Trastuzumab-Related Cardiotoxicity in Early Breast Cancer: A Cohort Study

Abstract

Background. Concerns have been raised about the cardiac safety profile of trastuzumab for the adjuvant treatment of early stage breast cancer in clinical practice. We assessed trastuzumab-related cardiotoxicity and its predictors in a large cohort of Italian women. Methods. Through a record linkage between four regional health care databases, we identified the rate of severe cardiac adverse events among women treated with trastuzumab for early breast cancer in Lombardy. The cumulative risk of cardiotoxicity was estimated using the Kaplan-Meier method, and independent predictors were assessed using the Cox model. Results. Of 2,046 trastuzumab users, 53 (2.6%) experienced at least one hospitalization for a cardiac event, and there were two cardiac deaths. The cumulative risk of cardiotoxicity increased up to 2 years after starting treatment, reaching a plateau at 2.8%. The risk was low (0.2%) among young women, whereas the incidence was approximately 10% in women aged Ն70 years, irrespective of cardiovascular risk factors. Age and history of cardiac disease were strong predictors of cardiotoxicity, with a hazard ratio of 11.3 (95% confidence interval [CI]: 3.5-36.6) for women aged Ն70 years as compared with those Ͻ50 years of age. Hazard ratio was 4.4 (95% CI: 2.1-9.5) for women with a history of cardiac disease compared with those without a history of cardiac disease. Conclusions. Cardiotoxicity of trastuzumab varies considerably across subgroups of patients. The long-term safety profile was less favorable than in the largest clinical trial. Strategies to reduce cardiotoxicity in high-risk women should be investigated. The Oncologist 2013;18:795-801 Implications for Practice: Concerns have been raised about the safety profile of trastuzumab for older, less healthy, unselected populationsoutsideofclinicaltrials.Cliniciansneedinformationontheincidenceofcardiotoxicityoftrastuzumab-basedadjuvantregimens in patients with HER-2 positive early invasive breast cancer in clinical practice, according to patient characteristics. This large cohort suggests that the incidence of short-term severe cardiotoxicity (not only congestive heart failure) in clinical practice is higher than that recorded in clinical trials that tested the same regimen. Age and history of cardiac disease are strong predictors of cardiotoxicity. The risk/ benefit profile of trastuzumab should be quantitatively assessed, and strategies to reduce cardiotoxicity-especially in older women (Ն70 years) and women Ͼ50 years of age with several cardiovascular risk factors-should be developed.

Effectiveness of Trastuzumab in First-Line HER2+ Metastatic Breast Cancer After Failure in Adjuvant Setting: A Controlled Cohort Study

“…However, our analysis moved from drug (T) rather than cancer subtype (HER2), and the criteria for patients' enrollment were based on T administration. We have discussed the problem of the quality of HER2 status ascertainment in a previous article [14]. However, there is no reason why the quality of ascertainment of HER2 status should differ between our two groups.…”

“…Older age, comorbidities, and the presence of a brain metastasis were strong predictors for not receiving T for mBC after failure in the adjuvant setting in our data.There is strong evidence that older patients are undertreated [23]. Moreover, the cardiotoxicity of T [14] has likely discouraged its use in women at high risk of cardiac disease, as did the presence of a brain metastasis, for which the use of T has been debated [24,25].…”

“…T is dispensed by hospital pharmacies only, and since January 2006 in Lombardy, it is mandatory to register each dispensation in a special file (File F). In previous work, we built a cohort of more than 2,000 women who had usedT foreBC by record linkage of several regional administrative health care databases, and we analyzed cardiotoxicity [14] and estimated OS and progression-free survival [15,16] in clinical practice. …”

“…A more detailed description of the databases used for the record linkage and of the operative procedures used to identify the various groups of women are given in supplemental Appendix 1 and previous publications [14,16].…”

Preemptive Cardioprotective Strategies in Patients Receiving Chemotherapy

“…Also, while concurrent or previous anthracycline use certainly increases the likelihood of LV dysfunction from trastuzumab [21,22], concomitant radiation therapy to the chest does not [26]. In general, patients with history of pre-existing structural cardiovascular disease and cardiovascular risk factors (diabetes, dyslipidemia, hypertension) are also more likely to develop cardiotoxicity with trastuzumab [27,28].…”