Department of Pharmacy, USA
*Corresponding author:Cole Lightfoot, Froedtert Health, Department of Pharmacy, USA
Submission: September 27, 2019;Published: October 31, 2019
ISSN: 2578-0204Volume3 Issue1
Background: Human epidermal growth factor receptor 2 (HER2) over expression has been identified as an important drug target for the treatment of many cancers. Trastuzumab (Herceptin, Genentech, CA, USA) is an anti-HER2 monoclonal antibody effective at inducing cell death in patients who overexpress this gene. The degree of HER2 expression is a determining factor in the decision to treat patients with trastuzumab. At Froedtert & the Medical College of Wisconsin, a dual probe fluorescent in situ hybridization is completed and the decision to treat is then made based on the results which are reported as a ratio of HER2 gene signals relative to those of chromosome 17 (CEP17). A patient may qualify for treatment by meeting the minimum threshold requirement of HER2 expression (HER2:CEP17 ratio ≥2 or if HER2:CEP17 ratio <2 and ≥6 HER2 signals/cell), while other patients may far surpass the minimum level. Trastuzumab contains a warning for possible cardiomyopathy associated with symptomatic and asymptomatic reductions in left ventricular ejection fraction (LVEF). There has been no investigation as to whether the degree of HER2 expression is related to the patient’s risk for developing trastuzumab-induced cardiotoxicity.
Methods: We performed a retrospective cohort review of patients having received trastuzumab within Froedtert & the Medical College of Wisconsin Health System in an effort to identify and describe the relationship between degree of HER2 expression and incidence of cardiotoxicity in patients receiving trastuzumab therapy. The primary objective of this study was to identify the correlation between HER2 receptor expression and cardiotoxicity in patients treated with trastuzumab. The secondary objectives were to identify the correlation between HER2 expression and absolute change in LVEF and time to cardiotoxicity in patients treated with trastuzumab. For the purposes of this study, cardiotoxicity was defined as a decrease in LVEF ≥ 16% from baseline or a LVEF <50% and ≥10% decrease from baseline. Change in global peak systolic longitudinal strain of ≥15%, grade ≥3 left ventricular systolic dysfunction as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events v 4.03 (NCI CTCAE), or treatment discontinuation due to trastuzumab cardiotoxicity as determined by physician was also used to meet criteria for primary end point of cardiotoxicity. Froedtert & the Medical College of Wisconsin IRB approved completion of this study.
Results: There were 44 (34 non-metastatic and 10 metastatic) patients with cardiotoxicity event(s) and 11 deaths without cardiotoxicity (all metastatic patients) within 18 months of follow-up. Overall one-year incidence of cardiotoxicity was 14.2% [10.7%, 18.9%], with incidences of 13.6% [9.9%, 18.8%] in non-metastatic patients and 16.7% [9.1%, 30.5%] in metastatic patients. The median survival time (time at which half of all patients are expected to experience cardiotoxicity) was not reached within 18 months. There was no significant difference in survival from cardiotoxicity between HER2:CEP17 groups (<3, 3-6, 6-9, 9+) among non-metastatic patients (log-rank test p=0.72) or metastatic patients (log-rank test p=0.17). The HER2:CEP17 ratio (continuous) was not significantly associated with cardiotoxicity in non-metastatic patients (aHR 1.00 [0.94, 1.07], p=0.95) or metastatic patients (aHR 0.88 [0.72, 1.07], p=0.19) after adjusting for baseline age, comorbidities, radiation exposure, and anthracycline exposure. In the multiple regression analysis of non-metastatic patients, anthracycline exposure (aHR 2.73 [1.28, 5.81], p=0.009), baseline comorbidities (aHR 2.41 [1.14, 5.09], p=0.021), and younger age at first dose (aHR 0.95 [0.92, 0.98], p=0.002) were significantly associated with increased hazard of cardiotoxicity. There were 56 (47 non-metastatic and 9 metastatic) patients with LVEF reduction. Overall one-year incidence of LVEF reduction was 17.4% [13.5%, 22.3%], with incidences of 18.6% [14.2%, 24.4%] in non-metastatic patients and 12.3% [6.2%, 24.8%] in metastatic patients. The median time to LVEF reduction was not reached within 18 months. The HER2:CEP17 ratio (continuous) was not significantly associated with LVEF reduction in non-metastatic patients (aHR 1.02 [0.97, 1.07], p = 0.53) or metastatic patients (aHR 0.81 [0.62, 1.05], p = 0.12) after adjusting for age, baseline comorbid conditions, radiation exposure, and anthracycline exposure (Tables 1-3). Only anthracycline exposure was significantly associated with increased hazard of LVEF reduction (aHR 2.37 [1.27, 4.43], p = 0.007) in non-metastatic patients.
Conclusion: Tumor cell HER2:CEP17 ratio does not predict incidence or time to onset of cardiotoxicity associated with trastuzumab.
Keywords: Trastuzumab; Cardiotoxicity; HER2
Abbreviations: HER2: Human Epidermal Growth Factor Receptor 2; LVEF: Left Ventricular Ejection Fraction; IHC: Immunohistochemistry; CEP17: Chromosome 17; FISH: Fluorescent Insitu Hybridization; MUGA: Multigated Acquisition Scan; NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events