Risk of male breast cancer after Hodgkin lymphoma.

Female survivors of Hodgkin lymphoma (HL) treated with chest radiotherapy have a strongly increased risk of breast cancer (BC), but the treatment-specific BC risk in male survivors of HL has not been evaluated. We assessed BC risk in a cohort of 3077 male survivors of 5-year HL treated at age ≤51 years in 20 Dutch hospitals between 1965 and 2013. We estimated standardized incidence ratios (SIRs), absolute excess risks per 10 000 person-years, and cumulative BC incidences. After a 20-year median follow-up, we observed 8 cases of male with BC. Male survivors of HL experienced a 23-fold (95% confidence interval [CI], 10.1-46.0) increased BC risk compared with the general population, representing 1.6 (95% CI, 0.7-3.3) excess BC incidences per 10 000 person-years. The 20- and 40-year cumulative BC incidences after HL treatment were 0.1% (95% CI, 0.02-0.3) and 0.7% (95% CI, 0.3-1.4), respectively. Treatment with chest radiotherapy without alkylating chemotherapy yielded a strongly increased SIR (20.7; 95% CI, 2.5-74.8), which was not significantly different for chest radiotherapy and alkylating chemotherapy (41.1; 95% CI, 13.4-96.0). Males treated with chest radiotherapy and anthracyclines had an SIR of 48.1 (95% CI, 13.1-123.1). Two patients died from BC (median follow-up, 4.7 years). To ensure early diagnosis and treatment, clinicians should be alert to BC symptoms in male survivors of HL.

Prevalence of neoplasia at colonoscopy among testicular cancer survivors treated with platinum-based chemotherapy.

Testicular cancer survivors (TCS) treated with platinum-based chemotherapy have an increased risk of colorectal cancer (CRC). We determined the yield of colonoscopy in TCS to assess its potential in reducing CRC incidence and mortality. We conducted a colonoscopy screening study among TCS in four Dutch hospitals to assess the yield of colorectal neoplasia. Neoplasia was defined as adenomas, serrated polyps (SPs), advanced adenomas (AAs: ≥10 mm diameter, high-grade dysplasia or ≥25% villous component), advanced serrated polyps (ASPs: ≥10 mm diameter or dysplasia) or CRC. Advanced neoplasia (AN) was defined as AA, ASP or CRC. Colonoscopy yield was compared to average-risk American males who underwent screening colonoscopy (n = 24,193) using a propensity score matched analysis, adjusted for age, smoking status, alcohol consumption and body mass index. A total of 137 TCS underwent colonoscopy. Median age was 50 years among TCS (IQR 43-57) vs 55 years (IQR 51-62) among American controls. A total of 126 TCS were matched to 602 controls. The prevalence of AN was higher in TCS than in controls (8.7% vs 1.7%; P = .0002). Nonadvanced adenomas and SPs were detected in 45.2% of TCS vs 5.5% of controls (P < .0001). No lesions were detected in 46.0% of TCS vs 92.9% of controls (P < .0001). TCS treated with platinum-based chemotherapy have a higher prevalence of neoplasia and AN than matched controls. These results support our hypothesis that platinum-based chemotherapy increases the risk of colorectal neoplasia in TCS. Cost-effectiveness studies are warranted to ascertain the threshold of AN prevalence that justifies the recommendation of colonoscopy for TCS.

The effects of contemporary treatment of DCIS on the risk of developing an ipsilateral invasive Breast cancer (iIBC) in the Dutch population.

PURPOSE: To assess the effects of contemporary treatment of ductal carcinoma in situ (DCIS) on the risk of developing an ipsilateral invasive breast cancer (iIBC) in the Dutch female population. METHODS: Clinical data was obtained from the Netherlands Cancer Registry (NCR), a nationwide registry of all primary malignancies in the Netherlands integrated with the data from PALGA, the Dutch nationwide network and registry of histo- and cytopathology in the Netherlands, on all women in the Netherlands treated for primary DCIS from 2005 to 2015, resulting in a population-based cohort of 14.419 women. Cumulative iIBC incidence was assessed and associations of DCIS treatment type with subsequent iIBC risk were evaluated by multivariable Cox regression analyses. RESULTS: Ten years after DCIS diagnosis, the cumulative incidence of iIBC was 3.1% (95% CI: 2.6-3.5%) in patients treated by breast conserving surgery (BCS) plus radiotherapy (RT), 7.1% (95% CI: 5.5-9.1) in patients treated by BCS alone, and 1.6% (95% CI: 1.3-2.1) in patients treated by mastectomy. BCS was associated with a significantly higher risk for iIBC compared to BCS + RT during the first 5 years after treatment (HR 2.80, 95% CI: 1.91-4.10%). After 5 years of follow-up, the iIBC risk declined in the BCS alone group but remained higher than the iIBC risk in the BCS + RT group (HR 1.73, 95% CI: 1.15-2.61). CONCLUSIONS: Although absolute risks of iIBC were low in patients treated for DCIS with either BCS or BCS + RT, risks remained higher in the BCS alone group compared to patients treated with BCS + RT for at least 10 years after DCIS diagnosis.

