Dose-Dense (dd) Doxorubicin and Cyclophosphamide (AC) Followed by Weekly Paclitaxel (P) with Trastuzumab (T) and Lapatinib (L) in Early Breast Cancer (EBC); Troponin I and C-Reactive Protein as Biomarkers of Cardiotoxicity

BackgroundThe early detection of cardiotoxicity and congestive heart failure (CHF) from anthracyclines and anti-HER2 agents is currently limited to measuring changes in left ventricular ejection fraction (LVEF) at arbitrary time points. This approach has limited sensitivity and specificity and has led to the investigation of putative biomarkers such as cardiac Troponin I (TnI), a highly specific marker of myocardial damage and C-reactive protein (CRP), a sensitive inflammatory marker. In a pre-planned analysis we investigated these as biomarkers of cardiotoxicity within a prospective study testing the feasibility of ddAC- followed by weekly P with T and L.Materials and MethodsPatients (pts) with HER2+ EBC enrolled at MSKCC and DF/HCC and received ddAC (A 60mg/m2 + C 600mg/m2) x 4 → weekly P (80mg/m2) x 12 + T + L (1000mg/day). T+L continued for a total of 1yr. At baseline pts had LVEF ≥50%. Pts with unstable angina, CHF, recent MI, uncontrolled arrhythmia, grade 3 QT prolongation were excluded. LVEF was assessed by MUGA scan at mths 0, 2, 6, 9 and 18. TnI and CRP were measured every 2 wks right before treatment (Rx) during ddAC-PTL, then at mths 6, 9 and 18. TnI was categorized as “undetectable” (< 0.06 ng/ml; MSKCC, 0.31ng/ml). Elevated CRP was defined as (>0.8mg/dl; MSKCC, >0.3mg/dl; DF/HCC). Investigators were blinded to these results until pts completed 18mth follow-up (F/U).ResultsFrom Apr 07- Apr 08, 95 pts were enrolled; 39/95 (41%) withdrew due to PTL toxicities (incl. 3 with asymptomatic LVEF (aLVEF) declines and 3 with CHF). Final biomarker results were available in 84 pts (88%) and 11 pts (12%) continue on study. During Rx, minimal elevations in TnI occurred in 55 pts (65%). One pt had ↑TnI above normal range with AC#4; MUGA 1 wk later was unchanged (LVEF 75%), but she died from sepsis during subsequent Rx without evidence of CHF. Elevations in TnI occurred only during chemoRx and no pt had a ↑TnI during TL or at 18mth F/U. Of 55pts with elevated TnI, 25 (45%) had aLVEF declines (3 ↓ ≥16%, 10 ↓ 10-15%, 12 ↓ 5 Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3088.