Naomi B. Boekel

Cardiovascular Disease Risk in a Large, Population-Based Cohort of Breast Cancer Survivors

PURPOSE To conduct a large, population-based study on cardiovascular disease (CVD) in breast cancer (BC) survivors treated in 1989 or later. METHODS AND MATERIALS A large, population-based cohort comprising 70,230 surgically treated stage I to III BC patients diagnosed before age 75 years between 1989 and 2005 was linked with population-based registries for CVD. Cardiovascular disease risks were compared with the general population, and within the cohort using competing risk analyses. RESULTS Compared with the general Dutch population, BC patients had a slightly lower CVD mortality risk (standardized mortality ratio 0.92, 95% confidence interval [CI] 0.88-0.97). Only death due to valvular heart disease was more frequent (standardized mortality ratio 1.28, 95% CI 1.08-1.52). Left-sided radiation therapy after mastectomy increased the risk of any cardiovascular event compared with both surgery alone (subdistribution hazard ratio (sHR) 1.23, 95% CI 1.11-1.36) and right-sided radiation therapy (sHR 1.19, 95% CI 1.04-1.36). Radiation-associated risks were found for not only ischemic heart disease, but also for valvular heart disease and congestive heart failure (CHF). Risks were more pronounced in patients aged <50 years at BC diagnosis (sHR 1.48, 95% CI 1.07-2.04 for left- vs right-sided radiation therapy after mastectomy). Left- versus right-sided radiation therapy after wide local excision did not increase the risk of all CVD combined, yet an increased ischemic heart disease risk was found (sHR 1.14, 95% CI 1.01-1.28). Analyses including detailed radiation therapy information showed an increased CVD risk for left-sided chest wall irradiation alone, left-sided breast irradiation alone, and internal mammary chain field irradiation, all compared with right-sided breast irradiation alone. Compared with patients not treated with chemotherapy, chemotherapy used ≥1997 (ie, anthracyline-based chemotherapy) increased the risk of CHF (sHR 1.35, 95% CI 1.00-1.83). CONCLUSION Radiation therapy regimens used in BC treatment between 1989 and 2005 increased the risk of CVD, and anthracycline-based chemotherapy regimens increased the risk of CHF.

Genetic variants in TGFβ-1 and PAI-1 as possible risk factors for cardiovascular disease after radiotherapy for breast cancer

BACKGROUND AND PURPOSE It has been established that radiotherapy can increase cardiovascular disease (CVD) risk. Genetic variants, which play a role in the tissue, damage response and angiogenesis regulating TGFβ pathway might give us insight into the mechanisms underlying radiation-induced CVD. We examined the effects of two polymorphisms, TGFβ1 29C>T and PAI-1 5G>4G, on CVD incidence. MATERIALS AND METHODS This retrospective cohort study included 422 10-year breast cancer survivors, aged <50 years at diagnosis, treated between 1977 and 1995. We collected information on treatment, oncological follow-up, CVD, CVD risk factors and genotypes. RESULTS During a mean follow-up of 19.4 years, 61 patients developed CVD. Internal mammary chain (IMC) irradiation, exposing a part of the heart to radiation, was associated with a hazard ratio of 2.36 (95% CI: 1.27-4.37, p=0.01) compared to no IMC irradiation. Compared to the C/C+C/T genotype, the T/T genotype of the TGFβ1 polymorphism was associated with hazard ratios of 1.79 (0.99-3.26, p=0.06) and 1.74 (0.90-3.34, p=0.10) in the total and IMC-irradiated group, respectively. We found no evidence for an association between PAI-1 5G>4G and CVD risk. CONCLUSION Our study suggests there might be an association between the TGFβ1 29C>T polymorphism and CVD risk in long-term breast cancer survivors.

