PTEN loss-of-function alterations are associated with intrinsic resistance to BRAF inhibitors in metastatic melanoma Journal Article
| Authors: | Catalanotti, F.; Cheng, D. T.; Shoushtari, A. N.; Johnson, D. B.; Panageas, K. S.; Momtaz, P.; Higham, C.; Won, H. H.; Harding, J. J.; Merghoub, T.; Rosen, N.; Sosman, J. A.; Berger, M. F.; Chapman, P. B.; Solit, D. B. |
| Article Title: | PTEN loss-of-function alterations are associated with intrinsic resistance to BRAF inhibitors in metastatic melanoma |
| Abstract: | PurposeTheclinical use ofBRAFinhibitors 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. © 2018 American Society of Clinical Oncology. |
| Keywords: | adult; cancer survival; controlled study; human tissue; aged; chronic myelomonocytic leukemia; human cell; major clinical study; overall survival; exon; histopathology; monotherapy; treatment duration; allele; disease association; ipilimumab; progression free survival; gene expression profiling; tumor regression; prediction; gene identification; drug response; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; cancer tissue; loss of function mutation; metastatic melanoma; b raf kinase inhibitor; pten gene; vemurafenib; mitogen activated protein kinase kinase inhibitor; akt signaling; next generation sequencing; response evaluation criteria in solid tumors; dabrafenib; trametinib; nivolumab; human; male; female; priority journal; article; pembrolizumab; cobimetinib |
| Journal Title: | JCO Precision Oncology |
| Volume: | 1 |
| ISSN: | 2473-4284 |
| Publisher: | American Society of Clinical Oncology |
| Date Published: | 2017-01-01 |
| Start Page: | PO.16.00054 |
| Language: | English |
| DOI: | 10.1200/po.16.00054 |
| PROVIDER: | scopus |
| PMCID: | PMC7446400 |
| PUBMED: | 32913971 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 13 January 2023 -- Source: Scopus |
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