title: Evaluation of stromal HGF immunoreactivity as a biomarker for melanoma response to RAF inhibitors.
abstract: Of more than 150 000 published studies evaluating new biomarkers, fewer than 100 biomarkers have been implemented for patient care. One reason for this is lack of rigorous testing by the medical community to validate claims for biomarker clinical relevance, and potential reluctance to publish negative results when confirmation is not obtained. Here we sought to determine the utility and reproducibility of immunohistochemical detection of hepatocyte growth factor (HGF) in melanoma tissue, an approach of potential assistance in defining patients with innate resistance to BRAF inhibitor therapy. To this end, a published and a revised method that retained sensitivity but with greater specificity for HGF detection, were evaluated in cells known to endogenously express HGF, and in models where HGF is upregulated via cytokine induction and via overexpression by gene transfection. Consequent patient evaluation in collaboration with the Melanoma Institute Australia of a cohort of 41 melanoma specimens with extensive clinical annotation failed to validate HGF immunohistochemistry as a predictor of response to BRAF inhibitors. Targeted therapies for advanced melanoma and other cancers show great promise, and rigorous validation studies are thus indicated for approaches that seek to personalize such therapies to maximize therapeutic efficacy.
authors.affiliation: 1] Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA [2] Harvard Medical School, Boston, MA, USA.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Lezcano
authors.affiliation: 1] Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA [2] Harvard Medical School, Boston, MA, USA.
authors.forename: Chung-Wei
authors.initials: CW
authors.lastname: Lee
authors.affiliation: 1] Harvard Medical School, Boston, MA, USA [2] Department of Dermatology, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Allison R
authors.initials: AR
authors.lastname: Larson
authors.affiliation: 1] Melanoma Institute Australia, Sydney, NSW, Australia [2] The University of Sydney, Camperdown, NSW, Australia.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Menzies
authors.affiliation: 1] Melanoma Institute Australia, Sydney, NSW, Australia [2] The University of Sydney, Camperdown, NSW, Australia [3] Westmead Institute for Cancer Research, NSW, Sydney, Australia.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Kefford
authors.affiliation: 1] Melanoma Institute Australia, Sydney, NSW, Australia [2] The University of Sydney, Camperdown, NSW, Australia [3] Mater Hospital, Sydney, NSW, Australia [4] Royal Prince Alfred Hospital, Sydney, NSW, Australia.
authors.forename: John F
authors.initials: JF
authors.lastname: Thompson
authors.affiliation: 1] Harvard Medical School, Boston, MA, USA [2] Department of Dermatology, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Martin C
authors.initials: MC
authors.lastname: Mihm
authors.affiliation: 1] Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA [2] Harvard Medical School, Boston, MA, USA [3] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [4] Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
authors.affiliation: 1] Melanoma Institute Australia, Sydney, NSW, Australia [2] The University of Sydney, Camperdown, NSW, Australia [3] Westmead Institute for Cancer Research, NSW, Sydney, Australia.
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
authors.affiliation: 1] Melanoma Institute Australia, Sydney, NSW, Australia [2] The University of Sydney, Camperdown, NSW, Australia [3] Royal Prince Alfred Hospital, Sydney, NSW, Australia.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
authors.affiliation: 1] Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA [2] Harvard Medical School, Boston, MA, USA.
authors.forename: George F
authors.initials: GF
authors.lastname: Murphy
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D002460:Cell Line; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D007150:Immunohistochemistry; D007211:Indoles / Q000627:therapeutic use; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010091:Oximes / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012867:Skin / Q000166:cytology; D012878:Skin Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D013449:Sulfonamides / Q000627:therapeutic use; D014162:Transfection; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007093:Imidazoles; D007211:Indoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D013449:Sulfonamides; D000077484:Vemurafenib; D017228:Hepatocyte Growth Factor; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib