Final Version of 2009 AJCC Melanoma Staging and Classification

Erasmus Universiteit Rotterdam, Rotterdam, South Holland, Netherlands
Journal of Clinical Oncology (Impact Factor: 18.43). 11/2009; 27(36):6199-206. DOI: 10.1200/JCO.2009.23.4799
Source: PubMed


To revise the staging system for cutaneous melanoma on the basis of data from an expanded American Joint Committee on Cancer (AJCC) Melanoma Staging Database.
The melanoma staging recommendations were made on the basis of a multivariate analysis of 30,946 patients with stages I, II, and III melanoma and 7,972 patients with stage IV melanoma to revise and clarify TNM classifications and stage grouping criteria.
Findings and new definitions include the following: (1) in patients with localized melanoma, tumor thickness, mitotic rate (histologically defined as mitoses/mm(2)), and ulceration were the most dominant prognostic factors. (2) Mitotic rate replaces level of invasion as a primary criterion for defining T1b melanomas. (3) Among the 3,307 patients with regional metastases, components that defined the N category were the number of metastatic nodes, tumor burden, and ulceration of the primary melanoma. (4) For staging purposes, all patients with microscopic nodal metastases, regardless of extent of tumor burden, are classified as stage III. Micrometastases detected by immunohistochemistry are specifically included. (5) On the basis of a multivariate analysis of patients with distant metastases, the two dominant components in defining the M category continue to be the site of distant metastases (nonvisceral v lung v all other visceral metastatic sites) and an elevated serum lactate dehydrogenase level.
Using an evidence-based approach, revisions to the AJCC melanoma staging system have been made that reflect our improved understanding of this disease. These revisions will be formally incorporated into the seventh edition (2009) of the AJCC Cancer Staging Manual and implemented by early 2010.

