implications for long-term surveillance.

Long-term risk of subsequent cancer incidence among hereditary and nonhereditary retinoblastoma survivors.

BACKGROUND: Increased sarcoma and melanoma risks after hereditary retinoblastoma are well established, whereas less is known about epithelial subsequent malignant neoplasms (SMNs) and risks for multiple (≥2) SMNs. METHODS: Leveraging long-term follow-up and detailed histologic information, we quantified incident SMN risk among 1128 hereditary and 924 nonhereditary retinoblastoma survivors (diagnosed 1914-2006; follow-up through 2016). Standardised incidence ratios (SIRs) compared cancer risk after retinoblastoma relative to the general population. We estimated cumulative incidence accounting for competing risk of death. RESULTS: Hereditary survivors had statistically significantly increased SMN risk (N = 239; SIR = 11.9; 95% confidence interval [CI] 10.4-13.5), with SIRs >80-fold for sarcomas, nasal cavity tumours and pineoblastoma. Significantly increased risks were also observed for melanoma and central nervous system, oral cavity and breast SMNs (SIRs = 3.1-17), but not the uterus, kidney, lung, bladder, pancreas or other types. Cumulative incidence 50 years following hereditary retinoblastoma was 33.1% (95% CI 29.0-37.2) for a first SMN and 6.0% (95% CI 3.8-8.2) for a second SMN. SMN risk was not increased after nonhereditary retinoblastoma (N = 25; SIR = 0.8; 95% CI 0.5-1.2). CONCLUSION: Beyond the established sarcoma and melanoma risks after hereditary retinoblastoma, we demonstrate increased risk for a more limited number of epithelial malignancies than previously suggested. Cumulative incidence estimates emphasise long-term SMN burden after hereditary retinoblastoma.

Racial and ethnic differences in risk of second primary cancers among prostate cancer survivors.

PURPOSE: Previous studies have shown an overall decreased risk of second cancers among prostate cancer survivors, but this has not been comprehensively examined by race/ethnicity. We conducted a retrospective cohort study of 716,319 one-year survivors of prostate cancer diagnosed at ages 35-84 during 2000-2015 as reported to 17 US Surveillance, Epidemiology and End Results (SEER) registries. METHODS: We estimated standardized incidence ratios (SIRs) for second primary non-prostate malignancies by race/ethnicity (non-Latino white, Black, Asian/Pacific Islander [API] and Latino), by Gleason, and by time since prostate cancer diagnosis. Poisson regression models were used to test heterogeneity between groups with the expected number as the offset. RESULTS: 60,707 second primary malignancies were observed. SIRs for all second cancers combined varied significantly by race/ethnicity: SIRwhite: 0.88 (95% confidence interval: 0.87-0.89), SIRLatino: 0.92 (0.89-0.95), SIRBlack: 0.97 (0.95-0.99), and SIRAPI: 1.05 (1.01-1.09) (p-heterogeneity < 0.001). SIRs for all cancers combined were higher among survivors of higher vs. lower Gleason prostate cancers irrespective of race/ethnicity. We observed significant heterogeneity by race/ethnicity in SIRs for 9 of 14 second cancer types investigated including lung, bladder, kidney, and liver. CONCLUSIONS: Our results confirm that most prostate cancer survivors have lower risks of second cancers than expected, but the magnitude varied by race/ethnicity. Exceptionally, API men had small but significantly increased risk. Further research to understand drivers of the observed race/ethnicity heterogeneity is warranted.