Role of Troponins I and T and N-Terminal Prohormone of Brain Natriuretic Peptide in Monitoring Cardiac Safety of Patients With Early-Stage Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer Receiving Trastuzumab: A Herceptin Adjuvant Study Cardiac Marker Substudy

Abstract

Purpose Women receiving trastuzumab with chemotherapy are at risk for trastuzumab-related cardiac dysfunction (TRCD). We explored the prognostic value of cardiac markers (troponins I and T, N-terminal prohormone of brain natriuretic peptide [NT-proBNP]) to predict baseline susceptibility to develop TRCD. We examined whether development of cardiac end points or significant left ventricular ejection fraction (LVEF) drop was associated with markers' increases. Patients and Methods Cardiac marker assessments were coupled with LVEF measurements at different time points for 533 patients from the Herceptin Adjuvant (HERA) study who agreed to participate in this study. Patients with missing marker assessments were excluded, resulting in 452 evaluable patients. A primary cardiac end point was defined as symptomatic congestive heart failure of New York Heart Association class III or IV, confirmed by a cardiologist, and a significant LVEF drop, or death of definite or probable cardiac causes. A secondary cardiac end point was defined as a confirmed significant asymptomatic or mildly symptomatic LVEF drop. Results Elevated baseline troponin I (> 40 ng/L) and T (> 14 ng/L), occurring in 56 of 412 (13.6%) and 101 of 407 (24.8%) patients, respectively, were associated with an increased significant LVEF drop risk (univariate analysis: hazard ratio, 4.52; P < .001 and hazard ratio, 3.57; P < .001, respectively). Few patients had their first elevated troponin value recorded during the study (six patients for troponin I and 25 patients for troponin T). Two patients developed a primary and 31 patients a secondary cardiac end point (recovery rate of 74%, 23 of 31). For NT-proBNP, higher increases from baseline were seen in patients with significant LVEF drop. Conclusion Elevated troponin I or T before trastuzumab is associated with increased risk for TRCD. A similar conclusion for NT-proBNP could not be drawn because of the lack of a well-established elevation threshold; however, higher increases from baseline were seen in patients with TRCD compared with patients without.

Troponins and brain natriuretic peptides for the prediction of cardiotoxicity in cancer patients: a meta‐analysis

“…Radiotherapy and HER2 inhibitor therapy without concomitant chemotherapy had no detectable effect upon troponin levels (OR 3.4, 95% CI 1.0–12.2; n = 810 for HER2 inhibitor therapy; and OR 1.0, 95% CI 0.1–16.4; n = 125 for radiotherapy, respectively). The frequency of troponin elevations in studies that assessed troponin I was similar to the frequency in studies investigating troponin T [OR 12.2 for troponin I vs. OR 8.9 for troponin T; Chi 2 = 0.09; P = 0.77 for subgroup differences; total n = 1863 with three studies ( n = 426) included for both forms of troponin] (online supplementary Figure ). Within anthracycline‐treated patients with or without concomitant HER2 inhibitor therapy, the risk for troponin elevation was similar in patients receiving < 240 and ≥ 240 mg/m 2 doxorubicin equivalent dose (OR 17.2 for < 240 mg/m 2 vs. OR 19.3 for ≥ 240 mg/m 2 doxorubicin equivalent dose; Chi 2 = 0.04; P = 0.84 for subgroup differences; n = 1129) (online supplementary Figure ).…”

Arginine-Nitric Oxide Metabolites and Cardiac Dysfunction in Patients With Breast Cancer

“…The primary outcome measure of CTRCD was a priori defined as a reduction in LVEF by ≥10% from baseline prior to chemotherapy, to an absolute value of <50%. Although there is no universally accepted definition of CTRCD, this definition has been commonly used in the cardio-oncology literature (22–24). …”

Cardiotoxicity From Human Epidermal Growth Factor Receptor‐2 (HER2) Targeted Therapies

“…Cardiac troponins are well‐established markers of myocardial injury and appear to correlate best with incident cardiac dysfunction following chemotherapy. Three studies have reported that elevated and increasing troponin I following chemotherapy, particularly if such increase persists at 1 month after treatment,84 is associated with subsequent cardiac dysfunction as well as with lower likelihood of cardiac recovery in patients receiving trastuzumab 85, 86, 87. During treatment, negative cardiac troponin has a high negative predictive value; however, minute elevations can be commonly detected in patients following chemotherapy and have low positive predictive value 88.…”