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Originally published as JCO Early Release 10.1200/JCO.2003.11.020 on January 3 2003 © 2003 American Society for Clinical Oncology
The Prognostic Role of Detection of Circulating Melanoma Cells in the Blood
Our Lady of Mercy Cancer Center, Bronx, NY CIRCULATING MALIGNANT cells have been detected in the blood of patients diagnosed with a variety of solid tumors, not only in breast and prostate cancer, but in other cancers as well.1–3 Methodologic questions continue to be raised regarding the reliability of reverse transcriptase polymerase chain reaction (RT-PCR) techniques compared with immunohistochemistry (IHC) for the detection of such cells, and the reliability of RT-PCR continues to be debated.4,5 The prognostic significance of circulating malignant cells in patients with solid tumors in various stages continues to be evaluated, but at the least, it is a demonstration of systemic disease. The goal of detection of circulating cancer cells is to identify either an earlier marker of disease progression or a sign of more aggressive disease that might change treatment options. Therefore, studies of the early stages of cancer are evaluating the correlation between circulating cells and risk of relapse or time to relapse, whereas those studying patients with advanced disease (either locally advanced or metastatic) seek correlation with overall survival.6 Similar questions are being asked in studies of early- and late- stage melanoma, in which the presence of circulating melanoma cells has been detected using RT-PCR techniques, demonstrating minuscule numbers of cells that express one or more of several melanoma-associated markers. Questions regarding the use of a single marker compared with a composite of several markers continue to be asked. Debates on the optimal techniques of analysis also continue, as they do in the discussion of breast and prostate cancer.7,8 Many studies evaluate the single marker, tyrosinase,7,9–14 and others, including the article in this issue, evaluate a composite score of several markers (melanA/MART 1 or p97).15,16 The prognostic import of the presence of circulating melanoma cells (CMCs) continues to be debated, however.7,13,14,16,17 Studies evaluating their presence at the time of diagnosis and staging indicate that they have clinical relevance, but whether this is an important prognostic factor independent of other clinical prognostic factors remains to be determined.7,9,13,14,16,17 In the current study by Palmieri et al,16 patients initially diagnosed with melanoma underwent evaluation of blood samples for markers of CMCs, using the RT-PCR technique. They used three markers in an additive fashion to detect such cells (tyrosinase, MART 1, and p97). In their study, and in five additional studies, using multivariate analysis, the presence of CMCs correlated with initial stage of disease, a prognostic factor known to correlate with time to recurrence and overall survival.14,17–20 Thus, in these studies, the presence of CMCs appeared to be a surrogate for clinical staging. Other studies have indicated a possible independent role for CMC in prognosing disease-free and overall survival.9,15,21–24 However, in these studies, multivariate analysis, which could have assessed interaction among prognostic factors, was not performed. Therefore, an interaction with stage in these studies could not be determined. Evaluation of these studies indicates that whereas the detection of circulating melanoma cells at the time of diagnosis may be a harbinger of the subsequent development of metastatic disease, it may also simply reflect the stage of disease at diagnosis. Recently, a revision of the staging of melanoma has been published that has an effect on the definitions of the early stages of disease, with an effort to better predict survival groups.25 It is important that the distinction between clinical and micrometastatic evidence of nodal disease has been made. The presence or absence of CMCs will need to be further evaluated in the context of the new staging to reassess its role as an independent or a covariate prognostic factor. At present, stage of disease remains the overriding prognostic factor.25 Mellado et al26 have recently addressed the effect of CMCs in quite a different way, evaluating patients with more advanced disease (stages IIA-IV), using RT-PCR for tyrosinase as a marker of cells in the blood. All of these patients were considered candidates for systemic therapy because of the extent of their disease. The study goal was to determine whether a change in CMCs during interferon