Cancer risks for other sites in addition to breast in CHEK2 c.1100delC families.

PURPOSE: Female CHEK2 c.1100delC heterozygotes are eligible for additional breast surveillance because of an increased breast cancer risk. Increased risks for other cancers have been reported. We studied whether CHEK2 c.1100delC is associated with an increased risk for other cancers within these families. METHODS: Including 10,780 individuals from 609 families, we calculated standardized incidence rates (SIRs) and absolute excess risk (AER, per 10,000 person-years) by comparing first-reported cancer derived from the pedigrees with general Dutch population rates from 1970 onward. Attained-age analyses were performed for sites in which significant increased risks were found. Considering the study design, we primarily focused on cancer risk in women. RESULTS: We found significant increased risks of colorectal cancer (CRC; SIR = 1.43, 95% CI = 1.14-1.76; AER = 1.43) and hematological cancers (SIR = 1.32; 95% CI = 1.02-1.67; AER = 0.87). CRC was significantly more frequent from age 45 onward. CONCLUSION: A significantly increased risk of CRC, and hematological cancers in women was found, starting at a younger age than expected. Currently, colorectal surveillance starts at age 45 in high-risk individuals. Our results suggest that some CHEK2 c.1100delC families might benefit from this surveillance as well; however, further research is needed to determine who may profit from this additional colorectal surveillance.

Chronotype in relation to shift work: A cohort study among 37,731 female nurses.

Chronotype may affect tolerance for circadian disruption induced by shift work. This study examines the association between chronotype, self-reported sleep timing, shift type preference, and sleep problems among nurses, and studies chronotype stability over time. The study included 37,731 Dutch female nurses who completed a baseline (2011) and follow-up questionnaire (2017), with information on shift work (e.g., job history, shift type preference [collected in 2017 only]), and sleep characteristics (e.g., chronotype, preferred sleep-wake time in a work-free period [collected in 2017 only], and sleep problems between working days according to Medical Outcomes Study-Sleep Problem Index II [MOS-SPI-II]). The association between chronotype and sleep timing was examined using (age-adjusted) linear regression. Associations between chronotype and shift type preference and sleep problems (MOS-SPI-II >30) were examined using ordered logistic and Poisson regression, respectively. With later chronotype, midsleep time increased (definite evening vs. intermediate types [reference]: ß = 55 min, 95% confidence interval [95% CI]: 54-55), the odds ratio (OR) for 1-point increase in preference for night (2.68; 95% CI: 2.48-2.90) and evening shifts increased (OR 2.20; 95% CI: 2.03-2.38), while the odds for day (OR 0.17; 95% CI: 0.16-0.18) and morning shifts (OR 0.22; 95% CI: 0.21-0.24) decreased. Intermediate chronotype was associated with fewer sleep problems (median MOS-SPI-II = 27.2, p < 0.01), compared with definite morning (28.9) and evening types (31.7). This study shows that chronotype is associated with sleep-wake times in a work-free period, shift type preference, and sleep problems in nurses. Future studies on the association of shift work-induced circadian disruption and health outcomes should therefore consider chronotype as effect-modifier.

Pathology review identifies frequent misdiagnoses in recurrent classic Hodgkin lymphoma in a nationwide cohort: implications for clinical and epidemiological studies.

