Troponin I and C-Reactive Protein Are Commonly Detected in Patients with Breast Cancer Treated with Dose-Dense Chemotherapy Incorporating Trastuzumab and Lapatinib

Abstract

Purpose: There are no validated methods of early detection of cardiotoxicity from trastuzumab (T) following anthracycline-based chemotherapy. Currently changes in left ventricular ejection fraction (LVEF) are assessed but this approach has limited sensitivity and specificity. Within a prospective feasibility study of dose-dense (dd) doxorubicin and cyclophosphamide (AC) ! weekly paclitaxel (P) with T and lapatinib (L), we included a preplanned analysis of correlative cardiac Troponin I (cTnI) and C-reactive protein (CRP) as early biomarkers of cardiotoxicity.Experimental Design: As previously described, patients received ddACx 4!PTL!TL. LVEF was assessed at months 0, 2, 6, 9, and 18 and cTnI and CRP measured every 2 weeks during chemotherapy then at months 6, 9, and 18. These biomarkers were correlated with changes in LVEF.Results: Ninety-five patients enrolled. Overall, 3 (3%) patients withdrew during AC and 41 (43%) withdrew during PTL!TL, mostly due to diarrhea. Median LVEF was 68% (baseline), 69% (month 2), 65% (month 6), 65% (month 9), and 65% (month 18). The majority (67%) had a detectable cTnI during the study. The proportion of detectable cTnIs increased over time; 4% at baseline, 11% at month 2, and 50% at month 3. The timing of these detectable cTnIs preceded maximum-recorded decline in LVEF. However, overall, maximum cTnI levels did not correlate with LVEF declines. A detectable CRP was seen in 74/95 (78%) but did not correlate with LVEF declines.Conclusion: In patients receiving ddAC!PTL, cTnIs are commonly detected. These elevations may precede changes in LVEF but, as assessed in this trial, do not predict CHF.

Expert Consensus for Multimodality Imaging Evaluation of Adult Patients during and after Cancer Therapy: A Report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging

“…Furthermore, a value .30 pg/mL was associated with specificity of 73% and negative predictive value of 77% for subsequent CTRCD. In contrast, Morris et al 179 demonstrated that TnI increases in patients receiving both trastuzumab and the tyrosine kinase inhibitor lapatinib were common, occurring in 67% of individuals; these elevations were not associated with subsequent CTRCD as detected by serial MUGA scans. Schmidinger et al 180 also reported an increase in troponin T in 10%…”

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

“…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. Additionally, optimal timing and frequency of measurement as well as the ideal cutoff have not yet been determined.…”

Early Detection and Prediction of Cardiotoxicity - Biomarker and Echocardiographic Evaluation

“…In prospective study including ninety-five patients with breast cancer treated with dose-dense doxorubicin and cyclophosphamide, than weekly paclitaxel with trastuzumab and lapatinib, the levels of Creactive protein were measured every 2 weeks during chemotherapy then at months 6, 9 and 18. During chemotherapy a detectable C-reactive protein was seen in 78% but did not correlate with ejection fraction declines (Morris et al, 2010).…”