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.
Authors: Morris P. , Chen C. , Lin N. , Moy B. , Come S. , Abbruzzi A. , Patil S. , Winer E. , Norton L. , Hudis C. , Dang C. 
Published: December 2010

Abstract
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” (&lt; 0.06 ng/ml; MSKCC, &lt;0.04 ng/ml; DF/HCC), “minimally elevated” (&lt;0.31 ng/ml) and “elevated” (&gt;0.31ng/ml). Elevated CRP was defined as (&gt;0.8mg/dl; MSKCC, &gt;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&lt;10%). Of 29 pts with undetectable TnI, 7 (24%) had aLVEF declines (1 ↓ ≥16%, 4 ↓ 10-15%, 2↓ 5&lt;10%). Elevations in CRP occurred in 61/84 (73%) pts during chemoRx but only in 22 (26%) during TL or at 18mth F/U. Three pts discontinued Rx for aLVEF ↓ at mths 4, 5 and 7 respectively; 2 (66%) had rises in CRP and 2 had minimal elevation in TnI. Three pts developed CHF at mths 3, 6, and 12 respectively, all had rises in CRP; 1 pt had a single ↑TnI of 0.08 ng/ml during chemoRx, and 2pts had no ↑TnIs.ConclusionsIn pts receiving ddAC-PTL fluctuations in TnI and CRP are common but do not persist after chemoRx (during TL). These biomarkers do not appear to predict for CHF. One possibility is that the timing of the drawing of these biomarkers (immediately preceding the specified treatment cycle and after Rx completion) may have been suboptimal. We plan to assess for potential biomarkers by assessing both immediately preceding and following therapy in a planned trial. Updated results will be presented.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3088.