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Keynote lecture: the biology of cancer metastasis

  1. Top of page
  2. Keynote lecture: the biology of cancer metastasis
  3. SMR plenary session I: new insights into melanoma biology
  4. SMR plenary session II: novel drivers of melanoma initiation, progression, and resistance
  5. Special SMR session: late-breaking clinical trial results, part 1
  6. SMR breakout session IA: understanding melanoma biology through model systems
  7. Transcriptional control and epigenetic regulation of melanoma: SMR breakout session IB
  8. Breakout session IIA of the SMR: new therapeutic targets and strategies in melanoma
  9. Breakout session IIB – implications of melanocyte development for understanding and treating melanoma
  10. SMR/Centers Joint Symposium I: melanoma susceptibility, epidemiology, and prevention
  11. Joint SMR/Centers Symposium II ‘Immunology: from bench to bedside’
  12. Special Session of the SMR Meeting and Melanoma Centres Meeting ‘Late-breaking clinical trial results (previously unreported data), part 2’
  13. Joint SMR/Centres Symposium III: clinically important breakthroughs in melanoma genetic and genomics
  14. Joint SMR/Centers Symposium IV: working together to overcome drug resistance in melanoma
  15. Joint Symposium 1: interdisciplinary melanoma/skin cancers centres meeting and melanoma update for primary care physicians, surgeons, oncologists, and dermatologists: 30 000 foot view: what is new in melanoma 2011
  16. The fourth International Melanoma Pathology Symposium
  17. Difficult case presentations
  18. Session 3: special techniques and molecular advances
  19. Conclusion

This year’s keynote lecture was given by Dr Joan Massague (Memorial Sloane Kettering Cancer Center, New York, NY, USA) who described exciting work ongoing in his laboratory focused upon the biology of breast cancer metastasis. Dr Massague began by outlining the metastatic process and explaining that often micrometastases have disseminated to distant organs even before the primary tumor is clinically apparent. He then went onto describe some interesting and provocative work on the ‘self-seeding’ hypothesis of tumor progression, where metastasis can be viewed as two-way process in which the primary tumor seeds the metastases and the metastases reciprocally seed the primary tumor. In the final part of his presentation, Dr Massague elaborated upon recent published work identifying Tenascin-C as a novel mediator of aggressive pulmonary metastasis. In his closing remarks, Dr Massague reminded the audience that although his work was mostly in breast cancer, the concepts outlined in his lecture were equally applicable to melanoma.

SMR plenary session I: new insights into melanoma biology

  1. Top of page
  2. Keynote lecture: the biology of cancer metastasis
  3. SMR plenary session I: new insights into melanoma biology
  4. SMR plenary session II: novel drivers of melanoma initiation, progression, and resistance
  5. Special SMR session: late-breaking clinical trial results, part 1
  6. SMR breakout session IA: understanding melanoma biology through model systems
  7. Transcriptional control and epigenetic regulation of melanoma: SMR breakout session IB
  8. Breakout session IIA of the SMR: new therapeutic targets and strategies in melanoma
  9. Breakout session IIB – implications of melanocyte development for understanding and treating melanoma
  10. SMR/Centers Joint Symposium I: melanoma susceptibility, epidemiology, and prevention
  11. Joint SMR/Centers Symposium II ‘Immunology: from bench to bedside’
  12. Special Session of the SMR Meeting and Melanoma Centres Meeting ‘Late-breaking clinical trial results (previously unreported data), part 2’
  13. Joint SMR/Centres Symposium III: clinically important breakthroughs in melanoma genetic and genomics
  14. Joint SMR/Centers Symposium IV: working together to overcome drug resistance in melanoma
  15. Joint Symposium 1: interdisciplinary melanoma/skin cancers centres meeting and melanoma update for primary care physicians, surgeons, oncologists, and dermatologists: 30 000 foot view: what is new in melanoma 2011
  16. The fourth International Melanoma Pathology Symposium
  17. Difficult case presentations
  18. Session 3: special techniques and molecular advances
  19. Conclusion

Dr Glenn Merlino (The National Institutes of Health, Bethesda, MD, USA) opened the session by discussing the ongoing investigations of his laboratory into the role of ultraviolet radiation (UV) in melanoma development through the use of UV-responsive mouse melanoma models. Previous work from Dr Merlino showed that intense sunburn in neonatal mice leads to melanoma development through as yet unknown mechanisms. In his presentation, Dr Merlino presented data implicating UV-induced inflammation as a causative factor in melanomagenesis. His talk ended with a discussion of the hypothesis that metastatic melanoma cells may exploit some of the mechanisms used by melanoblasts during embryonic development as well as a discussion of new mouse melanoma models being developed at NIH for the preclinical testing of novel anti-melanoma drugs.

The second speaker was Dr David Fisher, (Dana-Faber Cancer Center, Boston, MA, USA), who began by reviewing the critical role of the microphthalmia-associated transcription factor (MITF) in melanocyte biology and melanoma development. He then described recent work identifying a novel hereditary (or germ line) mutation in MITF, E318K, that affects a sumoylation site, leads to a gain-of-function in the protein, and increases the risk of developing melanoma. After discussing new developments in melanoma targeted therapy, Dr Fisher then turned his attention to ongoing work in his laboratory looking at the role of UV-induced β-endorphin release in the skin. Through an elegant series of mouse experiments, Dr Fisher demonstrated that UV-treated mice showed enhanced β-endorphin levels in their plasma and that this was associated with an increased pain threshold. It was suggested that chronic low-dose UV exposure leads to marked behavioral changes in the mice and that withdrawal symptoms were observed when opiate antagonists were administered.

The focus of Dr Marisol Soengas’ talk (Spanish National Cancer Institute, Madrid, Spain) was upon the role of endosomal/lysosomal vesicle trafficking in melanoma progression and the response to therapy. As her major focus, Dr Soengas discussed the role of endosome-associated small GTPase Rab7. It was concluded that Rab7 was both a melanoma oncogene and a phenotypic regulator of melanoma behavior.

The lecture by Dr Daniel Peeper (the Netherlands Cancer Institute, Amsterdam, Holland) focused upon the role of oncogene-induced senescence (OIS) in melanoma development. The main area covered by Dr Peeper in his lecture was upon the role of glycolysis signaling in OIS. He presented new data from his laboratory showing that senescent cells had an increased oxidative tricarboxylic acid (TCA) cycle flux that was mediated through the deregulation of PDK, PDP2, and PDH. In the second part of his talk, Dr Peeper outlined a synthetic lethality screen currently being undertaken in his laboratory to identify novel mechanisms of resistance to BRAF inhibitors.

SMR plenary session II: novel drivers of melanoma initiation, progression, and resistance

  1. Top of page
  2. Keynote lecture: the biology of cancer metastasis
  3. SMR plenary session I: new insights into melanoma biology
  4. SMR plenary session II: novel drivers of melanoma initiation, progression, and resistance
  5. Special SMR session: late-breaking clinical trial results, part 1
  6. SMR breakout session IA: understanding melanoma biology through model systems
  7. Transcriptional control and epigenetic regulation of melanoma: SMR breakout session IB
  8. Breakout session IIA of the SMR: new therapeutic targets and strategies in melanoma
  9. Breakout session IIB – implications of melanocyte development for understanding and treating melanoma
  10. SMR/Centers Joint Symposium I: melanoma susceptibility, epidemiology, and prevention
  11. Joint SMR/Centers Symposium II ‘Immunology: from bench to bedside’
  12. Special Session of the SMR Meeting and Melanoma Centres Meeting ‘Late-breaking clinical trial results (previously unreported data), part 2’
  13. Joint SMR/Centres Symposium III: clinically important breakthroughs in melanoma genetic and genomics
  14. Joint SMR/Centers Symposium IV: working together to overcome drug resistance in melanoma
  15. Joint Symposium 1: interdisciplinary melanoma/skin cancers centres meeting and melanoma update for primary care physicians, surgeons, oncologists, and dermatologists: 30 000 foot view: what is new in melanoma 2011
  16. The fourth International Melanoma Pathology Symposium
  17. Difficult case presentations
  18. Session 3: special techniques and molecular advances
  19. Conclusion

Dr JW Harbour (Washington University, St Louis, MO, USA) started the second plenary session with a lecture about the latest developments in uveal melanoma. He began by describing the essential differences between uveal and cutaneous melanoma in terms of its pattern of metastatic spread (mainly haematological as opposed to locally lymphatic) and the fact that BRAF/NRAS/c-KIT mutations are rare in uveal melanoma but GNAQ and GNA11 mutations are relatively common. He then described an exon capture, deep sequencing approach that led to the discovery of BAP1 loss as mechanism of class I uveal melanoma development. Data were presented identifying rare germ line mutations of BAP1 that conveyed increased risk of uveal melanoma, lung cancer, and mesothelioma.

Dr Levi Garraway (The Broad Institute, Cambridge, MA, USA) outlined high-throughput strategies for the interrogation of BRAF inhibitor resistance in melanoma. In his lecture, Dr Garraway reviewed recent work from his laboratory demonstrating the role of overexpression of COT, a MAPK pathway agonist, in mediating vemurafenib resistance as well as the role of activating MEK1 mutations. He ended his lecture by describing new work from his group that identified different kinases being responsible for resistance to inhibitors of either BRAF or MEK.

