ABSTRACT
BACKGROUND: The cardiac safety of trastuzumab concurrent with pegylated liposomal doxorubicin (PLD) in an adjuvant breast cancer treatment regimen is unknown. PATIENTS AND METHODS: Women with resected node-positive or intermediate-risk node-negative HER2 overexpressing breast cancer and baseline left ventricular ejection fraction (LVEF)≥55% were randomized (1:2) to doxorubicin 60 mg/m2 (A)+cyclophosphamide 600 mg/m2 (C) every 21 days (q21d) for four cycles or PLD 35 mg/m2+C q21d+trastuzumab 2 mg/kg weekly (H) for 12 weeks. Both groups then received paclitaxel (Taxol, T) 80 mg/m2 with H for 12 weeks followed by H to complete 1 year. The primary end point was cardiac event rate or inability to administer 1 year of trastuzumab. RESULTS: Of 181 randomized patients, 179 underwent cardiac analysis. The incidence of cardiac toxicity or inability to administer trastuzumab due to cardiotoxicity was 18.6% [n=11; 95% confidence interval (CI) 9.7% to 30.9%] with A+CâT+H and 4.2% (n=5; 95% CI 1.4% to 9.5%) with PLD+C+HâT+H (P=0.0036). All events, except one, were asymptomatic systolic dysfunction or mildly symptomatic heart failure. Mean absolute LVEF reduction at cycle 8 was greater with doxorubicin (5.6% versus 2.1%; P=0.0014). CONCLUSION: PLD+C+HâT+H is feasible and results in lower early cardiotoxicity rates compared with A+CâT+H.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Heart Diseases/chemically induced , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Chemotherapy, Adjuvant , Doxorubicin/administration & dosage , Doxorubicin/analogs & derivatives , Female , Humans , Middle Aged , Polyethylene Glycols/administration & dosage , Stroke Volume/drug effects , Trastuzumab , Ventricular Function, Left/drug effects , Young AdultABSTRACT
Using the polymerase chain reaction and Southern blot analysis the expression was detected of a bcr-abl mRNA lacking abl exon a2. This was due to a corresponding unusual localization of the breakpoint in the c-abl gene and was seen in a patient with Philadelphia (Ph) chromosome positive chronic myelogeneous leukemia in chronic phase. This type of mRNA has been described only once before in two Ph-positive acute lymphoblastic leukemia patients, by Soekarman et al. (1). The abl exon a2 sequences, which are missing in the three reported patients, code for a part of the SH3 region of the abl protein, which is supposed to be involved in negative regulation of the kinase domain. The clinical significance of this finding is discussed.