therapy (becoming negative) predicted a better outcome with therapy. In their study, before interferon therapy, 18% of patients demonstrated CMCs and 82% were negative in the blood for tyrosinase-containing cells. During interferon therapy, 36% were positive and 64% were negative for tyrosinase. In multivariate analysis, stage of disease was prognostic, and dose of interferon used was determined by stage, in that patients with a more advanced stage were treated with high-dose interferon. However, the absence of CMCs during interferon therapy was significantly associated with improved disease-free survival (DFS), in that the median DFS was not reached among the group that had negative RT-PCR during interferon therapy, whereas those patients who remained or became positive had a median DFS of 20 months. Actuarial survival was also improved for the RT-PCR negative group (5-year DFS, 62% for CMC-negative v 38% for CMC-positive patients). The authors concluded that those who became or remained negative for CMCs during therapy demonstrated a better prognosis than those who remained or became positive during therapy.26 This was a more dynamic study of the change in status throughout treatment, and although stage was an important prognostic factor, the change in CMC status was also prognostic.22,26 The authors also suggest that eradication of CMCs was more likely in those patients treated with high-dose interferon, which could have an effect on prognosis. This hypothesis deserves further prospective evaluation. In the other studies cited, the effect of treatment on CMCs was not addressed.12–16 In summary, the clinical and prognostic role of detection of CMCs in melanoma remains controversial. It does not appear from two recently published studies16,26 and from several additional studies in the literature that the use of multiple markers over the use of tyrosinase alone improves detection.18,23,24 In the majority of published studies that make use of multivariate analysis, the strongest correlation of CMCs is with stage at diagnosis, rather than as an independent prognostic factor. A reanalysis of these data using the recently published revised staging system should be encouraged, to evaluate the presence of CMCs in the setting of micro- versus macro-nodal metastases. At present, an independent prognostic role for the detection of CMCs is yet to be defined, and therefore, its general use is not warranted. Whether the detection of CMCs should direct treatment in patients undergoing adjuvant therapy, has not yet been determined. If the results reported by Mellado et al26 are observed by other investigators, it is possible that detection of CMC could direct selection of high-risk patients for high-dose interferon therapy. Whether an interaction of interferon treatment and CMCs exists is an interesting thesis and deserves further investigation. Of interest, in the recent Eastern Cooperative Oncology Group studies of adjuvant interferon therapy, the patients who appeared to derive the greatest benefit from interferon in delay of recurrence were those with nodal disease.27 These patients might be more likely to demonstrate CMCs as well. Why they might be more responsive to interferon therapy remains to be determined, and whether the status of CMCs changed with therapy was not investigated. Therefore, studies of CMCs, prospectively correlated with response to treatment in either the adjuvant or advanced setting, are of interest. REFERENCES 1. Klein CA, Blankenstein TJ, Schmidt-Kittler O, et al: Genetic heterogeneity of single disseminated tumour cells in minimal residual disease. Lancet 360:683–689, 2002[CrossRef][Medline]
2. Solakoglu O, Maierhofer C, Lahr G, et al: Heterogeneous proliferative potential of occult metastatic cells in bone marrow of patients with solid epithelial tumors. Proc Natl Acad Sci U S A 99:2246–2251, 2002
3. Ylikoski A, Pettersson K, Nurmi J, et al: Simultaneous quantification of prostate-specific antigen and human glandular kallikrein 2 mRNA in blood samples from patients with prostate cancer and benign disease. Clin Chem 48:1265–1271, 2002 4. Llanes L, Ferruelo A, Paez A, et al: The clinical utility of the prostate specific membrane antigen reverse-transcription/polymerase chain reaction to detect circulating prostate cells: An analysis in healthy men and women. Br J Urol Int 89:882–885, 2002 5. Ghossein RA, Bhattacharya S: Molecular detection and characterization of ciculating tumor cells and micrometastases in prostatic, urothelial and renal cell carcinomas. Semin Surg Oncol 20:304–311, 2001[CrossRef][Medline] 6. Janni W, Rjosk D, Braun S: Clinical relevance of occult metastatic cells in the bone marrow of patients with different stages of breast cancer. Clin Breast Cancer 1:217–225, 2000[Medline] 7. Glaser R, Rass K, Seiter S, et al: Detection of circulating melanoma cells by specific amplification of tyrosinase complementary DNA is not a reliable tumor marker in melanoma patients: A clinical two-center study. J Clin Oncol 15:2818–2825, 1997[Abstract] 8. Keilholz U: Diagnostic PCR in melanoma, methods and quality assurance. Epalinges, Switzerland, 26/27 January 1996. Eur J Cancer 32A:1661–1663, 1996[CrossRef]