Dr Gavin Robertson (Pennsylvania State University, Hershey, PA, USA) spoke on epigenetic silencing which is regulated by vemurafenib and that promotes the invasive properties of melanoma cells. This mechanism involves BRAF regulation of DNA methyl transferases (DNMTs). Upon BRAF targeting with siRNAs or vemurafenib, Dr Robertson observed upregulation of DNMT1 and DNMT3A. Concomitant with the regulation of DNMTs, he described hypermethylation of the CD82 promoter (also known as KAI1) and decreased expression of CD82. CD82 is a metastasis suppressor gene, and its ectopic expression decreased melanoma cell invasion and lung colonization. Use of the DNA demethylating agent, 5AzaC, reversed the silencing of CD82 and inhibited invasive properties. These findings may have implications for the use of demethylating agents to decrease the invasiveness of vemurafenib-treated tumors.

Before the final talk in this session, Professor Richard Marais (The Institute of Cancer Research, London, UK) accepted the Estella Medrano Memorial Award. He then described studies on the regulation of proliferation of melanoma cells by the 5′ AMP-activated protein kinase (AMPK). AMPK senses the cellular AMP/ATP ratio and regulates the protein translation via the TORC1 complex and is activated by the therapeutic agent, metformin. Dr Marais described how activating AMPK elicits differential effects in BRAF mutant versus NRAS mutant melanoma cells.

Special SMR session: late-breaking clinical trial results, part 1

  1. Top of page
  2. Keynote lecture: the biology of cancer metastasis
  3. SMR plenary session I: new insights into melanoma biology
  4. SMR plenary session II: novel drivers of melanoma initiation, progression, and resistance
  5. Special SMR session: late-breaking clinical trial results, part 1
  6. SMR breakout session IA: understanding melanoma biology through model systems
  7. Transcriptional control and epigenetic regulation of melanoma: SMR breakout session IB
  8. Breakout session IIA of the SMR: new therapeutic targets and strategies in melanoma
  9. Breakout session IIB – implications of melanocyte development for understanding and treating melanoma
  10. SMR/Centers Joint Symposium I: melanoma susceptibility, epidemiology, and prevention
  11. Joint SMR/Centers Symposium II ‘Immunology: from bench to bedside’
  12. Special Session of the SMR Meeting and Melanoma Centres Meeting ‘Late-breaking clinical trial results (previously unreported data), part 2’
  13. Joint SMR/Centres Symposium III: clinically important breakthroughs in melanoma genetic and genomics
  14. Joint SMR/Centers Symposium IV: working together to overcome drug resistance in melanoma
  15. Joint Symposium 1: interdisciplinary melanoma/skin cancers centres meeting and melanoma update for primary care physicians, surgeons, oncologists, and dermatologists: 30 000 foot view: what is new in melanoma 2011
  16. The fourth International Melanoma Pathology Symposium
  17. Difficult case presentations
  18. Session 3: special techniques and molecular advances
  19. Conclusion

BREAK-2: a phase IIA trial of the selective BRAF kinase inhibitor GSK2118436 in patients with BRAF (V600E/K)-positive metastatic melanoma

In the phase II trial of GSK2118436, 92 patients with BRAF V600 mutations were enrolled on this single-arm, phase 2 trial. Objective response was the primary endpoint. Seventy-six patients with V600E mutations and 16 patients with V600K mutations were enrolled. Cutaneous squamous cell carcinomas were relatively infrequently observed (eight cases, representing 9%). Objective response rate in the V600E cohort was 59% (95% CI 48–70%), while only two V600K patients had objective responses (13%; 95% CI 0–29%). The median progression-free survival was 27 and 20 weeks, respectively, in the two mutation subsets. These results provide important corroboration as to the high level of clinical activity observed with this BRAF inhibitor, which compares favorably to the FDA-approved vemurafenib.

Vemurafenib improves overall survival compared to dacarbazine in advanced BRAFV600E-mutated melanoma: An update from the phase III randomized, open-label, multicenter BRIM3 trial

In the updated analysis of the BRIM3 trial, median follow-up was 7 months. The overall survival continued to be significantly improved with vemurafenib compared to dacarbazine, but some attenuation in the magnitude of effect was observed [Hazard ratio 0.44 (95% CI; 0.33–0.59)]. Although longer-term follow-up of these cohorts is of great interest to the field, with those who were still alive on the control arm group having crossed over to vemurafenib, the difference in survival between the two initial randomized cohorts would be expected to diminish. The early analysis of this trial clearly established that vemurafenib has a profound protective effect at the level of melanoma-related fatality for those patients with the most advanced or aggressive disease. But the question that remains is whether vemurafenib improves survival to a similar extent in patients with low disease burden or more indolent disease.

Phase II study of the MEK1/MEK2 inhibitor GSK1120212 in patients with metastatic BRAF V600E/K mutant cutaneous melanoma previously treated with or without a BRAF inhibitor

GSK 1120212 represents the most extensively evaluated MEK inhibitor in BRAF mutant melanoma. Results of a phase I clinical trial, in which patients with BRAF mutant melanoma were enriched, suggested that this MEK inhibitor has more single agent activity than any other tested in this subpopulation. In this phase II trial, 40 patients who had previously received a BRAF inhibitor were enrolled and 57 patients who were BRAF inhibitor naïve were included. 12% of patients had V600K mutations, the rest being V600E. As with other MEK inhibitors, the most common toxicities were rash, diarrhea, peripheral edema, and fatigue. Minimal evidence of antitumor activity was observed in the BRAF inhibitor refractory cohort, with only two patients having objective responses, and those being patients who have previously discontinued BRAF inhibitor therapy because of toxicity, not disease progression. The median progression-free survival in this cohort was 1.8 months. In the BRAF inhibitor naïve cohort, the response rate was 25% (95% CI 14–38%), and the median duration of response was 5.7 months. Median progression-free survival for the BRAF inhibitor naïve cohort overall was 4.0 months. While this degree of antitumor activity continues to represent the best observed with a MEK inhibitor, the results suggest that selective BRAF inhibitors have greater clinical efficacy as single agents.

Phase I/II expansion cohort of BRAF inhibitor GSK2118436 + MEK inhibitor GSK1120212 in patients with BRAF mutant metastatic melanoma who progressed on a prior BRAF inhibitor

One cohort of patients included in the first trial to combine a selective BRAF inhibitor (GSK2118436) with a MEK inhibitor (GSK1120212) was reported for the first time at the SMR Congress. Specifically, 26 patients with metastatic melanoma harboring V600 mutant BRAF who had previously been treated until disease progression with either GSK2118436 alone or vemurafenib alone were enrolled as a separate cohort in the larger phase I/randomized II trial testing this combination in BRAF inhibitor naïve patients. Six of the patients had also previously received a MEK inhibitor. The median time since discontinuing prior BRAF inhibitor therapy was 1.1 months. Sixty-two percent of patients had some degree of tumor regression. The response rate was 19% and median progression-free survival was 3.6 months. Given that the vast majority of these patients had just recently had disease progression on the BRAF inhibitor and an additional subset had also previously received an MEK inhibitor, these efficacy data strongly suggested that this regimen has significant clinical activity. It is hoped that the impact could be even more significant in patients who are BRAF inhibitor naïve, and the results of the randomized phase II portion of this trial are awaited in that population.

SMR breakout session IA: understanding melanoma biology through model systems

  1. Top of page
  2. Keynote lecture: the biology of cancer metastasis
  3. SMR plenary session I: new insights into melanoma biology
  4. SMR plenary session II: novel drivers of melanoma initiation, progression, and resistance
  5. Special SMR session: late-breaking clinical trial results, part 1
  6. SMR breakout session IA: understanding melanoma biology through model systems
  7. Transcriptional control and epigenetic regulation of melanoma: SMR breakout session IB
  8. Breakout session IIA of the SMR: new therapeutic targets and strategies in melanoma
  9. Breakout session IIB – implications of melanocyte development for understanding and treating melanoma
  10. SMR/Centers Joint Symposium I: melanoma susceptibility, epidemiology, and prevention
  11. Joint SMR/Centers Symposium II ‘Immunology: from bench to bedside’
  12. Special Session of the SMR Meeting and Melanoma Centres Meeting ‘Late-breaking clinical trial results (previously unreported data), part 2’
  13. Joint SMR/Centres Symposium III: clinically important breakthroughs in melanoma genetic and genomics
  14. Joint SMR/Centers Symposium IV: working together to overcome drug resistance in melanoma
  15. Joint Symposium 1: interdisciplinary melanoma/skin cancers centres meeting and melanoma update for primary care physicians, surgeons, oncologists, and dermatologists: 30 000 foot view: what is new in melanoma 2011
  16. The fourth International Melanoma Pathology Symposium
  17. Difficult case presentations
  18. Session 3: special techniques and molecular advances
  19. Conclusion

Several new mouse models of melanoma were described in the ‘Understanding melanoma biology through model systems’ session. Dr Martin McMahon (University of California, San Francisco, CA, USA) described a new model involving activation of PI3K signaling that exhibits several features of a model that he co-developed involving BRAF activation and PTEN loss. The new model will be useful for preclinical evaluation of therapeutics, including the effects of AKT and PI3K inhibitors. Dr Lionel Larue (Institute Curie, Paris, France) described models that involve regulation of Wnt signaling by modulation of beta-catenin levels. Larue demonstrated that beta-catenin alters melanocyte migration in vivo, functions to reduce p16INK4A levels, and can synergize with activated NRAS to result in melanoma formation and higher rates of lung seeding in tail vein metastasis assays. Dr David Olmeda (Spanish National Cancer Research Center, Madrid, Spain) from Marisol Soengas’ group presented findings from an exciting new model in which lymphatic vessels are marked by fluorescent protein expression. This model makes it possible to characterize lymphangiogenesis during melanoma formation. Dr Devarti Mitra (Dana-Faber Cancer Center, Boston, MA, USA) from David Fisher’s laboratory demonstrated that partial loss of melanocortin 1 receptor function not only results in blond/red hair in mice, but also enhances melanoma formation even in the absence of exposure to ultraviolet light.

