Risk of heart failure in breast cancer patients after anthracycline and trastuzumab treatment: a retrospective cohort study

Abstract

Background: Clinical trials demonstrated that women treated for breast cancer with anthracycline or trastuzumab are at increased risk for heart failure and/or cardiomyopathy (HF/CM), but the generalizability of these findings is unknown. We estimated real-world adjuvant anthracycline and trastuzumab use and their associations with incident HF/CM.

Methods: We conducted a population-based, retrospective cohort study of 12,500 women diagnosed with incident, invasive breast cancer from January 1, 1999 through December 31, 2007, at eight integrated Cancer Research Network health systems. Using administrative procedure and pharmacy codes, we identified anthracycline, trastuzumab, and other chemotherapy use. We identified incident HF/CM following chemotherapy initiation and assessed risk of HF/CM with time-varying chemotherapy exposures vs no chemotherapy. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for age at diagnosis, stage, Cancer Research Network site, year of diagnosis, radiation therapy, and comorbidities.

Results: Among 12 500 women (mean age = 60 years, range = 22-99 years), 29.6% received anthracycline alone, 0.9% received trastuzumab alone, 3.5% received anthracycline plus trastuzumab, 19.5% received other chemotherapy, and 46.5% received no chemotherapy. Anthracycline and trastuzumab recipients were younger, with fewer comorbidities than recipients of other chemotherapy or none. Compared with no chemotherapy, the risk of HF/CM was higher in patients treated with anthracycline alone (adjusted HR = 1.40, 95% CI = 1.11 to 1.76), although the increased risk was similar to other chemotherapy (adjusted HR = 1.49, 95% CI = 1.25 to 1.77); the risk was highly increased in patients treated with trastuzumab alone (adjusted HR = 4.12, 95% CI = 2.30 to 7.42) or anthracycline plus trastuzumab (adjusted HR = 7.19, 95% CI = 5.00 to 10.35).

Conclusions: Anthracycline and trastuzumab were primarily used in younger, healthier women and associated with increased HF/CM risk compared with no chemotherapy. This population-based observational study complements findings from clinical trials on cancer treatment safety.

Figure 1.

Cumulative incidence of heart failure and/or cardiomyopathy (HF/CM) in women with invasive breast cancer over 5 years by adjuvant chemotherapy group. Adjusted cumulative incidence of HF/CM and number of patients at risk by exposure group (anthracycline only, trastuzumab only, anthracycline + trastuzumab, other chemotherapy, or none) for the first 5 years of follow-up. Cumulative incidence was adjusted for Cancer Research Network (CRN) site (eight sites), age at diagnosis (<55, 55–64, 65–74, ≥75 years), Charlson comorbidity index (0, 1, 2, ≥3), summary stage at diagnosis (local vs regional), year of diagnosis (categorical for each year), and radiation treatment (yes vs no).

Figure 2.

Cumulative incidence of heart failure and/or cardiomyopathy (HF/CM) in women with invasive breast cancer over 5 years by adjuvant chemotherapy and age groups. Adjusted cumulative incidence of HF/CM and number of patients at risk by exposure group (anthracycline only, trastuzumab only, anthracycline + trastuzumab, other chemotherapy, or none) for the first 5 years of follow-up, by age at diagnosis. Cumulative incidence was adjusted for Cancer Research Network (CRN) site (eight sites), age at diagnosis (<55, 55–64, 65–74, ≥75 years), Charlson comorbidity index (0, 1, 2, ≥3), summary stage at diagnosis (local vs regional), year of diagnosis (categorical for each year), and radiation treatment (yes vs no). A) Age <55 years. B) Age 55–64 years. C) Age 65–74 years. D) Age ≥75 years.

Figure 2.

Cumulative incidence of heart failure and/or cardiomyopathy (HF/CM) in women with invasive breast cancer over 5 years by adjuvant chemotherapy and age groups. Adjusted cumulative incidence of HF/CM and number of patients at risk by exposure group (anthracycline only, trastuzumab only, anthracycline + trastuzumab, other chemotherapy, or none) for the first 5 years of follow-up, by age at diagnosis. Cumulative incidence was adjusted for Cancer Research Network (CRN) site (eight sites), age at diagnosis (<55, 55–64, 65–74, ≥75 years), Charlson comorbidity index (0, 1, 2, ≥3), summary stage at diagnosis (local vs regional), year of diagnosis (categorical for each year), and radiation treatment (yes vs no). A) Age <55 years. B) Age 55–64 years. C) Age 65–74 years. D) Age ≥75 years.

Figure 2.

Cumulative incidence of heart failure and/or cardiomyopathy (HF/CM) in women with invasive breast cancer over 5 years by adjuvant chemotherapy and age groups. Adjusted cumulative incidence of HF/CM and number of patients at risk by exposure group (anthracycline only, trastuzumab only, anthracycline + trastuzumab, other chemotherapy, or none) for the first 5 years of follow-up, by age at diagnosis. Cumulative incidence was adjusted for Cancer Research Network (CRN) site (eight sites), age at diagnosis (<55, 55–64, 65–74, ≥75 years), Charlson comorbidity index (0, 1, 2, ≥3), summary stage at diagnosis (local vs regional), year of diagnosis (categorical for each year), and radiation treatment (yes vs no). A) Age <55 years. B) Age 55–64 years. C) Age 65–74 years. D) Age ≥75 years.

Figure 2.

Cumulative incidence of heart failure and/or cardiomyopathy (HF/CM) in women with invasive breast cancer over 5 years by adjuvant chemotherapy and age groups. Adjusted cumulative incidence of HF/CM and number of patients at risk by exposure group (anthracycline only, trastuzumab only, anthracycline + trastuzumab, other chemotherapy, or none) for the first 5 years of follow-up, by age at diagnosis. Cumulative incidence was adjusted for Cancer Research Network (CRN) site (eight sites), age at diagnosis (<55, 55–64, 65–74, ≥75 years), Charlson comorbidity index (0, 1, 2, ≥3), summary stage at diagnosis (local vs regional), year of diagnosis (categorical for each year), and radiation treatment (yes vs no). A) Age <55 years. B) Age 55–64 years. C) Age 65–74 years. D) Age ≥75 years.