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Journal of Clinical Oncology, Vol 25, No 9 (March 20), 2007: pp. 1140-1141 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.1538
What Is the Role of Sequential Reverse-Transcriptase Polymerase Chain Reaction Analysis of Melanoma-Specific mRNA in the Peripheral Blood of Melanoma Patients?Department of Biomedical Sciences and Human Oncology, Section of Dermatologic Oncology, University of Turin, Turin, Italy
Department of Genetics, Biology, and Biochemistry, University of Turin, Turin, Italy
Department of Public Health and Microbiology, University of Turin, Turin, Italy To the Editor: We read with great interest the article by Scoggins et al1 that reports the results obtained by reverse-transcriptase polymerase chain reaction (RT-PCR) analysis of melanoma-specific mRNA detected on both sentinel lymph node (SLN) biopsies and peripheral blood mononuclear cells (PBMCs) in patients included in the Sunbelt Melanoma Trial. In particular, RT-PCR analyses using four markers (tyrosinase, MART1, MAGE3, and GP-100) were performed on PBMCs to detect occult melanoma cells in a very large number of patients (n = 820) both at study entry and during follow-up (3 months after surgery and annually thereafter). The results appear to exclude a prognostic relevance of RT-PCR on peripheral blood. There were no differences in disease-free survival (DFS), distant disease-free survival, and overall survival (OS) rates when comparing patients with at least one positive marker at any time during follow-up and patients with markers that were always negative; only patients with more than one RT-PCR marker in the peripheral blood showed a significantly lower DFS and distant disease-free survival, but not OS, with respect to the others. It would be of great interest, in our opinion, to evaluate RT-PCR results in peripheral blood according to the disease stage, thus separating SLN-negative stage II patients from SLN-positive stage III patients. Indeed, according to the data reported by Scoggins et al in their Table 2,1 SLN status defined by using standard hematoxylin/eosin and immunohistochemistry is associated with significant differences in PBMC RT-PCR expression in as much as the percentage of SLN-positive patients was significantly higher in the RT-PCR–positive group (36%) than in the RT-PCR–negative group (24%; P = .006). Actually, literature data failed to demonstrate a prognostic relevance of RT-PCR (tyrosinase in the majority of cases) in stage I-II patients.2 In contrast, the majority of studies that analyzed tyrosinase expression in the peripheral blood using sequential determinations at set intervals during the follow-up of stage III patients demonstrated by means of multivariate analysis that the finding of at least one RT-PCR tyrosinase-positive determination carries an adverse independent prognostic significance (reviewed in Quaglino et al3). This is in contrast with the results obtained from single tyrosinase determination studies, the majority of which failed to demonstrate a prognostic significance of the RT-PCR assay.4 Moreover, it would also be interesting to analyze baseline and follow-up data separately. In fact, in our experience studying 110 stage III patients, the baseline expression of tyrosinase RT-PCR was not associated with significant differences in DFS; in contrast, the finding of at least one positive sample at any time during follow-up was found to play an independent adverse prognostic relevance together with Breslow thickness of the primary and lymph node involvement according to the American Joint Committee on Cancer classification.5 Finally, from a statistical point of view, it is important to point out that as RT-PCR positivity occurs at a certain time during the follow-up, the sequential RT-PCR results need to be included in the multivariate analysis model as a time-dependent covariate. Scoggins et al1 state that a variable measuring the time elapsed from study entry until the first positive sample was added to the Cox model and found to be significant, but no further data are reported. The results reported by Voit et al6 in a cohort of 111 patients with stage II-III melanoma who were observed over a long period of time (median, 6.3 years), with blood samples taken every 3 to 6 months, confirmed time-dependent tyrosinase RT-PCR as a significant prognostic variable for DFS with a hazard ratio of 15.8. In our study, multivariate analysis achieved an even higher significance in a cohort of 127 stage III patients (Table 1): the Cox regression analysis selected the time-dependent covariate RT-PCR tyrosinase as the only significant variable among a series of variables that included sex, age, Breslow thickness of the primary, ulceration, and American Joint Committee on Cancer stage (IIIA, IIIB, IIIC), with an unexpectedly high risk ratio of 23.07 (95% CI, 12.8 to 41.5).
It is our opinion that this topic deserves careful analysis and broad discussion for both its clinical and biologic implications. Therefore, the large series of patients included and studied by Scoggins et al1 gives a unique opportunity to reach more insight into the prognostic relevance of RT-PCR analysis during the follow-up of melanoma patients. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The authors indicated no potential conflicts of interest.
REFERENCES
1. Scoggins CR, Ross MI, Reitgen DS, et al: Prospective multi-institutional study of reverse transcriptase polymerase chain reaction for molecular staging of melanoma. J Clin Oncol 24:2849-2857, 2006 2. Schmidt H, Sorensen BS, Sjoegren P, et al: Circulating tyrosinase and MART-1 mRNA does not independently predict relapse or survival in patients with AJCC stage I-II melanoma. J Invest Dermatol 126:849-854, 2006[CrossRef][Medline] 3. Quaglino P, Savoia P, Osella-Abate S, et al: RT-PCR tyrosinase expression in the peripheral blood of melanoma patients: From research bench to clinical practice. Expert Rev Mol Diagn 4:727-741, 2004[CrossRef][Medline] 4. Palmieri G, Ascierto PA, Perrone F, et al: Prognostic value of circulating melanoma cells detected by reverse transcriptase-polymerase chain reaction. J Clin Oncol 21:767-773, 2003 5. Osella-Abate S, Savoia P, Quaglino P, et al: Tyrosinase expression in the peripheral blood of stage III melanoma patients is associated with a poor prognosis: A clinical follow-up study of 110 patients. Br J Cancer 89:1457-1462, 2003[CrossRef][Medline] 6. Voit C, Kron M, Rademaker J, et al: Molecular staging in stage II and III melanoma patients and its effect on long-term survival. J Clin Oncol 23:1218-1227, 2005 Related Reply
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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