Cancer stems cells have been a central focus in melanoma biology over the past few years. Dr Mark Shackleton (Peter MacCallum Cancer Center, Melbourne, Australia) presented new data that demonstrated dynamic intratumoral heterogeneity. This was demonstrated by evaluating the genomic copy number variation and DNA methylation changes present in xenografts derived from serial single cell xenografts. Dr Sandy Anderson (Moffitt Cancer Center, Tampa, FL, USA) described efforts in modeling the complex process of tumor formation based on mathematical models. In the case of melanoma, this new field of mathematical oncology utilizes inputs from melanocyte, keratinocyte, and fibroblast signaling pathways to predict the effects of modulating particular signaling perturbations.

Transcriptional control and epigenetic regulation of melanoma: SMR breakout session IB

  1. Top of page
  2. Keynote lecture: the biology of cancer metastasis
  3. SMR plenary session I: new insights into melanoma biology
  4. SMR plenary session II: novel drivers of melanoma initiation, progression, and resistance
  5. Special SMR session: late-breaking clinical trial results, part 1
  6. SMR breakout session IA: understanding melanoma biology through model systems
  7. Transcriptional control and epigenetic regulation of melanoma: SMR breakout session IB
  8. Breakout session IIA of the SMR: new therapeutic targets and strategies in melanoma
  9. Breakout session IIB – implications of melanocyte development for understanding and treating melanoma
  10. SMR/Centers Joint Symposium I: melanoma susceptibility, epidemiology, and prevention
  11. Joint SMR/Centers Symposium II ‘Immunology: from bench to bedside’
  12. Special Session of the SMR Meeting and Melanoma Centres Meeting ‘Late-breaking clinical trial results (previously unreported data), part 2’
  13. Joint SMR/Centres Symposium III: clinically important breakthroughs in melanoma genetic and genomics
  14. Joint SMR/Centers Symposium IV: working together to overcome drug resistance in melanoma
  15. Joint Symposium 1: interdisciplinary melanoma/skin cancers centres meeting and melanoma update for primary care physicians, surgeons, oncologists, and dermatologists: 30 000 foot view: what is new in melanoma 2011
  16. The fourth International Melanoma Pathology Symposium
  17. Difficult case presentations
  18. Session 3: special techniques and molecular advances
  19. Conclusion

Dr Colin Goding (Ludwig Insitute for Cancer Research and University of Oxford, Oxford, UK) presented data on heterogeneity in melanoma. In his interesting talk, he highlighted the role of MITF and Brn-2 in generating tumor heterogeneity and plasticity and illustrated how different levels of these molecules can determine cell identity. It was demonstrated that low levels of MITF and high levels of Brn-2 result in invasive stem–like cells while increased MITF activity and low levels of Brn-2 yield proliferating or differentiated cells.

Dr Anja K. Bosserhoff (Institute of Pathology, Molecular Pathology, University of Regensburg, Germany) drew attention to the important role of cell–cell adhesion molecules to control transcriptional regulation. Choosing the example of c-Jun, she presented data revealing that c-Jun is a main transcriptional regulator in melanoma being part of the AP-1 transcription factor complex. Strong activity of AP-1 can be found in melanoma which is owing to the strong expression of c-Jun in the melanoma cells. Interestingly, she presented data showing that c-Jun expression is controlled post-transcriptionally by loss of E-cadherin.

Dr Richard White (Dana Farber Cancer Institute and Children’s Hospital Boston and Harvard Medical School, Boston, MA, USA) presented exciting new data derived from his zebrafish model of melanoma. He is using a model in which the MITF promoter is driving the expression of mutated BRAF on a p53-negative background. In this model, mostly singular melanomas arise in which abnormal overexpression of neural crest markers such as MITF or Sox10 is found. The approach outlined allowed for high-throughput screening of zebrafish embryos to be used as a tool to identify chemical modifiers of tumorigenesis.

Professor Jean-Christophe Marine (Laboratory of Molecular Cancer Biology, VIB-KU Leuven, CME and VIB-U Ghent, DMBR, Leuven, Belgium) talked about MDMX as a key therapeutic target in melanoma. It was shown that MDMX overexpression is causally linked to melanoma formation in vivo, as melanocyte-specific overexpression of MDMX in transgenic mice carrying the NRAS-Q61K mutation promotes melanoma formation. Finally he showed that a peptide antagonist of p53/MDMX interaction (SAH-p53-8) results in induction of apoptosis, inhibition of tumor growth in vivo, and in sensitization of the cells to chemotherapy.

Dr Julie C. Cronin (Genetic Disease Research Branch, National Human Genome Research Institute, NIH, Bethesda, MD USA), presented data showing SOX10 to be an essential regulator of melanoma cell proliferation. The group determined mutations of Sox10 in ∼1% of melanoma showing an enrichment of mutations in rare subtypes. Functionally, it was shown that siRNA knockdown of Sox10 resulted in a reduction in the proliferation of melanoma cells going together with an arrest in G1 and induction of senescence.

Professor Reinhard Dummer (Department of Dermatology, University Hospital of Zurich, Switzerland) summarized the model of phenotype switching that he and Keith Hoek developed in his laboratory. He described the clustering of melanoma cells into the two subtypes of proliferative and invasive and showed that switching between the two phenotypes can be found in vitro and in vivo. He presented data showing that inhibition of BRAF activity results in morphological changes resembling the invasive subtype. He claimed that therapeutic approaches to address the invasive subtypes of cells are missing today and need to be determined.

Breakout session IIA of the SMR: new therapeutic targets and strategies in melanoma

  1. Top of page
  2. Keynote lecture: the biology of cancer metastasis
  3. SMR plenary session I: new insights into melanoma biology
  4. SMR plenary session II: novel drivers of melanoma initiation, progression, and resistance
  5. Special SMR session: late-breaking clinical trial results, part 1
  6. SMR breakout session IA: understanding melanoma biology through model systems
  7. Transcriptional control and epigenetic regulation of melanoma: SMR breakout session IB
  8. Breakout session IIA of the SMR: new therapeutic targets and strategies in melanoma
  9. Breakout session IIB – implications of melanocyte development for understanding and treating melanoma
  10. SMR/Centers Joint Symposium I: melanoma susceptibility, epidemiology, and prevention
  11. Joint SMR/Centers Symposium II ‘Immunology: from bench to bedside’
  12. Special Session of the SMR Meeting and Melanoma Centres Meeting ‘Late-breaking clinical trial results (previously unreported data), part 2’
  13. Joint SMR/Centres Symposium III: clinically important breakthroughs in melanoma genetic and genomics
  14. Joint SMR/Centers Symposium IV: working together to overcome drug resistance in melanoma
  15. Joint Symposium 1: interdisciplinary melanoma/skin cancers centres meeting and melanoma update for primary care physicians, surgeons, oncologists, and dermatologists: 30 000 foot view: what is new in melanoma 2011
  16. The fourth International Melanoma Pathology Symposium
  17. Difficult case presentations
  18. Session 3: special techniques and molecular advances
  19. Conclusion

Dr Ann Richmond (Vanderbilt University Medical Center, Nashville, TN, USA) utilized an orthotopic melanoma implant model to investigate the response to RAF265, a multi-kinase inhibitor. Richmond demonstrated that the gene expression profile of the tumor implants may predict response to RAF265 and that this may be a useful therapy for patients whose melanomas do not harbor a BRAF mutation.

Dr Andrew Aplin (Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA) reported on the role of the stemness factor, FOXD3, and its targets in resistance to PLX4032. BRAF siRNA or vemurafenib increased expression levels of FOXD3 and consequently FOXD3 siRNA–sensitized melanoma cells to RAF inhibitors. Chromatin-immunoprecipitation followed by next-generation sequencing and expression array profiling revealed ERBB3 as a direct target of FOXD3.

Dr Keiran Smalley (Moffitt Cancer Center, Tampa, FL, USA) presented a unified strategy for overcoming multiple mechanisms of both intrinsic and acquired vemurafenib resistance. The HSP90 inhibitor XL888 was highly potent against vemurafenib-resistant cell lines, where it caused G2/M phase arrest and apoptosis in two- and three-dimensional cell culture as well as regression of xenografts. The development of drug-resistant colonies during long-term therapy with vemurafenib was completely abrogated by consecutive treatment with XL888.

Dr Penny Lovat (Newcastle University, Newcastle upon Tyne, UK) reported on the role of the autophagy regulatory protein WIPI-1 in linking oncogenic BRAF to deregulated autophagy in melanoma. It was concluded that WIPI-1 expression and deregulated autophagy may play a role in melanoma development, progression, and may provide novel therapeutic targets for melanoma therapy.

Dr Nikolas Haass (Centenary Institute, University of Sydney, Sydney, Australia), utilizing a real-time cell cycle imaging system, showed in 3D spheroid cell culture and in vivo that there is a subcompartment-specific distribution of differentially cycling tumor cells in melanoma. His data suggested that MITF expression may dictate the subcompartment-specific distribution of differentially cycling tumor cells in melanoma, which may result in differential sensitivity to apoptosis and therefore may contribute to the resistance of melanoma to therapy.

Dr Yardena Samuels (National Institutes of Health, Bethesda, MD, USA) utilized a whole-exome discovery screen to identify the ionotropic glutamate receptor GRIN2A as being mutated in 25% of melanoma samples. Ionotropic glutamate receptors are ligand-gated ion channels that allow cations to pass through the plasma membrane of the cell after the binding of glutamate to the receptors. Her data identified the glutamate pathway as a major player in melanoma and as a target for potential therapeutic intervention.