Cardiovascular Morbidity and Mortality After Treatment for Ductal Carcinoma In Situ of the Breast

Background Recent concerns about potential overdiagnosis and overtreatment of ductal carcinoma in situ of the breast (DCIS) render evaluation of late effects of treatment, such as cardiovascular disease (CVD), of great importance. We studied cardiovascular morbidity and mortality in a large population-based cohort of DCIS patients. Methods Data on all incident DCIS case patients in the Netherlands between 1989 and 2004 who were diagnosed before the age of 75 years were obtained (n = 10468). CVD data was acquired through linkage with population-based registries. Standardized mortality ratios were calculated by comparing mortality in our cohort with that in the Dutch female population, taking into account person-years of observation. Within-cohort comparisons were based on multivariable competing-risk regression. Results Compared with the general population, 5-year survivors of DCIS had a similar risk of dying due to any cause (standardized mortality ratio [SMR] = 1.04; 95% confidence interval [CI] = 0.97 to 1.11) but a lower risk of dying of CVD (SMR = 0.77; 95% CI = 0.67 to 0.89). No difference in CVD risk was found when comparing 5-year survivors treated with radiotherapy with those treated with surgery only. Left-sided vs right-sided radiotherapy also did not increase this risk (hazard ratio [HR] = 0.94; 95% CI = 0.67 to 1.32). In a subgroup analysis of all DCIS patients diagnosed between 1997 and 2005, we were able to account for history of CVD and did not observe a risk difference between treatment groups (left-sided vs right-sided radiotherapy: HR = 0.94; 95% CI = 0.68 to 1.29). Conclusions After a median follow-up of 10 years, we did not find an increased risk for cardiovascular morbidity or mortality after radiotherapy for DCIS when comparing surgery and radiotherapy vs surgery only, nor when comparing radiotherapy for left-sided vs right-sided DCIS. Compared with the general population, DCIS patients have a decreased risk of cardiovascular death, independent of treatment.

Cardiovascular morbidity and mortality in patients treated for ductal carcinoma in situ of the breast.

58 Background: Recent concerns about potential overdiagnosis and overtreatment of ductal carcinoma in situ of the breast (DCIS) render evaluation of late effects of treatment, such as cardiovascular disease (CVD), of great importance. We studied cardiovascular morbidity and mortality in a large population-based cohort of DCIS patients. METHODS Data on all incident DCIS diagnosed before the age of 75 years between 1989 and 2004 in the Netherlands were obtained (n = 10,468). Cardiovascular morbidity and mortality data was acquired through linkage with population-based registries. Risk of CVD in the study cohort was compared with general population rates and evaluated in Cox proportional hazards regression models. RESULTS Compared with the general population, five-year survivors of DCIS had a similar risk of dying due to any cause (standardized mortality ratio (SMR)=1.04 95% confidence interval (CI) 0.97-1.11), but a lower risk of dying of CVD (SMR=0.77 95% CI 0.67-0.89). When comparing treatment groups within the cohort, no difference in risk of CVD was found when comparing patients treated with radiotherapy to surgery only. Left- versus right-sided radiotherapy did also not increase this risk (hazard ratio (HR)=0.93 95% CI 0.67-1.30). In a subgroup analysis of patients diagnosed between 1997 and 2005, accounting for overall history of CVD before DCIS diagnosis, we did not observe a risk difference between treatment groups (left- versus right-sided radiotherapy HR=0.95 95% CI 0.69-1.30). When taking into account CVD that occurred two years prior to DCIS diagnosis only, however, a statistically non-significantly increased risk was seen for patients with a history of CVD (HR=1.84 95% CI 0.45-7.50). CONCLUSIONS After a median follow-up of ten years, we did not find an increased risk for cardiovascular morbidity or mortality after radiotherapy for DCIS when comparing surgery and radiotherapy versus surgery only, nor when comparing radiotherapy for left- versus right-sided DCIS. Compared to the general population, DCIS patients have a decreased risk of cardiovascular death, independent of treatment.

Cardiovascular disease incidence after internal mammary chain irradiation and anthracycline-based chemotherapy for breast cancer

BackgroundImproved breast cancer (BC) survival and evidence showing beneficial effects of internal mammary chain (IMC) irradiation underscore the importance of studying late cardiovascular effects of BC treatment.MethodsWe assessed cardiovascular disease (CVD) incidence in 14,645 Dutch BC patients aged <62 years, treated during 1970–2009. Analyses included proportional hazards models and general population comparisons.ResultsCVD rate-ratio for left-versus-right breast irradiation without IMC was 1.11 (95% CI 0.93–1.32). Compared to right-sided breast irradiation only, IMC irradiation (interquartile range mean heart doses 9–17 Gy) was associated with increases in CVD rate overall, ischaemic heart disease (IHD), heart failure (HF) and valvular heart disease (hazard ratios (HRs): 1.6–2.4). IHD risk remained increased until at least 20 years after treatment. Anthracycline-based chemotherapy was associated with an increased HF rate (HR = 4.18, 95% CI 3.07–5.69), emerging <5 years and remaining increased at least 10–15 years after treatment. IMC irradiation combined with anthracycline-based chemotherapy was associated with substantially increased HF rate (HR = 9.23 95% CI 6.01–14.18), compared to neither IMC irradiation nor anthracycline-based chemotherapy.ConclusionsWomen treated with anthracycline-based chemotherapy and IMC irradiation (in an older era) with considerable mean heart dose exposure have substantially increased incidence of several CVDs. Screening may be appropriate for some BC patient groups.

