Overexpression or amplification of human epidermal growth factor receptor 2 (HER2) occurs in roughly 15% of breast cancers, and is associated with poor prognosis. Anti-HER2 drugs such as the monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib are widely used for the treatment of HER2-positive breast cancer. However, anti-HER2 agents are associated with an increased risk of cardiotoxicity, occurring mostly during treatment and being generally reversible. To date, no cardiac biomarkers have been validated as predictive markers of cardiotoxicity in patients receiving anti-HER2 therapies.
Cardiac Troponin T (TnT) is a marker of myocyte damage and the amino-terminal fragment of brain natriuretic peptide (NT-proBNP) is a marker of increased ventricular distension. De Azambuja and colleagues evaluated these biomarkers for cardiotoxicity in patients who participated in the NeoALTTO study and who were treated with neoadjuvant anti-HER2 therapies.1 The aims of the study were to evaluate the utility of TnT and NT-proBNP as predictive biomarkers of anti-HER2-induced cardiotoxicity, to test changes in the levels of TnT and/or NT-proBNP after 2 weeks and 12 weeks of anti-HER2 therapy, to evaluate if increased levels of TnT and/or NT-proBNP at any time point correlate with the occurrence of cardiotoxicity, and to compare the incidence of cardiac events with lapatinib, trastuzumab or both in an anthracycline-naïve population.
In the NeoALTTO study 455 patients were randomized to receive either lapatinib (1500 mg; N= 154), trastuzumab weekly (4 mg/kg loading dose followed by 2 mg/kg; N=149), or lapatinib with trastuzumab for a total of 6 weeks (N=152).2 After this biological window, patients continued on additional 12 weeks of the assigned anti-HER2 therapy in combination with weekly paclitaxel (80 mg/m2). Definitive surgery was done 4 weeks after the last dose of paclitaxel. After surgery, patients received adjuvant FEC (3x) followed by the same HER2 therapy as in the neoadjuvant phase for further 34 weeks (to complete 52 weeks in total). Eligible patients had a left ventricular ejection fraction (LVEF) ≥50%. Cardiac biomarkers were centrally tested in plasma samples collected at baseline, week 2 and at surgery.
Elevated biomarker was defined as either TnT >0.015 µg/L or NT-proBNP >125 pg/mL. The small number of patients and rarity of marker elevations allowed only descriptive analyses. At a median follow-up of 3.8 years, 280 patients had cardiac biomarkers tested at baseline (61.5%): NT-proBNP was elevated in 39 patients (13.9%) while TNT was elevated in only 1 patient (0.35%). From those 39 patients with elevated NT-proBNP at baseline, only 1 patient experienced a cardiac event. Also, hypertension was presented in 14 patients with elevated NT-proBNP. Serial measurements were available in 173 patients (61.7%) and NT-proBNP was elevated in 39, 30 and 40 patients at baseline, week 2 and at surgery, respectively, while among 171 patients (61%) TNT was elevated in 1, 1 and 6 patients, respectively. There were 13 cardiac events in 11 patients in the entire trial. Five of these patients had a measurement of cardiac biomarkers at baseline (non-elevated NT-prBNP and TNT were observed in 4 and 5 patients, respectively), 9 of them had a measurement at week 2 (non-elevated NT-prBNP and TnT were observed in 8 and 9 patients, respectively) and 3 of them at surgery (non-elevated NT-prBNP and TnT were observed in 3 and 3 patients, respectively). During adjuvant phase, 13 patients experienced LVEF drop to <50% and none had either NT-proBNP elevated or TnT at surgery.
In summary: despite the small sample size, De Azambuja and colleagues demonstrated that cardiac biomarkers are rarely elevated in patients receiving anti-HER2 therapies, which is probably due to the absence of myocyte necrosis with respect to TNT, and the lack of chamber dilation in the case of NT-proBNP after exposure to these drugs. In addition, few cardiac events were present in this population not previously exposed to anthracycline-based chemotherapy. Therefore the use of cardiac biomarkers in this population may be unnecessary. However, a larger prospective trial should be performed to confirm this finding.
- De Azambuja E, Holmes AP, Piccart-Gebhart M, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014; 15: 1137-1146.
- De Azambuja E, Bradbury I, Ewer M, et al. Cardiac biomarkers for early detection and prediction of trastuzumab and/or lapatinib-induced cardiotoxicity in patients with HER2 positive early breast cancer (BIG 1-06). Poster presentation at the San Antonia Breast Cancer Congress 2016, abstract P4-21-09.