Breakout session IIB – implications of melanocyte development for understanding and treating melanoma

  1. Top of page
  2. Keynote lecture: the biology of cancer metastasis
  3. SMR plenary session I: new insights into melanoma biology
  4. SMR plenary session II: novel drivers of melanoma initiation, progression, and resistance
  5. Special SMR session: late-breaking clinical trial results, part 1
  6. SMR breakout session IA: understanding melanoma biology through model systems
  7. Transcriptional control and epigenetic regulation of melanoma: SMR breakout session IB
  8. Breakout session IIA of the SMR: new therapeutic targets and strategies in melanoma
  9. Breakout session IIB – implications of melanocyte development for understanding and treating melanoma
  10. SMR/Centers Joint Symposium I: melanoma susceptibility, epidemiology, and prevention
  11. Joint SMR/Centers Symposium II ‘Immunology: from bench to bedside’
  12. Special Session of the SMR Meeting and Melanoma Centres Meeting ‘Late-breaking clinical trial results (previously unreported data), part 2’
  13. Joint SMR/Centres Symposium III: clinically important breakthroughs in melanoma genetic and genomics
  14. Joint SMR/Centers Symposium IV: working together to overcome drug resistance in melanoma
  15. Joint Symposium 1: interdisciplinary melanoma/skin cancers centres meeting and melanoma update for primary care physicians, surgeons, oncologists, and dermatologists: 30 000 foot view: what is new in melanoma 2011
  16. The fourth International Melanoma Pathology Symposium
  17. Difficult case presentations
  18. Session 3: special techniques and molecular advances
  19. Conclusion

Dr Andrzej Slominski (University of Tennessee Health Sciences Center, Memphis, TN, USA) provided data demonstrating that intermediates of melanogenesis can be immunosuppressive, genotoxic, and mutagenic and that melanin can act as radioprotector and scavenger of cellular toxins. This would indicate that the inhibition of melanogenesis could be used as an adjunct to radiation or chemotherapy.

Dr Patrik Ernfors (The Karolinska Institute, Stockholm, Sweden) presented interesting new data outlining the possible source of melanoblasts. Classically, melanoblasts migrate from the neural crest by the dorsolateral pathway, while developing Schwann Cells and Neurons instead used the ventral migratory pathway. Through the use of a murine model that expressed yellow fluorescent protein (YFP) in Schwann cells, Dr Ernfors observed that melanocytes in the dermis and hair follicles also expressed YFP, indicating that they can also develop from Schwann cell precursors.

Dr Frank Meyskens’ (University of California, Irvine, CA, USA) talk addressed the role of neural nitric oxide synthetase nNOS in melanoma. nNOS was shown to be rapidly upregulated following UVA or UVB treatment, and the knockdown of nNOS decreased the invasive capacity of melanoma cells. nNOS was also associated with the adhesive capacity of melanoma cells, and the expression of nNOS was found to increase in the transition from thinner to thicker primary melanomas.

Dr Malin Pedersen (The Institute of Cancer Research, London, UK) reported on a murine model expressing NRAS-G12D under the control of the tyrosine promoter that exhibited a nevus and hyperpigmentation phenotype, but did not develop melanoma in adult animals. If, however, expression of NRAS-G12D was induced at E11.5, the animals developed congenital nevi. After a latency period, these animals did later develop pigmented tumors in the brain that were preceded by a melanosis of the leptomeninges.

Dr Patricia A. Possik (The Netherlands Cancer Institute, Amsterdam, Holland) demonstrated that BRAF-V600E-mediated OIS in melanocytes was overcome by the activation of the PI3-kinase pathway in vitro and in vivo. In accordance with this experimental data, immunohistochemistry on melanomas arising in association with a nevus exhibited loss of PTEN, upregulation of AKT3 and increased phosphorylation of AKT. Combined inhibition of BRAF and PI3K led to induction of apoptosis and effectively prevented the emergence of resistant clones.

‘Apoptosis-associated speck-like protein containing a CARD’ (ASC) is part of the inflammasome and regulates caspase-1 dependent secretion of pro-inflammatory cytokines like Il-1β and IL18. Dr Welmin Liu (University of Colorado, Denver, CO, USA) reported on a dual role of ASC in primary and metastatic melanoma. ASC was expressed at high levels in primary tumors while levels were found to be low in metastatic melanoma. In contrast to its effects in melanoma metastases, knockdown of ASC promoted growth and tumorigenesis in primary melanoma cells.

SMR/Centers Joint Symposium I: melanoma susceptibility, epidemiology, and prevention

  1. Top of page
  2. Keynote lecture: the biology of cancer metastasis
  3. SMR plenary session I: new insights into melanoma biology
  4. SMR plenary session II: novel drivers of melanoma initiation, progression, and resistance
  5. Special SMR session: late-breaking clinical trial results, part 1
  6. SMR breakout session IA: understanding melanoma biology through model systems
  7. Transcriptional control and epigenetic regulation of melanoma: SMR breakout session IB
  8. Breakout session IIA of the SMR: new therapeutic targets and strategies in melanoma
  9. Breakout session IIB – implications of melanocyte development for understanding and treating melanoma
  10. SMR/Centers Joint Symposium I: melanoma susceptibility, epidemiology, and prevention
  11. Joint SMR/Centers Symposium II ‘Immunology: from bench to bedside’
  12. Special Session of the SMR Meeting and Melanoma Centres Meeting ‘Late-breaking clinical trial results (previously unreported data), part 2’
  13. Joint SMR/Centres Symposium III: clinically important breakthroughs in melanoma genetic and genomics
  14. Joint SMR/Centers Symposium IV: working together to overcome drug resistance in melanoma
  15. Joint Symposium 1: interdisciplinary melanoma/skin cancers centres meeting and melanoma update for primary care physicians, surgeons, oncologists, and dermatologists: 30 000 foot view: what is new in melanoma 2011
  16. The fourth International Melanoma Pathology Symposium
  17. Difficult case presentations
  18. Session 3: special techniques and molecular advances
  19. Conclusion

The reasons for changing trends in melanoma incidence and mortality were central features of the ‘Melanoma epidemiology, susceptibility, and prevention’ session. Professor Julia Newton-Bishop (University of Leeds, Leeds, UK) summarized epidemiological assessment of risk related to ultraviolet light exposure and because of genetic loci identified by genome-wide association studies. Prevention of melanoma mortality was a central theme in this session. Dr Sandy Leachman (University of Utah, Salt Lake City, Utah) and Dr Doug Grossman described the effects of a variety of chemopreventive agents, including N-acetylcysteine, sulforaphane, and sulindac. Dr Jean-Jacques Grob (St Marguerite University Hospital, Marseille, France) described European Union efforts in melanoma prevention and emphasized the importance of image-based education, as well as targeting education efforts to populations with the highest potential for reduction in melanoma mortality. Dr Alan Geller (Harvard School of Public Health, MA, USA) highlighted the rapidly increasing mortality associated with melanoma in men older than 65, in contrast to patients with melanoma between 20 and 45 yrs of age. Dr Nick Hayward (Queensland Institute of Medical Research, Brisbane, Australia) described genetic characterization of 174 melanoma-prone families that lacked Cdkn2a mutation by exome sequencing. While Cdkn2a mutation accounts for nearly 40% of familial melanoma, it appears that no other gene will account for a significant proportion of the remainder of the genetic risk of familial melanoma. Mutation of a sumoylation site on MITF appears to represent a new form of incompletely penetrant familial melanoma and renal cell carcinoma in rare families. Dr Marianne Berwick (University of New Mexico, NM, USA) evaluated the data on vitamin D levels and signaling in melanoma, which remain somewhat inconclusive. Dr Martin Weinstock (Brown University, Providence, RI, USA) evaluated the possibility of histopathological ‘overdiagnosis’ of melanoma in recent years as a possible explanation for the rapid recent increase in melanoma incidence.

Joint SMR/Centers Symposium II ‘Immunology: from bench to bedside’

  1. Top of page
  2. Keynote lecture: the biology of cancer metastasis
  3. SMR plenary session I: new insights into melanoma biology
  4. SMR plenary session II: novel drivers of melanoma initiation, progression, and resistance
  5. Special SMR session: late-breaking clinical trial results, part 1
  6. SMR breakout session IA: understanding melanoma biology through model systems
  7. Transcriptional control and epigenetic regulation of melanoma: SMR breakout session IB
  8. Breakout session IIA of the SMR: new therapeutic targets and strategies in melanoma
  9. Breakout session IIB – implications of melanocyte development for understanding and treating melanoma
  10. SMR/Centers Joint Symposium I: melanoma susceptibility, epidemiology, and prevention
  11. Joint SMR/Centers Symposium II ‘Immunology: from bench to bedside’
  12. Special Session of the SMR Meeting and Melanoma Centres Meeting ‘Late-breaking clinical trial results (previously unreported data), part 2’
  13. Joint SMR/Centres Symposium III: clinically important breakthroughs in melanoma genetic and genomics
  14. Joint SMR/Centers Symposium IV: working together to overcome drug resistance in melanoma
  15. Joint Symposium 1: interdisciplinary melanoma/skin cancers centres meeting and melanoma update for primary care physicians, surgeons, oncologists, and dermatologists: 30 000 foot view: what is new in melanoma 2011
  16. The fourth International Melanoma Pathology Symposium
  17. Difficult case presentations
  18. Session 3: special techniques and molecular advances
  19. Conclusion

Dr Jedd Wolchok (Memorial Sloan Kettering Cancer Center, New York, NY, USA) discussed the preclinical and clinical development of the anti-CTLA4 antibody ipilimumab. Ipilimumab has resulted in low but reproducible antitumor responses in metastatic melanoma, including responses in patients with low-volume brain metastases. These responses follow different kinetics compared to those with cytotoxic agents, resulting in some cases where imaging scans may suggest progressive disease before tumors respond. In two pivotal randomized clinical trials, ipilimumab has demonstrated an improvement in overall survival.

