A B S T R A C T PurposeTo revise the staging system for cutaneous melanoma on the basis of data from an expanded American Joint Committee on Cancer (AJCC) Melanoma Staging Database. MethodsThe 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. ResultsFindings 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. ConclusionUsing 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.

The American Joint Committee on Cancer (AJCC) staging manual has become the benchmark for classifying patients with cancer, defining prognosis, and determining the best treatment approaches. Many view the primary role of the tumor, lymph node, metastasis (TNM) system as that of a standardized classification system for evaluating cancer at a population level in terms of the extent of disease, both at initial presentation and after surgical treatment, and the overall impact of improvements in cancer treatment. The rapid evolution of knowledge in cancer biology and the discovery and validation of biologic factors that predict cancer outcome and response to treatment with better accuracy have led some cancer experts to question the utility of a TNM-based approach in clinical care at an individualized patient level. In the Eighth Edition of the AJCC Cancer Staging Manual, the goal of including relevant, nonanatomic (including molecular) factors has been foremost, although changes are made only when there is strong evidence for inclusion. The editorial board viewed this iteration as a proactive effort to continue to build the important bridge from a "population-based" to a more "personalized" approach to patient classification, one that forms the conceptual framework and foundation of cancer staging in the era of precision molecular oncology. The AJCC promulgates best staging practices through each new edition in an effort to provide cancer care providers with a powerful, knowledge-based resource for the battle against cancer. In this commentary, the authors highlight the overall organizational and structural changes as well as "what's new" in the Eighth Edition. It is hoped that this information will provide the reader with a better understanding of the rationale behind the aggregate proposed changes and the exciting developments in the upcoming edition. CA Cancer J Clin 2017;67:93-99. © 2017 American Cancer Society.

Preclinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human cancer patients. Here we examined the oral and gut microbiome of melanoma patients undergoing anti–programmed cell death 1 protein (PD-1) immunotherapy (n = 112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders versus nonresponders. Analysis of patient fecal microbiome samples (n = 43, 30 responders, 13 nonresponders) showed significantly higher alpha diversity (P < 0.01) and relative abundance of bacteria of the Ruminococcaceae family (P < 0.01) in responding patients. Metagenomic studies revealed functional differences in gut bacteria in responders, including enrichment of anabolic pathways. Immune profiling suggested enhanced systemic and antitumor immunity in responding patients with a favorable gut microbiome as well as in germ-free mice receiving fecal transplants from responding patients. Together, these data have important implications for the treatment of melanoma patients with immune checkpoint inhibitors.

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SUMMARY Despite recent insights into melanoma genetics, systematic surveys for driver mutations are challenged by an abundance of passenger mutations caused by carcinogenic ultraviolet (UV) light exposure. We developed a permutation-based framework to address this challenge, employing mutation data from intronic sequences to control for passenger mutational load on a per gene basis. Analysis of large-scale melanoma exome data by this approach discovered six novel melanoma genes (PPP6C, RAC1, SNX31, TACC1, STK19 and ARID2), three of which - RAC1, PPP6C and STK19 - harbored recurrent and potentially targetable mutations. Integration with chromosomal copy number data contextualized the landscape of driver mutations, providing oncogenic insights in BRAF- and NRAS-driven melanoma as well as those without known NRAS/BRAF mutations. The landscape also clarified a mutational basis for RB and p53 pathway deregulation in this malignancy. Finally, the spectrum of driver mutations provided unequivocal genomic evidence for a direct mutagenic role of UV light in melanoma pathogenesis.