9. Kunter U, Buer J, Probst M, et al: Peripheral blood tyrosinase messenger RNA detection and survival in metastatic melanoma. J Natl Cancer Inst 88:590–594, 1996 10. Stevens GL, Scheer WD, Levine EA: Detection of tyrosinase mRNA from the blood of melanoma patients. Cancer Epidemiol Biomarkers Prev 5:293–296, 1996[Abstract]
11. Pittman K, Burchill S, Smith B, et al: Reverse transcriptase-polymerase chain reaction for expression of tyrosinase to identify malignant melanoma cells in peripheral blood. Ann Oncol 7:297–301, 1996 12. Jung FA, Buzaid AC, Ross MI, et al: Evaluation of tyrosinase mRNA as a tumor marker in the blood of melanoma patients. J Clin Oncol 15:2826–2831, 1997[Abstract] 13. Reinhold U, Ludtke Handjery HC, Schnautz S, et al: The analysis of tyrosinase specific mRNA in blood samples of melanoma patients by RT-PCR in not a useful test for metastatic tumor progression. J Invest Dermatol 108:166–169, 1997[CrossRef][Medline] 14. Aubin F, Chtourou M, Teyssier JR, et al: The detection of tyrosinase mRNA in the peripheral blood of stage I melanoma patients is not of clinical relevance in predicting metastasis risk and survival. Melanoma Res 10:113–118, 2000[Medline]
15. Hoon DSB, Wang Y, Dale PS, et al: Detection of occult melanoma cells in blood with a multiple-marker polymerase chain reaction assay. J Clin Oncol 13:2109–2116, 1995
16. 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
17. Palmieri G, Strazzullo M, Ascierto PA, et al: Polymerase chain reaction-based detection of circulating melanoma cells as an effective marker of tumor progresison. J Clin Oncol 17:304–311, 1999 18. Brownbridge GG, Gold J, Edward M, Mackie RM: Evaluation of the use of tyrosinase-specific and melanA/MART-1-specific reverse transcriptase-coupled-polymerase chain reaction to detect melanoma cells in peripheral blood samples from 299 patients with malignant melanoma. Br J Dermatol 144:279–287, 2001[CrossRef][Medline] 19. Waldman V, Wacker J, Deichmann M, et al: Prognosis of metastatic melanoma: No correlation of tyrosinase mRNA in bone marrow and survival time. Recent Result Cancer Res 158:118–125, 2001[Medline] 20. Strohal R, Mosser R, Kittler H, et al: MART-1/Melan-AS and tyrosinase transcripts in peripheral blood of melanoma patients: PCR analyses and follow-up testing in relation to clinical stage and disease progression. Melanoma Res 11:543–548, 2001[CrossRef][Medline] 21. Curry BJ, Myers K, Hersey P: Polymerase chain reaction detection of melanoma cells in the circulation: Relation to clinical stage, surgical treatment, and recurrence from melanoma. J Clin Oncol 15:1760–1769, 1998
22. Mellado B, Gutierrez L, Castel T, et al: Prognostic significance of the detection of circulating malignant cells by reverse transcriptive-polymerase chain reaction in long-term clinically disease-free melanoma patients. Clin Cancer Res 5:1843–1848, 1999 23. Schittek B, Bodingbauer Y, Ellwanger U, et al: Amplification of MelanA messenger RNA in addition to tyrosinase increases sensitivity of melanoma cell detection in peripheral blood and is associated with the clinical stage and prognosis of malignant melanoma. Br J Dermatol 141:30–36, 1999[CrossRef][Medline] 24. Schrader AJ, Probst-Kepper M, Grosse J, et al: Molecular and prognostic classification of advanced melanoma: A multi-marker microcontamination assay of peripheral blood stem cells. Melanoma Res 10:355–362, 2000[CrossRef][Medline]
25. Balch CM, Buzaid AC, Soong S-J, et al: Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 19:3635–3648, 2001
26. Mellado B, del Carmen Vela M, Gutierrez L, et al: Tyrosinase mRNA in blood of patients with melanoma treated with adjuvant interferon. J Clin Oncol 20:4032–4039, 2002 27. Dutcher JP, Kirkwood JM: Efficacy of high dose interferon as adjuvant therapy in high risk melanoma: Overview of ECOG studies 1684 and 1690. Symposium on Melanoma, Ruhr-University, Bochum In Zeitschrift fur Hautkrankh, H+G 4:220–223, 2000
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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