Dr Thomas Gajewski (University of Chicago, Chicago, IL, USA) discussed the current understanding of immunoregulatory barriers within the tumor microenvironment and how to overcome them. Features of the tumor microenvironment that could dominate at the effector phase of the antitumor T-cell response and limit efficacy of current immunotherapies include T-cell trafficking into tumors, immune suppressive mechanisms at tumor sites, tumor cell biology and susceptibility to immune-mediated killing, and the complexities of the tumor stroma (vasculature and fibrosis). It was concluded that an inflammatory gene expression profile in metastatic melanoma might have utility as a predictive biomarker for response to vaccines and other immunotherapies and that a major barrier to effective immune-mediated tumor destruction is poor T-cell migration. Dr Mario Sznol (Yale University, New Haven, CT, USA) discussed the preclinical and clinical results with anti-PD1 antibodies in the treatment for metastatic melanoma. Similar to CTLA4, PD-1 is a negative co-stimulatory regulator of T-cell function that is expressed in recently activated T cells and can be triggered by ligation to the PD-1 ligand (PD-L) in melanoma cells. The anti-human PD-1 antibody MDX-1106 (BMS-936558/ONO-4538) promotes T-cell responses in vitro and has been tested in phase 1/2 clinical trials in patients with advanced melanoma, renal cell carcinoma, prostate cancer, colorectal carcinoma, and non-small cell lung cancer (NSCLC). Among 46 patients with metastatic melanoma enrolled in this dose-ranging study, there were 15 patients with durable partial responses lasting between 5 and 18 months at the time of reporting.

Dr Jeffrey Weber (Moffitt Cancer Center, Tampa, FL, USA) discussed the current developments with adoptive cell transfer (ACT) strategies for the treatment of advanced melanoma, focusing on the expansion and infusion of tumor-infiltrating lymphocytes (TIL). A clinical trial using TIL ACT has been started at Moffitt (MCC 15781) with early evidence of antitumor activity.

Dr Antoni Ribas (University of California, Los Angeles, CA, USA) discussed the potential use of combinations of immunotherapy with BRAF inhibitors. BRAF inhibitors have features of immune-sensitizing agents, based on targeting a key oncogenic pathway specifically in cancer cells resulting in a high frequency of tumor responses, the potential for increasing the expression of ligands for immune cells while not having a detrimental effect on lymphocytes. This concept of combining immunotherapy and BRAF targeted therapy has been tested in a fully immunocompetent mouse model. Testing of the antitumor activity of vemurafenib (PLX4032) in combination with ACT therapy of TCR transgenic mice resulted in improved antitumor activity in two models (OT-1 and pmel-1 models). These data provide support for the clinical testing of such combinations and a model to analyze mechanisms of combinatorial effects that could be used as biomarkers in the clinic.

Dr Stephen Hodi (Dana Farber Cancer Institute, Boston, MA, USA) discussed combinatorial approaches to melanoma using immunotherapy strategies focusing on means to improve on the antitumor activity of the anti-CTLA4 antibody ipilimumab. One approach was data generated using ipilimumab after the melanoma vaccine GVAX. Based on data using a combination of ipilimumab and GM-CSF in patients with advanced prostate cancer, an ECOG phase II trial of GM-CSF plus Ipilimumab has been initiated in patients with advanced melanoma. In addition, an ongoing study is testing the potential synergies of blocking VEGF with bevacizumab in combination with ipilimumab.

Special Session of the SMR Meeting and Melanoma Centres Meeting ‘Late-breaking clinical trial results (previously unreported data), part 2’

  1. Top of page
  2. Keynote lecture: the biology of cancer metastasis
  3. SMR plenary session I: new insights into melanoma biology
  4. SMR plenary session II: novel drivers of melanoma initiation, progression, and resistance
  5. Special SMR session: late-breaking clinical trial results, part 1
  6. SMR breakout session IA: understanding melanoma biology through model systems
  7. Transcriptional control and epigenetic regulation of melanoma: SMR breakout session IB
  8. Breakout session IIA of the SMR: new therapeutic targets and strategies in melanoma
  9. Breakout session IIB – implications of melanocyte development for understanding and treating melanoma
  10. SMR/Centers Joint Symposium I: melanoma susceptibility, epidemiology, and prevention
  11. Joint SMR/Centers Symposium II ‘Immunology: from bench to bedside’
  12. Special Session of the SMR Meeting and Melanoma Centres Meeting ‘Late-breaking clinical trial results (previously unreported data), part 2’
  13. Joint SMR/Centres Symposium III: clinically important breakthroughs in melanoma genetic and genomics
  14. Joint SMR/Centers Symposium IV: working together to overcome drug resistance in melanoma
  15. Joint Symposium 1: interdisciplinary melanoma/skin cancers centres meeting and melanoma update for primary care physicians, surgeons, oncologists, and dermatologists: 30 000 foot view: what is new in melanoma 2011
  16. The fourth International Melanoma Pathology Symposium
  17. Difficult case presentations
  18. Session 3: special techniques and molecular advances
  19. Conclusion

Dr Vernon Sondak (Moffitt Cancer Center, Tampa, FL, USA) asked the question whether the benchmarks from the meta-analysis by Korn and colleagues (JCO 2008; 26:527–534) were still reliable for evaluating phase II clinical trials in stage IV melanoma in 2011. Sondak analyzed SWOG studies since 2005 and compared the results with the Korn data. All arms fell within the 95% confidence intervals of the Korn meta-analysis. In contrast to Korn, Sondak found no significant trial-arm variability for PFS6 or OS12 after adjusting for all prognostic factors. On multivariate analysis, PS1 and increased LDH were significantly associated with shorter PFS and OS, while patients <46 yr old had significantly shorter PFS. In conclusion, both benchmarks were consistent with the Korn data, with minimal between-arm variability.

Dr Thomas Henkel (Targos Molecular Pathology, Germany) reported on the analytic performance of the taqman-based cobas® 4800 BRAF V600E mutation test compared to bidirectional Sanger sequencing in a cohort of 498 specimens from the phase III BRIM3 trial, in which 47% of the cases harbored BRAF mutations.

Dr Grant McArthur (Peter MacCallum Cancer Centre, Melbourne, Australia) reported on a randomized, double-blind, placebo-controlled trial of the novel, orally bioavailable, small molecule PARP-1/PARP-2 inhibitor veliparib (ABT-888), 40 or 20 mg, plus temozolomide versus placebo plus temozolomide for patients with unresectable Stage III/IV metastatic melanoma. Veliparib was well tolerated; however, there was an increased frequency of thrombocytopenia, neutropenia, and leukopenia. The BRAF and NRAS mutation status had no significant impact; p16-positivity or downregulation of the base excision repair protein ERCC1 (by IHC) resulted in longer PFS in the experimental arm (predictive marker), but no significant effect on OS.

Dr Omid Hamid (The Angeles Clinic & Research Institute, Los Angeles, CA, USA) reported on a randomized, open-label, phase III study testing tasisulam sodium versus paclitaxel as second-line treatment in patients with metastatic melanoma. The acylsulfonamide tasisulam has shown activity in second-line metastatic melanoma patients in a previous phase II study. The phase III study compared OS of tasisulam and paclitaxel following first-line chemotherapy with dacarbazine or temozolomide. The analysis of PFS in all patients enrolled did not meet the futility rule, indicating that tasisulam would be unlikely to be superior to paclitaxel if all the patients were followed until progression and/or death.

Joint SMR/Centres Symposium III: clinically important breakthroughs in melanoma genetic and genomics

  1. Top of page
  2. Keynote lecture: the biology of cancer metastasis
  3. SMR plenary session I: new insights into melanoma biology
  4. SMR plenary session II: novel drivers of melanoma initiation, progression, and resistance
  5. Special SMR session: late-breaking clinical trial results, part 1
  6. SMR breakout session IA: understanding melanoma biology through model systems
  7. Transcriptional control and epigenetic regulation of melanoma: SMR breakout session IB
  8. Breakout session IIA of the SMR: new therapeutic targets and strategies in melanoma
  9. Breakout session IIB – implications of melanocyte development for understanding and treating melanoma
  10. SMR/Centers Joint Symposium I: melanoma susceptibility, epidemiology, and prevention
  11. Joint SMR/Centers Symposium II ‘Immunology: from bench to bedside’
  12. Special Session of the SMR Meeting and Melanoma Centres Meeting ‘Late-breaking clinical trial results (previously unreported data), part 2’
  13. Joint SMR/Centres Symposium III: clinically important breakthroughs in melanoma genetic and genomics
  14. Joint SMR/Centers Symposium IV: working together to overcome drug resistance in melanoma
  15. Joint Symposium 1: interdisciplinary melanoma/skin cancers centres meeting and melanoma update for primary care physicians, surgeons, oncologists, and dermatologists: 30 000 foot view: what is new in melanoma 2011
  16. The fourth International Melanoma Pathology Symposium
  17. Difficult case presentations
  18. Session 3: special techniques and molecular advances
  19. Conclusion

The session was opened by Dr Kevin Brown (The National Institutes of Health, Bethesda, MD, USA) who reported the discovery of a novel mutation in MITF that predisposed to melanoma development. In an Australian cohort, the variant allele was significantly over-represented in patients with a family history of melanoma, in those with multiple primary melanomas or in both of these groups. This mutation (also covered by David Fisher in his talk) was at E318K and was found to prevent the sumoylation of MITF. Patients with this germ line mutation were noted to have increased nevus counts and had blue eye color. These data provide the first real proof that MITF can act as a bona fide melanoma oncogene.

