Application of Sequencing, Liquid Biopsies, and Patient-Derived Xenografts for Personalized Medicine in Melanoma

Abstract

Targeted therapies and immunotherapies have transformed melanoma care, extending median survival from ∼9 to over 25 months, but nevertheless most patients still die of their disease. The aim of precision medicine is to tailor care for individual patients and improve outcomes. To this end, we developed protocols to facilitate individualized treatment decisions for patients with advanced melanoma, analyzing 364 samples from 214 patients. Whole exome sequencing (WES) and targeted sequencing of circulating tumor DNA (ctDNA) allowed us to monitor responses to therapy and to identify and then follow mechanisms of resistance. WES of tumors revealed potential hypothesis-driven therapeutic strategies for BRAF wild-type and inhibitor-resistant BRAF-mutant tumors, which were then validated in patient-derived xenografts (PDX). We also developed circulating tumor cell–derived xenografts (CDX) as an alternative to PDXs when tumors were inaccessible or difficult to biopsy. Thus, we describe a powerful technology platform for precision medicine in patients with melanoma. Significance: Although recent developments have revolutionized melanoma care, most patients still die of their disease. To improve melanoma outcomes further, we developed a powerful precision medicine platform to monitor patient responses and to identify and validate hypothesis-driven therapies for patients who do not respond, or who develop resistance to current treatments. Cancer Discov; 6(3); 286–99. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 217

Next-Generation Sequencing Analysis and Algorithms for PDX and CDX Models

“…The data utilized in this study were derived from a cutaneous melanoma (20) patient (patient 10) with a BRAF V600E mutation (3). The patient presented with primary melanoma on the back and bilateral axillary nodal metastasis.…”

“…They provide an excellent tool with which to investigate the dynamics of oncogenesis, tumor heterogeneity, evolution, and responses to therapy (1)(2)(3)(4)(5)(6)(7)(8). This has led to considerable interest in combining them with next-generation sequencing (NGS).…”

Prediction of Response to Immune Checkpoint Inhibitor Therapy Using Early-Time-Point18F-FDG PET/CT Imaging in Patients with Advanced Melanoma

“…Small trials have shown that circulating tumor DNA level changes can mirror radiologic changes in tumor burden and may predict eventual response to ICI (34,35). These emerging technologies, which require only serial blood sampling and laboratory analysis, may compare favorably with PET/CT in terms of feasibility and accessibility among an increasing population of patients undergoing therapy with ICI.…”

Patient-Derived-Tumor-Xenograft: modeling cancer for basic and translational cancer research

“…More recently, Girotti et al established a large cohort of 91 melanoma PDTX. Using WES, they integrated the data with ctDNA sequencing and PDTX functional studies to describe a novel strategy for the stratification of naïve patients [61]. Alternatively, PDTX can be used to find protein biomarkers related to drug response.…”