Patients treated for classic Hodgkin lymphoma (CHL) have a reported 13-fold increased risk of developing subsequent non-Hodgkin lymphoma (NHL). In light of the growing awareness of CHL mimickers, this study re-assesses this risk based on an in-depth pathology review of a nationwide cohort of patients diagnosed with CHL in the Netherlands (2006-2013) and explores the spectrum of CHL mimickers. Among 2,669 patients with biopsy-proven CHL, 54 were registered with secondary NHL. On review, CHL was confirmed in 25/54 patients. In six of these, the subsequent lymphoma was a primary mediastinal B-cell lymphoma/mediastinal gray zone lymphoma, biologically related to CHL and 19/25 were apparently unrelated B-cell NHL. In 29/54 patients, CHL was reclassified as NHL, including T-cell lymphomas with secondary Hodgkin-like B-blasts (n=15), Epstein Barr virus-positive diffuse large B-cell lymphoma (n=8), CD30+ T-cell lymphoma (n=3) and indolent B-cell proliferations (n=3). Higher age, disseminated disease at presentation, extensive B-cell marker expression and association with Epstein-Barr virus were identified as markers to alert for CHL mimickers. Based on these data, the risk of developing NHL after CHL treatment was re-calculated to 3.6-fold (standardized incidence ratio 3.61; confidence interval: 2.29-5.42). In addition, this study highlights the clinicopathological pitfalls leading to misinterpretation of CHL and consequences for the care of individual patients, interpretation of trials and epidemiological assessments.

Comparison of outcomes between Hodgkin's lymphoma patients treated in and outside clinical trials: A study based on the EORTC-Dutch late effects cohort-linked data.

Studies have shown higher survival rates for patients with Hodgkin lymphoma (HL) treated within clinical trials compared to patients treated outside clinical trials. However, endpoints are often limited to overall survival (OS). In this retrospective cohort study, we investigated the effect of trial participation on OS, the incidence of relapse, second cancer, and cardiovascular disease (CVD). The study population consisted of patients with HL, aged between 14 and 51 years at diagnosis, who started their treatment between 1962 and 2002 at three Dutch cancer centres. Patients were either included in the EORTC Lymphoma Group trials (H1-H9) or treated according to standard guidelines at the time. After adjusting for differences in baseline characteristics, trial participation was associated with longer OS (median OS: 29.4 years [95%CI: 27.0-31.6] for treatment inside trials versus 27.4 years [95%CI: 26.0-28.5] for treatment outside trials, p = .046), a lower incidence of relapse (HR = 0.79, 95%CI: 0.63-0.98, p = .036) and a higher incidence of CVD (HR = 1.49, 95%CI: 1.23-1.79, p < .001). The trial effect for CVD was present only for patients treated before 1983. No evidence of differences in the incidence of second cancer was found. Consequently, essential results from clinical trials should be implemented into standard practice without undue delay.

Breast cancer and cardiovascular outcomes after breast cancer in survivors of Hodgkin lymphoma.

BACKGROUND: Hodgkin lymphoma (HL) survivors treated with chest radiotherapy have an increased risk of breast cancer (BC). Prior HL treatment and associated cardiovascular disease (CVD) risk may limit BC treatment options. It is unknown how treatment adaptations affect BC and CVD outcomes. METHODS: The authors compared 195 BC patients treated with chest/axillary radiotherapy for HL (BC-HL) with 5988 age- and calendar year-matched patients with first primary BC (BC-1). Analyses included cumulative incidence functions and Cox regression models, accounting for tumor characteristics and BC treatment. RESULTS: Compared to BC-1 patients, BC-HL patients received anthracycline-containing chemotherapy (23.7% vs. 43.8%, p < .001) and breast-conserving surgery followed by radiotherapy (7.1% vs. 57.7%, p < .001) less often. BC treatment considerations were reported for 71% of BC-HL patients. BC-HL patients had a significantly higher risk of 15-year overall mortality than BC-1 patients (61% vs. 23%). Furthermore, risks of BC-specific mortality and nonfatal BC events were significantly increased among BC-HL patients, also when accounting for tumor and treatment characteristics (2.2- to 4.5-fold). BC-HL patients with a screen-detected BC had a significantly reduced (61%) BC-specific mortality. One-third of BC-HL patients had CVD at BC-diagnosis, compared to <0.1% of BC-1 patients. Fifteen-year CVD-specific mortality and CVD incidence were significantly higher in BC-HL patients than in BC-1 patients (15.2% vs. 0.4% and 40.4% vs. 6.8%, respectively), which was due to HL treatment rather than BC treatment. CONCLUSIONS: BC-HL patients experience a higher burden of CVD and worse BC outcomes than BC-1 patients. Clinicians should be aware of increased CVD risk when selecting BC treatment for HL survivors. LAY SUMMARY: Patients with breast cancer after Hodgkin lymphoma (BC-HL) may have limited options for BC treatment, due to earlier HL treatment and an associated increased risk of cardiovascular disease (CVD). BC treatment considerations were reported for 71% of BC-HL patients. We examined whether BC-HL patients have a higher risk of CVD or BC events (recurrences/metastases) compared to patients with breast cancer that had no earlier tumors (BC-1). We observed a higher burden of CVD and worse BC outcomes in HL patients compared to BC-1 patients. Clinicians should be aware of increased CVD risk when selecting BC treatment for HL survivors.

