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

Abstract

Background: Improved 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.

Methods: We 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.

Results: CVD 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.

Conclusions: Women 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.

Fig. 1

Within cohort comparison of ischemic heart disease rates by time since treatment and radiation therapy in patients diagnosed during 1970-1999. The analyses shown in this figure include all diagnoses of ischemic heart disease, e.g. including patients diagnosed with valvular heart disease or heart failure prior to ischemic heart disease. For women diagnosed with breast cancer during 1970-86, data on cardiovascular disease were available only for the period 10+years after treatment. IMC, internal mammary chain.Cox proportional hazard model including the following variables: radiation fields (right-), age at breast cancer treatment (<40, 40-49, 50-61 years), chemotherapy (none, CMF-like, anthracycline-based chemotherapy), cardiovascular risk factor at breast cancer diagnosis yes/no (hypertension, hypercholesterolemia, or diabetes), smoking (ever, never, or unknown), and other cardiovascular diseases diagnoses (time-dependent).In the period 2000-2009 follow-up duration was too short for reliable estimates (see Table 4)

Fig. 2

Cumulative risk of cardiovascular diseases in patients diagnosed during 1987-1999 and aged 50 years or younger at breast cancer diagnosis, by internal mammary chain irradiation and cardiovascular disease risk factors (including smoking) at breast cancer diagnosis. IMC, internal mammary chain; CVD, cardiovascular disease; CHD, ischemic heart disease; VHD, valvular heart disease; HF, heart failure. The analyses of ischemic heart disease, valvular heart disease, and heart failure shown in this figure include all diagnoses of cardiovascular disease, e.g. if a patient was diagnosed with ischemic heart disease and then later with valvular heart disease then both events are counted. Patients with a specific cardiovascular diagnosis before start of time at risk were excluded from analysis with that specific diagnosis as endpoint (n=50 for ischemic heart disease, n=18 for valvular heart disease, and n=36 for heart failure)