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Cluster Analysis of p53 and Ki67 Expression, Apoptosis, Alpha-Fetoprotein, and Human Chorionic Gonadotrophin Indicates a Favorable Prognostic Subgroup Within the Embryonal Carcinoma Germ Cell Tumor

Madhu Mazumdar, Jennifer Bacik, Satish K. Tickoo, Deborah Dobrzynski, Alessia Donadio, Dean Bajorin, Robert Motzer, Victor Reuter, George J. Bosl

From the Department of Epidemiology and Biostatistics, the Genitourinary Oncology Service, Division of Solid Tumor Oncology, and Department of Pathology, Memorial Sloan-Kettering Cancer Center; and Departments of Medicine and Pathology, Weill Medical College, Cornell University, New York, NY.

Address reprint requests to Madhu Mazumdar, PhD, Memorial Sloan-Kettering Cancer Center, 307 E 63rd St, 3rd Floor, New York, NY 10021; email: mazumdar{at}biost.mskcc.org.

Purpose: The prognostic information provided by alpha-fetoprotein and human chorionic gonadotrophin in the management of germ cell tumor (GCT) patients is a biochemical reflection of tumor differentiation. Ki67, p53, and apoptosis have been found to be related to proliferation (Ki67), cell death (p53, apoptosis), and possibly differentiation chemoresistance (p53). We sought to determine whether simultaneous expression of one or more of these markers could identify clinically relevant subgroups of patients with nonseminomatous GCT (NSGCT).

Patients and Methods: These five marker values were obtained for 95 previously untreated patients with embryonal carcinoma with or without other germ cell components. A multivariate cluster analysis was performed to identify patients with similar marker patterns.

Results: One prominent cluster (n = 37; 36 testis retroperitoneum), consisting of 26 (70%) good-risk (GR), nine (24%) intermediate-risk (IR), and two (6%) poor-risk (PR) patients, as defined by the International Germ Cell Consensus Cancer Group (IGCCCG), was observed. The 5-year survival of the prominent cluster (with 30% IR/PR patients) was 94% (95% confidence interval [CI], 86% to 100%), which is comparable to the 91% (95% CI, 89% to 93%) 5-year survival of the IGCCCG GR patients. IGCCCG risk status (P = .005) and cluster affiliation (P = .04) were independent predictors of outcome with hazard ratios of 5.0 (95% CI, 1.6 to 15.4) and 4.6 (95% CI, 1.04 to 20.1), respectively.

Conclusion: These results suggest that there is a subgroup of NSGCT patients with embryonal carcinoma (with or without other histologies) with a specific tumor biology profile (high Ki67, low apoptosis, and low p53) whose survival is better than that of the overall patient group. The unexpectedly good outcome for the prominent cluster and independent-risk status suggest that subgroups of GCT reflecting different abilities to respond to treatment exist within IGCCCG prognostic categories.

Presented in part at the Thirty-Seventh Annual Meeting of the American Society of Clinical Oncology, May 2001, San Francisco, CA.

Supported in part by the National Institutes of Health grants CA05826 and CA60126, and the Byrne Foundation.

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