The next talk was given by Dr Eric Lau (Dr Ronai’s laboratory at the Sanford-Burnham Medical Research Institute, San Diego, CA, USA) and described interesting new work outlining the role of PKC epsilon in the regulation of ATF2. Dr Lau identified a role for ATF2 at the mitochondria, contributing to cell death following genotoxic stress, which is lost in melanoma cells, pointing to its role in chemoresistance of melanoma cells.

Dr Marcus Bosenberg (Yale University, New Haven, CT, USA) presented data from his laboratory about the role of Wnt/beta-catenin in the regulation of melanoma metastasis in the setting of activation of BRAF and loss of PTEN in mouse models of melanoma and in human melanomas.

Dr David Solit (Memorial Sloane-Kettering Cancer Center, New York, NY, USA) summarized some of the ongoing studies from his group exploring the genetic basis of RAF inhibitor resistance in melanoma. New work was presented identifying a novel truncated (61 kDa) splice form of BRAF in mediating acquired vemurafenib resistance. The truncated mutant lacked a Ras-binding domain and had the capacity to homodimerize with itself. Cell lines with the BRAF truncation were found to be resistant to BRAF inhibitors but retained sensitivity to MEK inhibitors. There was evidence of BRAF truncations occurring in specimens from patients with melanoma failing BRAF inhibitor therapy.

Joint SMR/Centers Symposium IV: working together to overcome drug resistance in melanoma

  1. Top of page
  2. Keynote lecture: the biology of cancer metastasis
  3. SMR plenary session I: new insights into melanoma biology
  4. SMR plenary session II: novel drivers of melanoma initiation, progression, and resistance
  5. Special SMR session: late-breaking clinical trial results, part 1
  6. SMR breakout session IA: understanding melanoma biology through model systems
  7. Transcriptional control and epigenetic regulation of melanoma: SMR breakout session IB
  8. Breakout session IIA of the SMR: new therapeutic targets and strategies in melanoma
  9. Breakout session IIB – implications of melanocyte development for understanding and treating melanoma
  10. SMR/Centers Joint Symposium I: melanoma susceptibility, epidemiology, and prevention
  11. Joint SMR/Centers Symposium II ‘Immunology: from bench to bedside’
  12. Special Session of the SMR Meeting and Melanoma Centres Meeting ‘Late-breaking clinical trial results (previously unreported data), part 2’
  13. Joint SMR/Centres Symposium III: clinically important breakthroughs in melanoma genetic and genomics
  14. Joint SMR/Centers Symposium IV: working together to overcome drug resistance in melanoma
  15. Joint Symposium 1: interdisciplinary melanoma/skin cancers centres meeting and melanoma update for primary care physicians, surgeons, oncologists, and dermatologists: 30 000 foot view: what is new in melanoma 2011
  16. The fourth International Melanoma Pathology Symposium
  17. Difficult case presentations
  18. Session 3: special techniques and molecular advances
  19. Conclusion

Dr Michael Davies (MD Anderson, Houston, TX, USA) opened the Joint SMR/Centers symposium IV. He initially described the clinical manifestation of resistance to RAF inhibitors. Then, he proceeded to give a comprehensive overview of the pathways associated with resistance to RAF inhibitors. He described how these pathways broadly fall into two categories: ERK1/2 pathway reactivation (for example, secondary mutations in NRAS) and activation of alternative/compensatory pathways (for example, loss to the tumor suppressor PTEN leading to PI-3 kinase activation).

Dr Meenhard Herlyn (The Wistar Institute, Philadelphia, PA, USA) discussed melanoma heterogeneity in terms of a dynamic stemness model. Overall, he emphasized that input from the tumor microenvironment influenced the expression of stemness markers and highlighted two examples. In the first example, he showed that CD20 expression in melanoma cells was controlled by IGF-1 derived from the tumor-infiltrating B cells. Secondly, he showed that hypoxia was important for the regulation of both JARID1B and CD271 expression. JARID1B has been previously reported by the Herlyn group to be important for the maintenance of tumor growth properties during repeated passaging in mice. CD271 was shown by the Weissman group to be a marker of human melanoma-initiating cells.

Dr Roger Lo (University of California Los Angeles, CA, USA) focused his talk on resistance to BRAF inhibitors. One published mechanism of ERK1/2 pathway reactivation is the acquisition of activating MEK1 mutations (e.g., P124S). Dr Lo’s studies utilized deep sequencing to detect MEK1 mutations in tumors from mutant patients with BRAF in RAF inhibitor trials. Importantly, MEK1 mutations were present in the pretreatment as well as the relapse sample. Many of the BRAF/MEK1 mutant patients showed a partial response to RAF inhibitors. Furthermore, in cell-based assays, MEK1 P124S was not sufficient to confer resistance to RAF inhibitors. Together, these data argue that MEK1 mutations that are concurrent with BRAF mutations do not reactivate the pathway in the presence of RAF inhibitors.

Dr Richard Kefford (Westmead Hospital, Sydney, Australia) reviewed clinical observations with the combined use of the RAF inhibitor, GSK2118436, and the MEK inhibitor, GSK1120212. This trial is based on the knowledge that a high percentage of relapsed cases in RAF inhibitor alone–treated patients show MEK-ERK1/2 pathway reactivation and the observed synergy of the two drugs on the growth of melanoma cells in preclinical studies. Dr Kefford described an ongoing phase I/II study that has enrolled approximately 450 patients. In the dose escalation, it was found that both drugs could be given at full dose. The response rate was 50–77% depending on the dose given, and 83% of the patients remain on treatment. While these studies are ongoing, it is hoped that the combination of RAF and MEK inhibitors may abrogate some of the resistance observed with RAF inhibitors alone.

Professor Dirk Schadendorf (University Hospital Essen, Essen, Germany) gave an overview of the joint MEK inhibitor/PI3-kinase inhibitor trials. One study across multiple tumors types using the inhibitors GDC-0973 (MEK inhibitor) and GDC-0941 (PI3-kinase inhibitor) has enrolled 62 patients. Only six of the patients stayed on the drug combination after 14 weeks of treatment, three of whom were patients with melanoma. The combination is being well tolerated, there appear to be early signs of clinical activity, and the dose escalation continues. Multiple other trials involving MEK inhibitor and PI3-kinase inhibitor trials from other pharmaceutical companies are currently at early stages.

Dr Ravi Amaravadi (University of Pennsylvania, Philadelphia, PA, USA) discussed autophagy as a resistance mechanism to RAF inhibitors. He reviewed his published data showing that elevated tumor cell autophagy levels predict poor outcomes in patients with melanoma. In cell-based assays, use of hydroxychloroquine to inhibit autophagy enhanced vemurafenib-mediated cell death in intrinsically resistant melanoma cells. However, in cell lines that have acquired resistance to vemurafenib, basal autophagy was constitutively high. This led to the therapeutic strategy of RAF inhibitor, hydroxychloroquine plus rapamycin, the latter being used to induce autophagy further when combined with a BRAF inhibitor. This triple therapy induced apoptosis markers and cytotoxicity in MTT and 3D spheroid assays.

Finally in this session, Dr Amaya Viros (The Institute of Cancer Research, London, UK) described how RAF inhibitors accelerate the rate of growth of cutaneous squamous cell carcinomas (cuSCC)/keratoacanthomas (KA). Using the tumor initiator (DMBA)/tumor promoter (TPA), tumor promoter model that produces mutant HRAS tumors, PLX4720 accelerated the growth of cuSCC/KAs by shortening the latency to tumor development. In studies using RAS-transformed keratinocytes, PLX4720 hyperactivated the ERK1/2 pathway, enhanced BRAF-CRAF heterodimer formation, and promoted proliferation. Consistent with a role for the paradoxical activation of the MEK-ERK1/2 pathway, MEK inhibitors inhibited the PLX4720-induced acceleration of cuSCC/KA growth.

Joint Symposium 1: interdisciplinary melanoma/skin cancers centres meeting and melanoma update for primary care physicians, surgeons, oncologists, and dermatologists: 30 000 foot view: what is new in melanoma 2011

  1. Top of page
  2. Keynote lecture: the biology of cancer metastasis
  3. SMR plenary session I: new insights into melanoma biology
  4. SMR plenary session II: novel drivers of melanoma initiation, progression, and resistance
  5. Special SMR session: late-breaking clinical trial results, part 1
  6. SMR breakout session IA: understanding melanoma biology through model systems
  7. Transcriptional control and epigenetic regulation of melanoma: SMR breakout session IB
  8. Breakout session IIA of the SMR: new therapeutic targets and strategies in melanoma
  9. Breakout session IIB – implications of melanocyte development for understanding and treating melanoma
  10. SMR/Centers Joint Symposium I: melanoma susceptibility, epidemiology, and prevention
  11. Joint SMR/Centers Symposium II ‘Immunology: from bench to bedside’
  12. Special Session of the SMR Meeting and Melanoma Centres Meeting ‘Late-breaking clinical trial results (previously unreported data), part 2’
  13. Joint SMR/Centres Symposium III: clinically important breakthroughs in melanoma genetic and genomics
  14. Joint SMR/Centers Symposium IV: working together to overcome drug resistance in melanoma
  15. Joint Symposium 1: interdisciplinary melanoma/skin cancers centres meeting and melanoma update for primary care physicians, surgeons, oncologists, and dermatologists: 30 000 foot view: what is new in melanoma 2011
  16. The fourth International Melanoma Pathology Symposium
  17. Difficult case presentations
  18. Session 3: special techniques and molecular advances
  19. Conclusion

Dr Richard Scolyer (Melanoma Institute, Sydney, Australia) reported on evolving concepts in the histological and molecular classification of melanoma. Dr Scolyer showed data demonstrating that BRAF-mutated melanomas are typically tumors of the superficial spreading type with a high degree of pigmentation, pagetoid spread, are well circumcised and show a low degree of solar elastosis. BRAF mutations typically occur in younger patients with low degree of sun damage and more often on the trunk. C-KIT mutations were originally thought to be as frequent as in 30% of mucosal, acral lentiginous and chronically sun-damaged skin; although this has not been found to be reproducible. In the Australian experience, only about 10% of acral lentiginous harbor the C-KIT mutation, and these mutations are rare in chronically sun damage.

