Cardiac mortality after radiotherapy, chemotherapy and endocrine therapy for breast cancer: Cohort study of 2 million women from 57 cancer registries in 22 countries

Abstract

Comparisons of patients receiving different cancer treatments reflect the effects of both treatment and patient selection. In breast cancer, however, if radiotherapy decisions are unrelated to laterality, comparisons of left-sided and right-sided cancers can demonstrate the causal effects of higher-versus-lower cardiac radiation dose. Cardiac mortality was analysed using individual patient data for 1,934,248 women with breast cancer in 22 countries. The median date of diagnosis was 1996 and the interquartile range was 1987-2002. A total of 1,018,505 women were recorded as irradiated, 223,077 as receiving chemotherapy, 317,619 as receiving endocrine therapy and 55,264 died of cardiac disease. Analyses were stratified by time since breast cancer diagnosis, age at diagnosis, calendar year of diagnosis and country. Patient-selection effects were evident for all three treatments. For radiotherapy, there was also evidence of selection according to laterality in women irradiated 1990 or later. In patients irradiated before 1990, there was no such selection and cardiac mortality was higher in left-sided than right-sided cancer (rate ratio [RR]: 1.13, 95% confidence interval 1.09-1.17). Left-versus-right cardiac mortality RRs were greater among younger women (1.46, 1.19, 1.20, 1.09 and 1.08 after cancer diagnoses at ages <40, 40-49, 50-59, 60-69 and 70+ years, 2p_trend =0.003). Left-versus-right RRs also increased with time since cancer diagnosis (1.03, 1.11, 1.19 and 1.21 during 0-4, 5-14, 15-24 and 25+ years, 2p_trend =0.002) while for women who also received chemotherapy, the left-versus-right RR was 1.42 (95% confidence interval 1.13-1.77), compared to 1.10 (1.05-1.16) for women who did not (2p_difference = 0.03). These results show that the relative increase in cardiac mortality from cardiac exposure during breast cancer radiotherapy given in the past was greater in younger women, lasted into the third decade after exposure and was greater when chemotherapy was also given.

Keywords: breast cancer; heart disease; radiotherapy.

Figure 1

Treated versus untreated women: Cardiac mortality rate ratios for women recorded as receiving radiotherapy, chemotherapy or endocrine therapy, overall and by type of surgery and age at breast cancer diagnosis. Rate ratios estimated by Poisson regression with stratification by time since breast cancer diagnosis, age at breast cancer diagnosis, calendar year of breast cancer diagnosis and country.

Figure 2

Women with left‐sided breast cancer versus women with right‐sided breast cancer: Cardiac mortality rate ratios by calendar period, whether or not they were recorded as irradiated and type of surgery. Rate ratios estimated by Poisson regression with stratification by time since breast cancer diagnosis, age at breast cancer diagnosis, calendar year of breast cancer diagnosis and country. The subtotals and overall total are also stratified by radiotherapy.

Figure 3

Women recorded as irradiated with left‐sided breast cancer versus women recorded as irradiated with right‐sided breast cancer: Cardiac mortality rate ratios by patient, tumour and treatment characteristics and geographic region. Rate ratios estimated by Poisson regression with stratification by time since breast cancer diagnosis, age at breast cancer diagnosis, calendar year of breast cancer diagnosis and country. See Supporting Information Figure S2 for analyses of women irradiated <1990 and 1990+ combined.

Figure 4

Women recorded as irradiated with left‐sided breast cancer versus women recorded as irradiated with right‐sided breast cancer who were diagnosed with breast cancer before 1990: Cardiac mortality rate ratios by age at diagnosis of breast cancer and by other patient, tumour and treatment characteristics and geographic region. Rate ratios estimated by Poisson regression with stratification by time since breast cancer diagnosis, age at breast cancer diagnosis, calendar year of breast cancer diagnosis and country. See Supporting Information Figure S5 for corresponding analyses in women diagnosed 1990+.