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Molecular Load of Pathologically Occult Metastases in Pelvic Lymph Nodes Is an Independent Prognostic Marker of Biochemical Failure After Localized Prostate Cancer Treatment

Anna C. Ferrari, Nelson N. Stone, Ralf Kurek, Elizabeth Mulligan, Roy McGregor, Richard Stock, Pamela Unger, Ulf Tunn, Amir Kaisary, Michael Droller, Simon Hall, Heiner Renneberg, Kenneth J. Livak, Robert E. Gallagher, John Mandeli

From the New York University Cancer Institute; Mount Sinai School of Medicine, New York; Albert Einstein Cancer Center, Bronx, NY; Stadtische Kliniken, Offenbach, Germany; Royal Free Hospital, London, United Kingdom; and Applied Biosystems Inc, Foster City, CA

Address reprint requests to Anna C. Ferrari, MD, New York University Cancer Institute, New York University Medical School, 160 E 34th St, 8th Floor, New York, NY 10016; e-mail: anna.ferrari{at}nyumc.org

PURPOSE: Thirty percent of patients treated with curative intent for localized prostate cancer (PC) experience biochemical recurrence (BCR) with rising serum prostate-specific antigen (sPSA), and of these, approximately 50% succumb to progressive disease. More discriminatory staging procedures are needed to identify occult micrometastases that spawn BCR.

PATIENTS AND METHODS: PSA mRNA copies in pathologically normal pelvic lymph nodes (N0-PLN) from 341 localized PC patients were quantified by real-time reverse-transcriptase polymerase chain reaction. Based on comparisons with normal lymph nodes and PLN with metastases and on normalization to 5 x 10⁶ glyceraldehyde-3'-phosphate dehydrogenase mRNA copies, normalized PSA copies (PSA-N) and a threshold of PSA-N 100 or more were selected for continuous and categorical multivariate analyses of biochemical failure-free survival (BFFS) compared with established risk factors.

RESULTS: At median follow-up of 4 years, the BFFS of patients with PSA-N 100 or more versus PSA-N less than 100 was 55% and 77% (P = .0002), respectively. The effect was greatest for sPSA greater than 20 ng/mL, 25% versus 60% (P = .014), Gleason score 8 or higher, 21% versus 66% (P = .0002), stage T3c, 18% versus 64% (P = .001), and high-risk group (50% v 72%; P = .05). By continuous analysis PSA-N was an independent prognostic marker for BCR (P = .049) with a hazard ratio of 1.25 (95% CI, 1.001 to 1.57). By categorical analysis, PSA-N 100 or more was an independent variable (P = .021) with a relative risk of 1.98 (95% CI, 1.11 to 3.55) for BCR compared with PSA-N less than 100.

CONCLUSION: PSA-N 100 or more is a new, independent molecular staging criterion for localized PC that identifies high-risk group patients with clinically relevant occult micrometastases in N0-PLN, who may benefit from additional therapy to prevent BCR.

Supported by United States Public Health Service research Grants No. CA9813501 (A.C.F), CA86794 (R.E.G.), and the T.J. Martell Foundation for Cancer Leukemia and AIDS Research (A.C.F.).

Presented in part at the 40th Annual Meeting of American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004, and in an oral presentation at the American Society of Clinical Oncology, Prostate Cancer Symposium, Orlando, FL, February 17-19, 2005.

Authors' disclosures of potential con- flicts of interest and author contributions are found at the end of this article.

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