Trastuzumab and cardiac dysfunction: update on preclinical studies.

Trastuzumab, a humanized, recombinant antibody directed against HER2, can significantly improve survival in women with HER2-positive metastatic breast cancer. Treatment with trastuzumab has been associated with cardiac toxicity, most commonly manifested as asymptomatic decreases in left ventricular ejection fraction on multiple gated acquisition scans. These asymptomatic decreases appear to be reversible, and their clinical significance is not well understood. Fortunately, studies are beginning to show that the majority of women with decreases in left ventricular ejection fraction never develop clinical evidence of cardiac dysfunction. Although cardiotoxicity has been difficult to study, in part because of the small number of actual clinical events, preliminary evidence appears to indicate that the mechanism of trastuzumab-related cardiotoxicity is different than that induced by anthracyclines. The development of animal models may yield further understanding of the mechanism(s) of trastuzumab-associated cardiac dysfunction, and may provide a focus for clinical trials of treatment or prevention. Current investigations with rodent and primate models of cardiac dysfunction are briefly discussed in this article.

Prognostic value of thymidylate synthase, Ki-67, and p53 in patients with Dukes' B and C colon cancer: a National Cancer Institute-National Surgical Adjuvant Breast and Bowel Project collaborative study.

PURPOSE: To define the value of thymidylate synthase (TS), Ki-67, and p53 as prognostic markers in patients with stage II and III colon carcinoma. PATIENTS AND METHODS: We retrospectively analyzed the prognostic value of TS, Ki-67, and p53 in 706 patients with Dukes' B (291 patients) or Dukes' C (415 patients) colon carcinoma who were treated with either surgery alone (275 patients) or surgery plus fluorouracil (FU)-leucovorin chemotherapy (431 patients) in National Surgical Adjuvant Breast and Bowel Project (NSABP) protocols C01-C04. All three markers were assayed using immunohistochemical techniques. RESULTS: Using 5 years of follow-up data, our retrospective analysis demonstrated an association between TS intensity (relapse-free survival [RFS]: risk ratio [RR] = 1.46, P =.01; overall survival [OS]: RR = 1.54, P =.002), Ki-67 (RFS: RR = 0.76, P =.05; OS: RR = 0.62, P =.001), and p53 (RFS: RR = 1.49, P =.01; OS: RR = 1.21, P =.18) for RFS and OS. High TS intensity levels and positive p53 staining were associated with a worse outcome. Tumors containing a high percentage of Ki-67-positive cells enjoyed an improved outcome compared with those patients whose tumors contained relatively few positive cells. An interaction with treatment was not identified for any of the markers. CONCLUSION: This retrospective investigation demonstrated that TS, Ki-67, and p53 staining each had significant prognostic value for patients with Dukes' B and C colon carcinoma. However, none of the markers could be used to clearly discern groups of individuals who would be predicted to derive greater or lesser benefit from the use of adjuvant chemotherapy.