Normal cardiac biopsy results following co-administration of doxorubicin (A), Cyclophosphamide (C) and trastuzumab (H) to women with HER2 positive metastatic breast cancer

Abstract

572 Background: Trastuzumab (Herceptin, H) extends overall survival when administered with chemotherapy (CT) to patients (pts) with HER2+ metastatic breast cancer (MBC). An increase in cardiac dysfunction (CD) was seen in pts who received H + CT (paclitaxel or AC) in a phase III study. The mechanism by which H contributes to CD may include a pharmacokinetic (PK) interaction or increased cardiac sensitivity to A. This phase I study evaluated the PK of A, C, and H; the utility of CD monitoring by LVEF (echocardiogram (EC)/nuclear multigated cardiac scan (NCS)), by cardiac biopsy, and cardiac serum marker surveillance. Methods: Inclusion criteria: ages 18–60, no prior internal mammary/mediastinal XRT, no prior A or prior CT for HER2+ MBC. Pts received weekly H (4mg/kg load, 2mg/kg weekly) with AC (60/600) q3w x 6. Cardiac evaluations included physical examination, LVEF, and cardiac biopsy after C4 and/or at s/sx of CD. Biopsies were graded using published methods. Plasma for cardiac markers and PK was obtained. Results: 10 pts were enrolled. Median age: 43 years (range 29–55); Patients received a median of 35 H doses and a median A dose of 360 mg/m2 (range 240–360 mg/m2). The med baseline LVEF by EC was 63.5% (range, 57% - 70%) and 62%,65%,61%,60%,57%,53% at weeks 4,7,10,13,16,22, respectively. These results were confirmed by NCS. Cardiac biopsies (n=10) were grade 0 (no cardiac abnormalities) following C4. Two pts had CD (NYHA, grade II n=1, IV n=1) that was not predicted by prior LVEF results, and one asymptomatic LVEF decline from baseline ≥ 20%.(76% to 48%). Cardiac function normalized in all patients. There were no cardiac deaths. Cardiac marker and PK results will also be presented. The ORR was 100% (1 CR, 9 PR). Conclusion: The lack of significant cardiac biopsy findings coupled with some clinical evidence of short-lasting cardiac dysfunction established that the mechanism of CD from AC+H is different from anthracycline-induced CD. These findings may help explain the different clinical course when CD follows H treatment. 10 add'l pts will enroll and receive A over 72hrs Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech; Pfizer Genentech Bristol-Myers Squibb; Genentech Genentech