Interruptions in trastuzumab therapy for breast cancer are associated with adverse cardiovascular and oncologic outcomes

Trastuzumab is a monoclonal antibody that significantly reduces the risk of HER2-overexpressing breast cancer recurrence when used for up to 12 months in the adjuvant setting. However, trastuzumab is associated with dose-limiting cardiac dysfunction that may recover after interruption of therapy. In practice, adjuvant trastuzumab is often held if mild left ventricular dysfunction (LVD) develops. However, the effect of trastuzumab interruption on subsequent cardiovascular and oncologic outcomes is not clear. In this study, we sought to explore the associations between interrupting trastuzumab and cardiovascular and oncologic outcomes among breast cancer patients with treatment-emergent mild LVD. 2652 patients were identified in British Columbia who received trastuzumab with curative intent between September 1, 2005 and December 31, 2013. We identified 229 patients who had a drop in left ventricular ejection fraction (LVEF) to 40-50%. Trastuzumab was interrupted in 174 patients (76%) while 55 (24%) continued therapy. The risk of the primary composite outcome (all-cause mortality, heart failure (HF) hospitalization, outpatient diagnosis of HF, cancer recurrence) was significantly higher in the group experiencing an interruption in trastuzumab therapy (unadjusted HR 4.25, 95% CI 2.28, 7.91; Figure 1). After adjusting for age, baseline LVEF, comorbidities, and cancer characteristics, trastuzumab interruption remained a significant predictor of the primary composite outcome (adjusted HR 4.15, 95% CI 2.15, 8.00). Interruption was also a significant independent predictor of the risk of new outpatient HF diagnosis (adjusted HR 4.56, 95% CI 2.13, 9.79) but not of other components of the composite outcome. HF hospitalization occurred in 8 patients in the interruption group and none in the continuation group (log-rank p=0.04). Overall, 97 (47.2%) patients completed their planned 17 cycles of trastuzumab. Interruption in trastuzumab was associated with a 60% reduction in the odds of completion of therapy after adjusting for important covariates (p=0.007). In a population of patients receiving trastuzumab with curative intent for breast cancer, the risk of adverse cardiovascular and cancer outcomes was higher in patients experiencing an interruption in trastuzumab therapy after adjusting for age, comorbidities, and tumor characteristics. Contrary to common patterns of practice, continuation of trastuzumab in the context of LVD was not associated with increasing cardiovascular risk. This study underscores the importance of close cardiovascular follow-up for patients receiving trastuzumab therapy with the goal of adhering to regular trastuzumab dosing as closely as possible. Further studies to identify strategies to support patients while avoiding treatment interruptions are needed.