Effect of radiotherapy for breast cancer on the prognosis of a subsequent myocardial infarction

Authors contributed equally to this work. 1 Netherlands Cancer Institute, Epidemiology, Amsterdam, The Netherlands 2 Erasmus MCCancer Institute, Medical Oncology, Rotterdam, The Netherlands 3 Erasmus MCCancer Institute, Radiation Oncology, Rotterdam, The Netherlands 4 Netherlands Cancer Institute, Medical Oncology, Amsterdam, The Netherlands 5 Netherlands Cancer Institute, Surgery, Amsterdam, The Netherlands 6 Netherlands Cancer Institute, Radiation Oncology, Amsterdam, The Netherlands

Abstract P5-16-02: Risk of subsequent ipsilateral invasive breast cancer after a primary diagnosis of ductal carcinoma in situ

Background Since the introduction of population-based mammography screening the incidence of ductal carcinoma in situ of the breast (DCIS) has increased dramatically and concerns about overdiagnosis and overtreatment have been raised. DCIS is considered to be a precursor lesion of most invasive breast cancer, but the challenge remains to distinguish the progressive from the clinically indolent, i.e. harmless lesions. Therefore, we aim to assess the risk of developing a subsequent ipsilateral invasive breast cancer after a first cancer diagnosis of primary DCIS in a large cohort as a first step to solve this clinical dilemma. Methods We conducted a retrospective study using a nationwide cohort comprising 12,721 women with a first cancer diagnosis of breast carcinoma in situ in the Netherlands between 1 January 1989 and 31 December 2004 and follow-up data up to 31 December 2010, extracted from the Netherlands Cancer Registry (NCR). Women who had bilateral breast disease, a diagnosis other than pure DCIS, and patients who received chemo- or hormonal therapy for their DCIS were excluded, as well as patients who had any other previous cancer diagnosis except for non-melanoma skin carcinoma. Using data from NCR and PALGA, the Dutch Pathology Registry, information about treatment and outcomes was collected and analysed. Outcome was defined as a subsequent ipsilateral invasive breast cancer as first invasive recurrence. Women who had a contralateral invasive breast cancer first, were censored at this diagnosis date. Invasive recurrence rates were compared by age and treatment groups using Cox regression. Women were divided into three age groups: women who were within the age group eligible for participation in the Dutch screening programme, and women who were either younger or older. Results A total number of 10,276 women with pure DCIS were included. After a median follow-up of 11.6 years, 520 first ipsilateral invasive recurrences were identified. Preliminary results show that approximately half of the women were treated with breast-conserving surgery (BCS), and the other half underwent a mastectomy. Of the patients who underwent BCS, about half received additional radiotherapy (RT). The age-adjusted hazard ratio for ipsilateral invasive breast cancer in BCS only versus BCS + RT was 2.49 (95% CI: 1.99 – 3.12) and in mastectomy versus BCS + RT 0.32 (95% CI: 0.24 - 0.43). After adjusting for treatment, risk of subsequent ipsilateral invasive breast cancer was higher for women who were younger than the invitation age range for screening when diagnosed compared to women within the age group eligible for the Dutch screening programme (HR = 1.86; 95% CI: 1.51 – 2.29). Conclusion This unique nationwide DCIS cohort shows that young women and women treated with BCS only have an increased risk of developing a subsequent ipsilateral invasive breast cancer after a first cancer diagnosis of primary DCIS. Using this cohort with a large number of women with subsequent ipsilateral invasive breast cancer, we will subsequently evaluate the concordance of features of the primary DCIS and the subsequent invasive breast cancer, and the association of characteristics of the DCIS with the risk of developing invasive ipsilateral breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-16-02.