    • "Serum LDH is a standardised and simple marker, which is easy to use in the clinic. High LDH is a well-known marker for poor outcome in the era of chemotherapy (Eton et al, 1998;Manola et al, 2000;Agarwala et al, 2009;Balch et al, 2009). We have recently shown that in patients treated with ipilimumab, an increasing baseline LDH—as part of a prognostic score with ECOG performance status and number of involved organs—was independently associated with poor survival (Diem et al, 2015). "
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    ABSTRACT: Background: Treatment with programmed death receptor-1 (PD-1) antibodies is associated with high response rates in patients with advanced melanoma. Reliable markers for early response and outcome are still sparse. Methods: We evaluated 66 consecutive patients with advanced/metastatic melanoma treated with nivolumab or pembrolizumab between 2013 and 2014. The main objectives of this study were to investigate whether, first, serum lactate dehydrogenase (LDH) at baseline (normal vs above the upper limit of normal) correlates with overall survival (OS), and, second, whether the change of LDH during treatment predicts response before the first scan and OS in patients with an elevated baseline LDH. Results: After a median follow-up of 9 months, patients with an elevated baseline LDH (N=34) had a significantly shorter OS compared with patients with normal LDH (N=32; 6-month OS: 60.8% vs 81.6% and 12-month OS: 44.2% vs 71.5% (log-rank P=0.0292). In those 34 patients with elevated baseline LDH, the relative change during treatment was significantly associated with an objective response on the first scan: the 11 (32%) patients with partial remission had a mean reduction of -27.3% from elevated baseline LDH. In contrast, patients with progressive disease (N=15) had a mean increase of +39%. Patients with a relative increase over 10% from elevated baseline LDH had a significantly shorter OS compared with patients with ⩽10% change (4.3 vs 15.7 months, log-rank P<0.00623). Conclusions: LDH could be a useful marker at baseline and during treatment to predict early response or progression in patients with advanced melanoma who receive anti-PD-1 therapy.British Journal of Cancer advance online publication 21 January 2016; doi:10.1038/bjc.2015.467
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    • "Over 74000 new cases and ~10000 deaths due to melanoma are expected in 2015 in the United States (Siegel et al., 2015). Localized melanoma is curable with a 5-year survival of greater than 90% while metastatic melanoma has an extremely poor prognosis with a 5-year survival of about 15% (Balch et al., 2009).After lung and breast cancer, melanoma is the third most common cancer to metastasize to the brain (Gallego Perez-Larraya and Hildebrand, 2014). "
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    ABSTRACT: Small molecule inhibitors targeting the MAPK pathway (Braf/MEK/ERK) have had success in extending survival for metastatic melanoma patients. Unfortunately, resistance may occur via cross-activation of alternate signaling pathways. One approach to overcome resistance is to simultaneously target the PI3K/mTOR signaling pathway. Recent reports have shown that GSK2126458, a dual PI3K/mTOR inhibitor, can overcome acquired resistance to Braf and MEK inhibitors in vitro. These resistance mechanisms may be especially important in melanoma brain metastases because of limited drug delivery across the blood-brain barrier (BBB). The purpose of this study was to investigate factors that influence the brain distribution of GSK2126458 and to examine the efficacy of GSK2126458 in a novel patient-derived melanoma xenograft (PDX) model. Both in vitro and in vivo studies indicate that GSK2126458 is a substrate for P-gp and Bcrp, two dominant active efflux transporters in the BBB. The steady-state brain distribution of GSK2126458 was 8-fold higher in the P-gp/Bcrp knockout mice compared to wild-type. We also observed that when simultaneously infused to steady state, GSK212658, dabrafenib, and trametinib, a rational combination to overcome MAPK inhibitor resistance, all had limited brain distribution. Co-administration of elacridar, a P-gp/Bcrp inhibitor, increased the brain distribution of GSK2126458 by approximately 7-fold in wild-type mice. In the PDX model, GSK2126458 showed efficacy in flank tumors, but was ineffective in intracranial melanoma. These results show that P-gp and Bcrp are involved in limiting the brain distribution of GSK2126458 and provide a rationale for the lack of efficacy of GSK2126458 in the orthotopic PDX model.
    Preview · Article · Nov 2015 · Journal of Pharmacology and Experimental Therapeutics
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    • "However, the majority of identified markers have not been shown to improve the current AJCC staging (Balch et al, 2009), preventing their translation into routine clinical assessment. "
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    ABSTRACT: Background: We previously demonstrated an inverse correlation between tyrosinase-related protein 1 (TYRP1) mRNA expression in melanoma metastases and patient survival. However, TYRP1 protein was not detected in half of tissues expressing mRNA and did not correlate with survival. Based on a study reporting that 3' untranslated region (UTR) of TYRP1 mRNA contains two miR-155-5p (named miR-155) binding sites exhibiting single-nucleotide polymorphisms (SNPs) that promote (matched miRNA-mRNA interaction) mRNA decay or not (mismatched), we aimed to investigate the role of miR-155 in the regulation of TYRP1 mRNA expression and protein translation accounting for these SNPs. Methods: The effect of miR-155 on TYRP1 mRNA/protein expression was evaluated in two melanoma cell lines harbouring matched or mismatched miR-155-TYRP1 mRNA interaction after transfection with pre-miR-155. In parallel, 192 skin and lymph node melanoma metastases were examined for TYRP1 mRNA/protein, miR-155 and SNPs and correlated with patient survival. TYRP1 mRNA, SNPs at its 3'UTR and miR-155 were analysed by RT-qPCR, whereas TYRP1 protein was evaluated by western blot in cell lines and by immunohistochemistry in metastatic tissues. Results: The miR-155 induced a dose-dependent TYRP1 mRNA decay and hampered its translation into protein in the line with the 'match' genotype. In melanoma metastases, TYRP1 mRNA inversely correlated with miR-155 expression but not with TYRP1 protein in the 'match' group, whereas it positively correlated with protein but not with miR-155 in the 'mismatch' group. Consequently, in the latter group, TYRP1 protein inversely correlated with survival. Conclusion: Polymorphisms in 3'UTR of TYRP1 mRNA can affect TYRP1 mRNA regulation by miR-155 and its subsequent translation into protein. These SNPs can render TYRP1 mRNA and protein expression nonsusceptible to miR-155 activity and disclose a prognostic value for TYRP1 protein in a subgroup of melanoma patients. These data support the interest in the prognostic value of melanogenic markers and propose TYRP1 to refine prognosis in patients with advanced disease.
    Full-text · Article · Jun 2015 · British Journal of Cancer
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