Somatic hits in mismatch repair genes in colorectal cancer among non-seminoma testicular cancer survivors.

BACKGROUND: Non-seminoma testicular cancer survivors (TCS) have an increased risk of developing colorectal cancer (CRC) when they have been treated with platinum-based chemotherapy. Previously we demonstrated that among Hodgkin lymphoma survivors (HLS) there is enrichment of rare mismatch repair (MMR) deficient (MMRd) CRCs with somatic hits in MMR genes. We speculate that this phenomenon could also occur among other cancer survivors. We therefore aim to determine the MMR status and its underlying mechanism in CRC among TCS (TCS-CRC). METHODS: Thirty TCS-CRC, identified through the Dutch pathology registry, were analysed for MMR proteins by immunohistochemistry. Next-generation sequencing was performed in MMRd CRCs without MLH1 promoter hypermethylation (n = 4). Data were compared with a male cohort with primary CRC (P-CRC, n = 629). RESULTS: MMRd was found in 17% of TCS-CRCs vs. 9% in P-CRC (p = 0.13). MMRd was more often caused by somatic double or single hit in MMR genes by mutation or loss of heterozygosity in TCS-CRCs (3/30 (10%) vs. 11/629 (2%) in P-CRCs (p < 0.01)). CONCLUSIONS: MMRd CRCs with somatic double or single hit are more frequent in this small cohort of TCS compared with P-CRC. Exposure to anticancer treatments appears to be associated with the development of these rare MMRd CRC among cancer survivors.

Adjuvant aromatase inhibitor therapy and early markers for cardiovascular disease in breast cancer survivors.

PURPOSE: Aromatase inhibitors (AIs) are an important component of the adjuvant treatment of hormone receptor positive breast cancer (BC) but concerns regarding their cardiovascular safety remain. In this cross-sectional study nested in a breast cancer cohort, we investigated the association between AI exposure and early markers for cardiovascular disease in BC survivors. METHODS: The study population consisted of 569 women, who were 5-7 years (n = 277) or 10-12 years (n = 292) after BC diagnosis. All participants underwent carotid ultrasound, skin autofluorescence measurement and laboratory evaluation. To quantify AI exposure, we obtained the AI ratio by dividing the duration of AI use by the total duration of endocrine therapy (ET). Patients were classified according to their AI ratio into low (no ET or AI ratio < 0.40), intermediate (0.40 ≤ AI ratio ≤ 0.60) or high AI exposure (AI ratio > 0.60). The association between AI ratio and carotid intima media thickness (cIMT), advanced glycation end products (AGEs) and the presence of dyslipidemia was assessed using linear and logistic regression. RESULTS: Median age at study visit was 55.5 years (range 45.2-63.8). Forty percent (n = 231) of the study population had used AIs, of whom the majority sequentially with tamoxifen; median duration of AI use was 3.0 years. Mean cIMT and mean AGEs did not differ across AI exposure groups in univariable and multivariable analysis. The occurrence of dyslipidemia did not vary across AI exposure groups. Intermediate AI exposure was associated with more frequent occurrence of the combined endpoint (elevated cIMT, elevated AGEs and/or dyslipidemia). This association, however, was not present in the group with highest AI exposure. CONCLUSION: AI exposure was not associated with cIMT, AGEs or the presence of dyslipidemia. These results do not prompt a change in current clinical practice, although further research is warranted to validate our findings over time and in different BC populations. Trial registration number (clinicaltrials.gov): NCT02485626, June 30, 2015.