title: Targeted therapies and immune checkpoint inhibitors in the treatment of metastatic melanoma patients: a guide and update for pathologists.
abstract: The previously dismal prospects for patients with advanced stage metastatic melanoma have greatly improved in recent years. Enhanced understanding of both the pathogenesis of melanoma and its molecular drivers, as well as the importance and regulation of anti-tumour immune responses, have provided new therapeutic opportunities for melanoma patients. There are two major distinct categories of systemic treatments with activity for patients with metastatic melanoma: (1) targeted therapies, which act to inhibit the oncogenes that drive the aberrant growth and dissemination of the tumour; and (2) immune checkpoint inhibitor therapies, which act to enhance anti-tumour immune responses by blocking negative regulators of immunity. Pathologists play a critical and expanding role in the selection of the most appropriate treatment for individual metastatic melanoma patients in the modern era of personalised/precision medicine. The molecular pathology testing of melanoma tumour tissue for the presence of targetable oncogenic mutations is already part of routine practice in many institutions. In addition, other potential oncogenic therapeutic targets continue to be identified and pathology testing techniques must readily adapt to this rapidly changing field. Recent research findings suggest that pathological assessment of tumour associated immune cells and immunosuppressive ligand expression of the tumour are likely to be important in identifying patients most likely to benefit from immune checkpoint inhibitors. Similarly, pathological and molecular observations of on-treatment tumour tissue biopsies taken from patients on targeted therapies have provided new insights into the mechanisms of action of targeted molecular therapies, have contributed to the identification of resistance mechanisms to these novel therapies and may be of higher value for selecting patients most likely to benefit from therapies. These data have already provided a rational biological basis for the exciting prospect of combining them to further improve survival rates and this is currently being investigated in clinical trials. Ultimately it may be the responsibility of the pathologist to identify which therapy or combination of therapies is most likely to benefit individual patients.
authors.affiliation: Melanoma Institute Australia, North Sydney, Australia; The University of Sydney, Sydney, Australia.
authors.forename: Hojabr
authors.initials: H
authors.lastname: Kakavand
authors.affiliation: Melanoma Institute Australia, North Sydney, Australia; The University of Sydney, Sydney, Australia.
authors.forename: James S
authors.initials: JS
authors.lastname: Wilmott
authors.affiliation: Melanoma Institute Australia, North Sydney, Australia; The University of Sydney, Sydney, Australia.
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
authors.affiliation: Melanoma Institute Australia, North Sydney, Australia; The University of Sydney, Sydney, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia. Electronic address: richard.scolyer@sswahs.nsw.gov.au.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D060890:B7-H1 Antigen / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D015331:Cohort Studies; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; D015415:Biomarkers; C423236:CD274 protein, human; D008565:Membrane Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human
keywords: BRAF; PD-1; PD-L1; TILs; diagnosis; immune blockade; immunochemistry; melanoma; pathology; targeted therapy; therapy; treatment