Cardiovascular Risk After Adjuvant Trastuzumab in Early Breast Cancer: An Italian Population-Based Cohort Study

Abstract

Background: Although trastuzumab (T) represents the standard of care for the adjuvant treatment of HER2-positive early-stage breast cancer, contrasting results are available about the cardiac toxicity associated to its use. We conducted a multiregional population-based cohort investigation aimed to assess both the short- and long-term cardiovascular (CV) outcomes in women with early breast cancer treated with T-based or standard adjuvant chemotherapy (CT).

Materials and methods: We used health care use databases of six Italian regions, overall accounting for 42% of the Italian population. The study cohort was made by all women surgically treated for breast cancer who started a first-line adjuvant T-based or CT treatment. Patients treated with T were 1:2 matched to those treated with CT based on date of treatment start, age, and presence of CV risk factors. Short- and long-term CV outcomes (heart failure and cardiomyopathy) were measured, respectively, after 1 year and at the end of follow-up.

Results: Among 28,599 women who met the inclusion criteria, 6,208 T users were matched to 12,416 CT users. After a mean follow-up of 5.88 years, short- and long-term cumulative CV risk were 0.8% and 2.6% in patients treated with T and 0.2% and 2.8% in those treated with CT, respectively. Adjusted hazard ratios were 4.6 (95% confidence interval [CI], 2.6-8.0) for short-term and 1.2 (95% CI, 0.9-1.6) for long-term CV risk.

Discussion: In our large real-world investigation, T-associated cardiotoxicity was limited to the treatment period. The addition of T to adjuvant CT did not result in long-term worsening of CV events.

Implications for practice: Adjuvant trastuzumab-based chemotherapy represents the backbone therapy in patients with HER2-positive early breast cancer. Although well tolerated, cardiovascular events can manifest during or after therapy because of treatment-related toxicities. In this wide multicenter and unselected cohort, long-term symptomatic cardiotoxicity was low and limited to the treatment period. The findings suggest that developing tools that would be adequately able to predict cardiac toxicity at an early stage remains an important area in which additional research efforts are needed.

Keywords: Cardiotoxicity; Early breast cancer; Real world; Trastuzumab.

Figure 1

Flow‐chart of inclusion and exclusion criteria for each participant region, as well as in the entire investigated population

Figure 2

Kaplan‐Meier estimates of the cumulative risk of hospitalization for heart failure or cardiomyopathy in 6,208 and 12,416 breast cancer women on adjuvant therapy respectively with T‐based CT and CT alone. Abbreviations: CT, standard chemotherapy; T, trastuzumab.

Figure 3

Forest plot of the summarized associations between trastuzumab‐based adjuvant therapy and the short‐term and long‐term risk of hospitalization for heart failure or cardiomyopathy, compared use of standard chemotherapy alone. Estimates are shown for each participant region, and by summarizing region‐specific hazard ratios. Abbreviations: CI, confidence interval; CT, standard chemotherapy; IV, inverse variance; T, trastuzumab.