Troponins Do Not Predict Cardiotoxicity in a Pilot Study of Adjuvant Bevacizumab (B) Plus Dose-Dense Doxorubicin/Cyclophosphamide (AC) Followed by Nanoparticle Albumin-Bound Paclitaxel (nab-P).
Authors: McArthur H. , Rugo H. , Nulsen B. , Patil S. , Steingart R. , Melisko M. , Grothusen J. , Traina T. , Norton L. , Hudis C. , Dickler M. 
Published: December 2010

Background: We previously reported that dose dense (dd) q2wk AC-nab-P with concurrent bevacizumab (B) in early stage breast cancer is safe (McArthur, SABCS 2008). Prospective randomized studies of adjuvant B-containing, anthracycline-based regimens are ongoing with stringent cardiac monitoring strategies. However, accurate predictors of cardiotoxicity, including congestive heart failure (CHF), are lacking. Currently, treatment-related CHF is monitored by measuring left ventricular ejection fraction (LVEF) changes at various time points. Cardiac troponins (cTn) are myocardial contractile proteins that are released into the circulation after cardiac injury. As highly specific biomarkers of myocardial damage, cTns may augment existing cardiac monitoring strategies by providing earlier and more reliable evidence of myocyte damage. Consequently, we investigated cTnI as a potential biomarker of cardiotoxicity in our pilot study of cardiac safety with ddAC-nab-P+B.Methods: In this phase II study, B was administered concurrently (10 mg/kg IV q2wk x 8) with pegfilgrastim-supported chemotherapy (AC at 60/600 mg/m2 q2wk x4 then nab-paclitaxel at 260 mg/m2 q2wk x4) and continued at 15 mg/kg q3wk thereafter for a total one year of B therapy. The primary endpoint was cardiac safety. A secondary endpoint was the prospective exploration of TnI as a potential predictor of cardiotoxicity. Peripheral blood for TnI was collected at baseline; weeks 2, 4, 6, 8, 10, 12, and 14; and months 6, 9, and 18. In this pre-planned analysis, TnI values over time were examined as continuous variables by institution and as categorical variables. TnI values were categorized as undetectable (UN; &lt;0.06 MSKCC or &lt;0.05ng/ml UCSF), minimally detectable (MD; 0.06-0.31ng/ml MSKCC or 0.05-0.16ng/ml UCSF) or elevated (EL; &gt;0.31ng/ml MSKCC or &gt;0.16ng/ml UCSF). Baseline and maximum TnI values were compared with the maximum change in left ventricular ejection fraction (LVEF) values for all 80 enrolled patients over the study period using ANOVA or regressionResults: Median age: 48y (range, 27–75y). Median follow-up: 24.5mo (range, 1–32mo). Median baseline LVEF: 68% (range, 53–82%). The baseline TnI was MD for 1 pt and UN for 79 pts. Overall, 57 pts developed MD TnIs and 6 pts developed EL TnIs. There was no significant association between TnI and LVEF for the 6 pts who developed protocol-defined asymptomatic LVEF declines and the 1 pt who developed CHF versus not, or for 6 pts who develop EL TnI versus not. Furthermore, there was no significant association between continuous TnIs and the maximum % LVEF change [(max-min)/min)].Conclusions: In this prospective study, TnIs do not appear to predict for LVEF changes with B + ddAC-nab-P. Long-term follow-up continues for late CHF events. Accurate biomarkers of cardiotoxicity in this setting are needed.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3087.