Dr John Thompson (Melanoma Institute, Sydney, Australia) presented an update of the results of MSLT-1 and the role of sentinel lymph node (SLN) biopsy. Benefits of performing a SLN evaluation included more accurate staging with better information of prognosis as well as improved local control. Positive SLN status in patients with intermediate risk melanoma was prognostic for a higher recurrence rate. The prognostic significance was maintained in the high-risk group with tumors of thickness >3.5mm but not in tumors with a thickness of <1.2mm

Dr Sanjiv Agarwala (St Lukes Hospital, Bethlehem, PA, USA) gave an overview of the state of adjuvant therapy. He highlighted the need for adjuvant therapy given the high rate of progression in patients with stage III melanoma and the observation that tumor progression limited the chance of ever achieving a cure.

Dr Antoni Ribas (University of California, Los Angeles, CA, USA) discussed immunotherapy’s current state in the treatment for melanoma. He began by remarking that the ability of immunotherapy to elicit long-term survival in a small percentage of patients challenged the notion that metastatic cancer is a universally fatal disease. Activation of T lymphocytes can occur via cytokines such as IL-2, IFN, via vaccines or by preventing downregulation of T cells by drugs such as ipilimumab, anti-CD40 antibodies, or anti-PD-1 antibodies. Adoptive cell transfer therapy was noted to be another way to stimulate the immune system against the cancer.

Dr Grant McArthur (Peter MacCallum Cancer Centre, Melbourne, Australia) discussed the new genomic era of melanoma therapies. This era has been defined by BRAF inhibition and vemurafenib. Vemurafenib has been shown to improve overall survival in patients with BRAF mutant melanoma and the emerging data also suggest that clinical responses can be seen following the treatment of c-KIT-mutated melanoma patients with imatinib.

Dr Alexander Eggermont (Cancer Institute Gustave Roussy, France) presented the Keynote Address in which he offered a glimpse into the possible future of melanoma treatment. The key to the future of adjuvant therapy hinges upon the appropriate selection of patients.

The fourth International Melanoma Pathology Symposium

  1. Top of page
  2. Keynote lecture: the biology of cancer metastasis
  3. SMR plenary session I: new insights into melanoma biology
  4. SMR plenary session II: novel drivers of melanoma initiation, progression, and resistance
  5. Special SMR session: late-breaking clinical trial results, part 1
  6. SMR breakout session IA: understanding melanoma biology through model systems
  7. Transcriptional control and epigenetic regulation of melanoma: SMR breakout session IB
  8. Breakout session IIA of the SMR: new therapeutic targets and strategies in melanoma
  9. Breakout session IIB – implications of melanocyte development for understanding and treating melanoma
  10. SMR/Centers Joint Symposium I: melanoma susceptibility, epidemiology, and prevention
  11. Joint SMR/Centers Symposium II ‘Immunology: from bench to bedside’
  12. Special Session of the SMR Meeting and Melanoma Centres Meeting ‘Late-breaking clinical trial results (previously unreported data), part 2’
  13. Joint SMR/Centres Symposium III: clinically important breakthroughs in melanoma genetic and genomics
  14. Joint SMR/Centers Symposium IV: working together to overcome drug resistance in melanoma
  15. Joint Symposium 1: interdisciplinary melanoma/skin cancers centres meeting and melanoma update for primary care physicians, surgeons, oncologists, and dermatologists: 30 000 foot view: what is new in melanoma 2011
  16. The fourth International Melanoma Pathology Symposium
  17. Difficult case presentations
  18. Session 3: special techniques and molecular advances
  19. Conclusion

Perspectives on classification and staging of melanocytic neoplasms

Dr Artur Zembowicz (Tufts Medical School, Boston, MA, USA) opened the session by discussing the controversial area of diagnostically challenging melanocytic lesions that cannot be unequivocally classified as nevus or melanoma based on histologic evaluation of the primary tumor. Such lesions have been referred to as borderline or melanocytic tumors of uncertain malignant potential (MELTUMP). The term ‘melanocytoma’ has recently been proposed for this group of lesions. The nevus/melanocytoma/melanoma paradigm may provide a useful intellectual framework to understand, research, and clinically manage borderline melanocytic tumors.

The next speakers presented an update on the proper microscopic evaluation and reporting of primary cutaneous melanoma, as well as a reappraisal of some prognostic features. Dr Richard Scolyer (Melanoma Institute of Australia, Sydney, Australia), presented an update on the melanoma pathology report, including key elements and prognostic factors to be included. Dr Alan Spatz, McGill University, Montreal, Canada, delivered a critical reexamination of the AJCC and Melanoma Staging. Methodologies for the quantitative analysis of standardized panels of prognostic factors and biomarkers for melanoma were discussed in this presentation. The abandonment of outdated nomenclature and subjective, poorly reproducible histological and prognostic factors was encouraged. In particular, the lack of uniformity in reporting mitotic activity in the past was discussed, and the exact methodology endorsed by the AJCC was presented. Dr David Elder of University of Pennsylvania, Philadelphia, PA gave an update on prognosis in thin melanoma. He reviewed the multivariable model developed in the Penn Pigmented Lesion Group (PPLG) that identified patients with thin melanomas whose prognosis varies from 99% to about 70% disease-free survival. Prognosis declines with increasing thickness, modified by ulceration, mitotic rate, and other attributes. Mitogenicity appears to be of particular importance in thin melanomas. Dr Alistair Cochran (University of California, Los Angeles, CA, USA) presented a summary of the latest analyses from his institution concerning the prognostic impact of sentinel lymph node (SLN) biopsy. Mature analysis of patients with MSLT1 (median follow-up, 9.2 yr) has indicated a favorable outcome for patients with melanoma managed by SLNB with immediate completion lymphadenectomy for tumor-positive SN. These patients have achieved significantly longer regional and distant disease-free intervals and significantly better disease-specific survival. Dr Martin Cook, University of Surrey, Guildford, UK, presented a session entitled ‘A New Look at Nodular Melanoma’, to address the unresolved question of whether nodular melanoma (NM) is a predetermined aggressive melanoma or an aggressive end stage of other types. In common with other cutaneous melanomas, NRAS and BRAF are mutated in ∼31% and 43% of cases respectively of NM, suggesting that the apparently distinctive clinical and pathological features of NM are driven by genetic aberrations other than these common driver oncogenes. Preliminary data from whole-exome sequencing and array comparative genome hybridization were presented.

Difficult case presentations

  1. Top of page
  2. Keynote lecture: the biology of cancer metastasis
  3. SMR plenary session I: new insights into melanoma biology
  4. SMR plenary session II: novel drivers of melanoma initiation, progression, and resistance
  5. Special SMR session: late-breaking clinical trial results, part 1
  6. SMR breakout session IA: understanding melanoma biology through model systems
  7. Transcriptional control and epigenetic regulation of melanoma: SMR breakout session IB
  8. Breakout session IIA of the SMR: new therapeutic targets and strategies in melanoma
  9. Breakout session IIB – implications of melanocyte development for understanding and treating melanoma
  10. SMR/Centers Joint Symposium I: melanoma susceptibility, epidemiology, and prevention
  11. Joint SMR/Centers Symposium II ‘Immunology: from bench to bedside’
  12. Special Session of the SMR Meeting and Melanoma Centres Meeting ‘Late-breaking clinical trial results (previously unreported data), part 2’
  13. Joint SMR/Centres Symposium III: clinically important breakthroughs in melanoma genetic and genomics
  14. Joint SMR/Centers Symposium IV: working together to overcome drug resistance in melanoma
  15. Joint Symposium 1: interdisciplinary melanoma/skin cancers centres meeting and melanoma update for primary care physicians, surgeons, oncologists, and dermatologists: 30 000 foot view: what is new in melanoma 2011
  16. The fourth International Melanoma Pathology Symposium
  17. Difficult case presentations
  18. Session 3: special techniques and molecular advances
  19. Conclusion

This session highlighted some of the most persistent diagnostic controversies in the area of melanocytic pathology: spitzoid melanocytic lesions, melanocytic proliferations in sun-damaged skin, and desmoplastic melanocytic lesions. Dr Lori Lowe (University of Michigan, Ann Arbor, MI, USA) presented the latest data concerning diagnosis and management of Spitz Nevi and atypical Spitz tumors. Considerable controversy still surrounds the characterization of spitzoid melanocytic neoplasms, the ability to predict their natural history, and consequently their appropriate management. Dr Alistair Cochran then presented a reappraisal and critical literature review concerning the optimum margins for wide local excisions of melanocytic lesions. The extent of surgical margins needed for the management of atypical melanocytic lesions, including both in situ and invasive melanoma, remains a complex issue that has not yet been adequately addressed. Dr Jane Messina (Moffitt Cancer Center, Tampa, FL, USA) discussed issues concerning diagnosis and treatment for melanocytic proliferations in sun-damaged skin. Accurate diagnosis of melanocytic proliferations in chronically sun-damaged skin is challenging, in both biopsy and therapeutic excision settings. Methods used to analyze pigmented lesions suspected to represent lentigo maligna (LM) include (in addition to conventional microscopy) immunohistochemical staining, image analysis of nuclear morphometric features, and in vivo reflectance confocal microscopy. Dr Christopher Shea (University of Chicago, Chicago, IL, USA) presented a treatise on desmoplastic melanocytic lesions, highlighting the distinction between desmoplastic nevus, a wholly benign entity, and desmoplastic melanoma (DMM). DMM is notoriously easy to miss, for several reasons. First, DMM cells are frequently obscured by the stromal response, simulating a scar; this pitfall is especially hazardous in reexcision specimens in which both true scar tissue and DMM are present. Second, in contrast to most types of primary cutaneous melanoma, an in situ component is frequently absent from DMM. Third, DMM usually exhibits minimal if any immunohistochemical expression of specific markers of melanocytic differentiation such as gp100 (HMB-45), Melan A/MART-1, and microphthalmia transcription factor; however, expression of S-100 protein is uniformly strong. Clues to the diagnosis of DMM upon low-magnification inspection include the presence of deep infiltrates of lymphocytes deep in the dermis; at higher power, cytologically atypical spindle cells are evident.

Session 3: special techniques and molecular advances

  1. Top of page
  2. Keynote lecture: the biology of cancer metastasis
  3. SMR plenary session I: new insights into melanoma biology
  4. SMR plenary session II: novel drivers of melanoma initiation, progression, and resistance
  5. Special SMR session: late-breaking clinical trial results, part 1
  6. SMR breakout session IA: understanding melanoma biology through model systems
  7. Transcriptional control and epigenetic regulation of melanoma: SMR breakout session IB
  8. Breakout session IIA of the SMR: new therapeutic targets and strategies in melanoma
  9. Breakout session IIB – implications of melanocyte development for understanding and treating melanoma
  10. SMR/Centers Joint Symposium I: melanoma susceptibility, epidemiology, and prevention
  11. Joint SMR/Centers Symposium II ‘Immunology: from bench to bedside’
  12. Special Session of the SMR Meeting and Melanoma Centres Meeting ‘Late-breaking clinical trial results (previously unreported data), part 2’
  13. Joint SMR/Centres Symposium III: clinically important breakthroughs in melanoma genetic and genomics
  14. Joint SMR/Centers Symposium IV: working together to overcome drug resistance in melanoma
  15. Joint Symposium 1: interdisciplinary melanoma/skin cancers centres meeting and melanoma update for primary care physicians, surgeons, oncologists, and dermatologists: 30 000 foot view: what is new in melanoma 2011
  16. The fourth International Melanoma Pathology Symposium
  17. Difficult case presentations
  18. Session 3: special techniques and molecular advances
  19. Conclusion

This session kicked off with a spirited discussion of the nomenclature involved in diagnosis of so-called dysplastic nevi, as well as the pros and cons of grading of these lesions and the implications for therapy. Dr Lyn Duncan of Massachusetts General Hospital, Boston, MA, USA, presented a viewpoint concerning grading and treatment of dysplastic melanocytic nevi, emphasizing the importance of these lesions as mimics, risk markers, and precursors of melanoma. Dr Frank Glass from Moffitt Cancer Center, Tampa, FL, USA, presented the contrary viewpoint, countering that grading of dysplastic nevi does not predict transformation to melanoma. He highlighted the debate over the issue of whether ‘dysplastic nevi’ are potential precursors of melanoma and as well as over histologic grading of these lesions. After this discussion, Dr Michael Piepkorn of University of Washington, Seattle, WA, wrapped up the session with a talk entitled ‘How to Resolve the Problems of Dysplastic Nevi’. He emphasized that it is unlikely that many of the controversies surrounding dysplastic nevi will be put rest in the near future. However, new studies are currently underway that will likely provide new insights into why cutaneous melanocytic lesions prove so difficult to interpret. Dr Boris Bastian, PhD of University of California, San Francisco, CA, USA, then discussed molecular advances in melanoma, highlighting a recent investigations describing inactivating germ line mutations of BAP1, which encodes a ubiquitin carboxyterminal hydrolase in a series of patients with melanocytic neoplasms showing epithelioid cell features. Later, in the same session, the topic of FISH for melanocytic lesions was presented by Dr Pedram Gerami of Northwestern University, Chicago, IL. In this update, he reviewed initial studies which identified 6p25, 6q23, Cep6, and 11q13 as the four FISH probe panels with the greatest yield for differentiating melanoma from benign nevi. Recently, the addition of 9p21 as an adjunctive probe has been shown to significantly enhance the ability to identify melanomas with Spitzoid morphology. In addition, the probes 8q24 and 11q13 appear highly indicative of aggressive behavior in cases of unequivocal melanoma. Further, melanomas with copy number gains in 8q24 appear to identify an aggressive subgroup of melanomas with highly characteristic clinical and histopathologic features.

Dr Victor Prieto of MD Anderson Cancer Center, Houston, TX, USA, gave a review of mucosal melanocytic lesions. The general properties of benign and malignant melanocytic lesions involving mucosal surfaces were reviewed. Criteria for the distinction of benign nevi from malignant melanoma at these sites were presented.

Dr Gilles Landman of EPM-UNIFESP, Sao Paulo, BR, then showed several unusual presentations of metastatic melanoma. Melanoma metastases may pose difficulties in sorting out the differential diagnosis with a broad spectrum of tumors. Two unusual metastatic melanomas were presented. Dr Raymond Barnhill (University of California, Los Angeles, CA, USA) then presented an update on angiotropism and extravascular migratory metastasis in melanoma. Microscopic satellites (MS) are local micrometastases that correlate with melanoma recurrence and diminished survival. Analysis of the relationship between angiotropism and MS has confirmed that angiotropism is more prevalent in melanomas with MS (23/44, 52%) than in those without (12/44, 27%) (P = 0.017). Further angiotropism is the only factor among several other factors that independently predicts MS formation when analyzed by binary logistic regression (P < 0.02). Of particular interest, a subset of melanomas with diffuse (at least four MS) angiotropic MS seemed to predict for a fatal outcome.

Next, the issues of stem cells in melanoma which are germane to the pathologist were presented. Dr Joost van den Oord of Catholic University, Leuven, Belgium, detailed studies which have been conducted to isolate melanoma stem cells (CSC) starting from fresh frozen patient’s melanoma samples. Following this, Dr George F. Murphy of Brigham and Women’s Hospital, Boston, MA, USA, presented a talk entitled ‘Melanoma stem cells: not rare, but well-done’. Recent investigations in this rapidly evolving field were reviewed. New biomarkers such as the ABCB5 (ATP-binding cassette, subfamily B, member 5) transporter protein and CD271 are now available to identify and potentially target melanoma stem cells with potentially aggressive properties. Dr Victor Tron (Queen’s University, Kingston, ON, Canada) then discussed the application of microRNAs to melanocytic lesions. Previous studies have shown that miR-193b expression is reduced in melanoma relative to benign nevi and also that miR-193b represses Cyclin D1 and Mcl-1 expression.

Conclusion

  1. Top of page
  2. Keynote lecture: the biology of cancer metastasis
  3. SMR plenary session I: new insights into melanoma biology
  4. SMR plenary session II: novel drivers of melanoma initiation, progression, and resistance
  5. Special SMR session: late-breaking clinical trial results, part 1
  6. SMR breakout session IA: understanding melanoma biology through model systems
  7. Transcriptional control and epigenetic regulation of melanoma: SMR breakout session IB
  8. Breakout session IIA of the SMR: new therapeutic targets and strategies in melanoma
  9. Breakout session IIB – implications of melanocyte development for understanding and treating melanoma
  10. SMR/Centers Joint Symposium I: melanoma susceptibility, epidemiology, and prevention
  11. Joint SMR/Centers Symposium II ‘Immunology: from bench to bedside’
  12. Special Session of the SMR Meeting and Melanoma Centres Meeting ‘Late-breaking clinical trial results (previously unreported data), part 2’
  13. Joint SMR/Centres Symposium III: clinically important breakthroughs in melanoma genetic and genomics
  14. Joint SMR/Centers Symposium IV: working together to overcome drug resistance in melanoma
  15. Joint Symposium 1: interdisciplinary melanoma/skin cancers centres meeting and melanoma update for primary care physicians, surgeons, oncologists, and dermatologists: 30 000 foot view: what is new in melanoma 2011
  16. The fourth International Melanoma Pathology Symposium
  17. Difficult case presentations
  18. Session 3: special techniques and molecular advances
  19. Conclusion

The role of mutant BRAF in melanoma progression and as a therapeutic target has continued to be a major theme of the International Melanoma Congress and is likely to be so for many years to come. Our growing understanding of melanoma biology and the development of new agents to combine with BRAF inhibitors (such as immunotherapy and other signal transduction inhibitors) continues to drive progress at an incredible rate. We look forward to next year’s SMR meeting being held in Hollywood, CA, organized by Dr Antoni Ribas and Dr Roger Lo.