PTEN Loss-of-Function Alterations Are Associated With Intrinsic Resistance to BRAF Inhibitors in Metastatic Melanoma

Abstract

Purpose: The clinical use of BRAF inhibitors in patients with melanoma is limited by intrinsic and acquired resistance. We asked whether next-generation sequencing of pretreatment tumors could identify coaltered genes that predict for intrinsic resistance to BRAF inhibitor therapy in patients with melanoma as a prelude to rational combination strategies.

Patients and methods: We analyzed 66 tumors from patients with metastatic BRAF-mutant melanoma collected before treatment with BRAF inhibitors. Tumors were analyzed for > 250 cancer-associated genes using a capture-based next-generation sequencing platform. Antitumor responses were correlated with clinical features and genomic profiles with the goal of identifying a molecular signature predictive of intrinsic resistance to RAF pathway inhibition.

Results: Among the 66 patients analyzed, 11 received a combination of BRAF and MEK inhibitors for the treatment of melanoma. Among the 55 patients treated with BRAF inhibitor monotherapy, objective responses, as assessed by Response Evaluation Criteria in Solid Tumors (RECIST), were observed in 30 patients (55%), with five (9%) achieving a complete response. We identified a significant association between alterations in PTEN that would be predicted to result in loss of function and reduced progression-free survival, overall survival, and response grade, a metric that combines tumor regression and duration of treatment response. Patients with melanoma who achieved an excellent response grade were more likely to have an elevated BRAF-mutant allele fraction.

Conclusion: These results provide a rationale for cotargeting BRAF and the PI3K/AKT pathway in patients with BRAF-mutant melanoma when tumors have concurrent loss-of-function mutations in PTEN. Future studies should explore whether gain of the mutant BRAF allele and/or loss of the wild-type allele is a predictive marker of BRAFi sensitivity.

Conflict of interest statement

PTEN Loss-of-Function Alterations Are Associated With Intrinsic Resistance to BRAF Inhibitors in Metastatic MelanomaThe following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or po.ascopubs.org/site/ifc.Federica CatalanottiNo relationship to discloseDonavan T. ChengEmployment: Illumina, Gilead Sciences (I) Stock and Other Ownership Interests: Illumina, Gilead Sciences (I)Alexander N. ShoushtariConsulting or Advisory Role: Vaccinex, Castle Biosciences, Immunocore Research Funding: Bristol-Myers Squibb, Immunocore Travel, Accommodations, Expenses: Bristol-Myers SquibbDouglas B. JohnsonConsulting or Advisory Role: Bristol-Myers Squibb, Genoptix, Merck Research Funding: Incyte Patents, Royalties, Other Intellectual Property: Intellectual property and patents pending surrounding use of MHC-II and response to immune therapyKatherine S. PanageasNo relationship to discloseParisa MomtazNo relationship to discloseCatherine HighamNo relationship to discloseHelen H. WonNo relationship to discloseJames J. HardingNo relationship to discloseTaha MerghoubNo relationship to discloseNeal RosenStock and Other Ownership Interests: Beigene, Wellspring, Kura Honoraria: Novartis, Eli Lilly, Bayer Consulting or Advisory Role: AstraZeneca, Takeda-Millennium, Daiichi Sankyo, Chugai Pharma Research Funding: Wellspring/Araxes, Chugai Pharma Travel, Accommodations, Expenses: PlexxikonJeffrey A. SosmanHonoraria: Amgen, Merck, Array BioPharma Consulting or Advisory Role: Amgen, Merck, Array BioPharmaMichael F. BergerConsulting or Advisory Role: Cancer Genetics, SequenomPaul B. ChapmanHonoraria: Bristol-Myers Squibb, GlaxoSmithKline, Genentech, Provectus, Momenta Pharmaceuticals, Daiichi Sankyo Consulting or Advisory Role: Bristol-Myers Squibb, GlaxoSmithKline, Genentech, Daiichi Sankyo, Provectus, Momenta Pharmaceuticals Research Funding: GlaxoSmithKline, Genentech, Bristol-Myers Squibb, Pfizer Travel, Accommodations, Expenses: Bristol-Myers SquibbDavid B. SolitHonoraria: Loxo, Pfizer Consulting or Advisory Role: Pfizer, Loxo

© 2017 by American Society of Clinical Oncology.

Figures

Fig 1.

Response and response grade of patients with melanoma to BRAF-targeted therapy. (A) Classification of patients according to Response Evaluation Criteria in Solid Tumors (RECIST). (B) Patients were also stratified accordingly to response grade, which incorporates both tumor regression and response duration. (A and B) Left panel: patients treated with BRAF inhibitor (BRAFi) monotherapy; right panel: patients treated with the BRAFi plus MEK inhibitor (MEKi) combinations. (C) Waterfall plot showing best overall response. Left panel: BRAFi cohort (50 patients; in one patient, best overall response was not evaluable as a result of rapid clinical deterioration); right panel: BRAFi + MEKi (11 patients). Each bar represents an individual patient. CR, complete response; NE, not evaluable; PD, progression of disease; PR, partial response; SD, stable disease. (*) Indicates patients who had a PR according to RECIST but a poor response grade. (†) Indicates patient was treated with vemurafenib plus cobimetinib for chronic myelomonocytic leukemia.

Fig 2.

Landscape of most frequently mutated genes across the 66 patients with melanoma treated with BRAF inhibitors. (A) Each bar represents the total percentage of alterations found in each gene in either The Cancer Genome Atlas (TCGA) or Memorial Sloan Kettering/Vanderbilt cohort. P < .05 was considered significant. (B) BRAF mutations were found in all samples (100%), with three of 66 exhibiting coamplification of BRAF. Loss-of-function (LOF) mutations included deep deletions, nonsense mutations, and frameshift alterations predicted to result in early truncation and loss of expression.

Fig 3.

OncoPrint of key pathways altered in the three groups of responders. The OncoPrint highlights the pattern of comutation of 20 genes stratified by response grade into excellent (Exc), intermediate (Int), or poor cohorts. The red arrow identifies the patient tumor treated with the MEK inhibitor for chronic myelomonocytic leukemia. Orange dots indicate complete response and still alive; yellow dots indicate complete response and dead or disease progression. Dark green indicates recurrent and/or activating missense mutation; a cutoff of six recurrences or more reported in the Catalogue of Somatic Mutations in Cancer (COSMIC) in at least two tumor types was used to distinguish a recurrent mutation from a rare event. Light green indicates nonrecurrent missense variant of unknown significance; red indicates amplification; blue indicates deep deletion; black indicates truncating deletion; and orange indicates in-frame mutation.

Fig 4.

CDKN2A and PTEN mutation status as a function of response. Percentage of excellent, intermediate, and poor responders with wild-type (WT), loss-of-function (LOF), or missense mutations in (A) CDKN2A or (B) PTEN. Gold indicates WT; blue indicates missense mutation; gray indicates LOF mutation. (C) Progression-free survival (PFS) and (D) overall survival (OS) for patients with PTEN-mutant (gold line) and PTEN WT (blue line) melanomas.