Biomarkers in melanoma

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Abstract

Biomarkers are tumour- or host-related factors that correlate with tumour biological behaviour and patient prognosis. High-throughput analytical techniques—DNA and RNA microarrays—have identified numerous possible biomarkers, but their relevance to melanoma progression, clinical outcome and the selection of optimal treatment strategies still needs to be established. The review discusses a possible molecular basis for predictive tissue biomarkers such as melanoma thickness, ulceration and mitotic activity, and provides a list of promising new biomarkers identified from tissue microarrays that needs confirmation by independent, prospectively collected clinical data sets. In addition, common predictive serum biomarkers—lactate dehydrogenase, S100B and melanoma-inhibiting activity—as well as selected investigational serum biomarkers such as TA90IC and YKL-40 are also reviewed. A more accurate, therapeutically predictive classification of human melanomas and selection of patient populations that would profit from therapeutic interventions are among the major challenges expected to be addressed in the future.

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Most cited references 69

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Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma.

M Mihm, N Cascinelli, M Atkins … (2001)

To revise the staging system for cutaneous melanoma under the auspices of the American Joint Committee on Cancer (AJCC). The prognostic factors analysis described in the companion publication (this issue), as well as evidence from the published literature, was used to assemble the tumor-node-metastasis criteria and stage grouping for the melanoma staging system. Major changes include (1) melanoma thickness and ulceration but not level of invasion to be used in the T category (except for T1 melanomas); (2) the number of metastatic lymph nodes rather than their gross dimensions and the delineation of clinically occult (ie, microscopic) versus clinically apparent (ie, macroscopic) nodal metastases to be used in the N category; (3) the site of distant metastases and the presence of elevated serum lactic dehydrogenase to be used in the M category; (4) an upstaging of all patients with stage I, II, and III disease when a primary melanoma is ulcerated; (5) a merging of satellite metastases around a primary melanoma and in-transit metastases into a single staging entity that is grouped into stage III disease; and (6) a new convention for defining clinical and pathologic staging so as to take into account the staging information gained from intraoperative lymphatic mapping and sentinel node biopsy. This revision will become official with publication of the sixth edition of the AJCC Cancer Staging Manual in the year 2002.

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Gene expression profiling of primary cutaneous melanoma and clinical outcome.

, Stefan Michiels, Digna van Schaik … (2006)

Gene expression profiling data for human primary cutaneous melanomas are scarce because of the lack of retrospective collections of frozen tumors. To identify differentially expressed genes that may be involved in melanoma progression and prognosis, we investigated the relationship between gene expression profiles and clinical outcome in a cohort of patients with primary melanoma. Labeled complementary RNA (cRNA) from each tissue sample was hybridized to a pangenomic 44K 60-mer oligonucleotide microarray. Class comparison and class prediction analyses were performed to identify genes whose expression in primary melanomas was associated with 4-year distant metastasis-free survival among 58 patients with at least 4 years of follow-up, distant metastasis, or death. Results were validated immunohistochemically at the protein level in 176 independent primary melanomas from patients with a median clinical follow-up of 8.5 years. Survival was analyzed with a Cox multivariable model and stratified log-rank test. All statistical tests were two-sided. We identified 254 genes that were associated with distant metastasis-free survival of patients with primary melanoma. These 254 genes include genes involved in activating DNA replication origins, such as minichromosome maintenance genes and geminin. Twenty-three of these genes were studied at the protein level; expression of five (MCM4, P = .002; MCM3, P = .030; MCM6, P = .004; KPNA2, P = .021; and geminin, P = .004) was statistically significantly associated with overall survival in the validation set. In a multivariable Cox model adjusted for tumor thickness, ulceration, age, and sex, expression of MCM4 (hazard ratio [HR] of death = 4.04, 95% confidence interval [CI] = 1.39 to 11.76; P = .010) and MCM6 (HR of death = 7.42, 95% CI = 1.99 to 27.64; P = .003) proteins was still statistically significantly associated with overall survival. We identified 254 genes whose expression was associated with metastatic dissemination of cutaneous melanomas. These genes may shed light on the molecular mechanisms underlying poor prognosis in melanoma patients.

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Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial.

Alexander MM Eggermont, Stefan Suciu, Mario Santinami … (2008)

Any benefit of adjuvant interferon alfa-2b for melanoma could depend on dose and duration of treatment. Our aim was to determine whether pegylated interferon alfa-2b can facilitate prolonged exposure while maintaining tolerability. 1256 patients with resected stage III melanoma were randomly assigned to observation (n=629) or pegylated interferon alfa-2b (n=627) 6 mug/kg per week for 8 weeks (induction) then 3 mug/kg per week (maintenance) for an intended duration of 5 years. Randomisation was stratified for microscopic (N1) versus macroscopic (N2) nodal involvement, number of positive nodes, ulceration and tumour thickness, sex, and centre. Randomisation was done with a minimisation technique. The primary endpoint was recurrence-free survival. Analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00006249. All randomised patients were included in the primary efficacy analysis. 608 patients in the interferon group and 613 patients in the observation group were included in safety analyses. The median length of treatment with pegylated interferon alfa-2b was 12 (IQR 3.8-33.4) months. At 3.8 (3.2-4.2) years median follow-up, 328 recurrence events had occurred in the interferon group compared with 368 in the observation group (hazard ratio 0.82, 95% CI 0.71-0.96; p=0.01); the 4-year rate of recurrence-free survival was 45.6% (SE 2.2) in the interferon group and 38.9% (2.2) in the observation group. There was no difference in overall survival between the groups. Grade 3 adverse events occurred in 246 (40%) patients in the interferon group and 60 (10%) in the observation group; grade 4 adverse events occurred in 32 (5%) patients in the interferon group and 14 (2%) in the observation group. In the interferon group, the most common grade 3 or 4 adverse events were fatigue (97 patients, 16%), hepatotoxicity (66, 11%), and depression (39, 6%). Treatment with pegylated interferon alfa-2b was discontinued because of toxicity in 191 (31%) patients. Adjuvant pegylated interferon alfa-2b for stage III melanoma has a significant, sustained effect on recurrence-free survival.

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Author and article information

Journal

Journal ID (nlm-ta): Ann Oncol

Journal ID (hwp): annonc

Journal ID (publisher-id): annonc

Title: Annals of Oncology

Publisher: Oxford University Press

ISSN (Print): 0923-7534

ISSN (Electronic): 1569-8041

Publication date (Print and electronic): August 2009

Publication date (Print): August 2009

Publication date PMC-release: August 2009

Volume: 20

Issue: suppl_6 , Melanoma: Perspectives of the Global Melanoma Task Force

Pages: vi8-vi13

Affiliations

[1 ]First Department of Medicine, Medical School, University of Athens, Greece

[2 ]Department of Surgical Oncology, Erasmus University Medical Center–Daniel den Hoed Cancer Center, Rotterdam, The Netherlands

[3 ]Department of Dermatology, University of Kiel, Kiel, Germany

[4 ]Immunology and Oncology Unit, Calvary Mater Newcastle Hospital, New South Wales, Australia

[5 ]Department of Dermatology, Elbe-Klinikum Buxtehude, Buxtehude, Germany

[6 ]Department of Dermatology, University Hospital Essen, Essen, Germany

[7 ]Department of Pathology, Sir Mortimer B. Davis Jewish General Hospital and McGill University, Montreal, Canada

[8 ]Department of Dermatology, University of Zürich Hospital, Zürich, Switzerland

Author notes

[* ] Correspondence to: Helen Gogas, Assistant Professor of Medical Oncology, First Department of Medicine, University of Athens Medical School, 24 Karneadou STR, Athens, 10675, Greece; Tel: +30-6944681159; Fax: +30-2107781517; E-mail: hgogas@ 123456hol.gr

Article

DOI: 10.1093/annonc/mdp251

PMC ID: 2712589

PubMed ID: 19617299

SO-VID: 0e404f95-66a0-4650-80cb-4abe16711fbe

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Biomarkers in melanoma

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Journal of Circulating Biomarkers

Most cited references 69

Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma.

Gene expression profiling of primary cutaneous melanoma and clinical outcome.

Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial.

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