Identification of Actionable Genomic Alterations Using Circulating Cell-Free DNA

Nora S. Sánchez, PhD; Michael P. Kahle, PhD; Ann Marie Bailey, PhD; Chetna Wathoo, MD; Kavitha Balaji, PhD; Mehmet Esat Demirhan, MD, Dong Yang, PhD; Milind Javle, MD; Ahmed Kaseb, MD; Cathy Eng, MD; Vivek Subbiah, MD; Filip Janku, MD, PhD; Victoria M. Raymond, MS; Richard B. Lanman, MD; Kenna R. Mills Shaw, PhD; Funda Meric-Bernstam, MD

Disclosures

JCO Precis Oncol. 2019;2019(3) 

In This Article

Abstract and Introduction

Abstract

Purpose Cell-free DNA (cfDNA) next-generation sequencing is a noninvasive approach for genomic testing. We report the frequency of identifying alterations and their clinical actionability in patients with advanced/metastatic cancer.

Patients and Methods Prospectively consented patients had cfDNA testing performed. Alterations were assessed for therapeutic implications.

Results We enrolled 575 patients with 37 tumor types. Of these patients, 438 (76.2%) had at least one alteration detected, and 205 (35.7%) had one or more alterations of high potential for clinical action. In diseases with 10 or more patients enrolled, 50% or more had at least one alteration deemed of high potential for clinical action. Trials were identified in 80% of patients (286 of 357) with any alteration and in 92% of patients (188 of 205) with one or more alterations of high potential for clinical action of whom 57.6% (118 of 205) had 6 or more months of follow-up available. Of these patients, 10% (12 of 118) had received genomically matched therapy through enrollment in clinical trials (n = 8), off-label drug use (n = 3), or standard of care (n = 1). Although 88.6% of all patients had a performance status of 0 or 1 upon enrollment, the primary reason for not acting on alterations was poor performance status at next treatment change (28.1%; 27 of 96).

Conclusion cfDNA testing represents a readily accessible method for genomic testing and allows for detection of genomic alterations in most patients with advanced disease. Utility may be higher in patients interested in investigational therapeutics with adequate performance status. Additional study is needed to determine whether utility is enhanced by testing earlier in the treatment course.

Introduction

Molecular profiling of tumors through circulating cell-free DNA (cfDNA) has gained significant traction in recent years because of its noninvasiveness, sensitivity, and quick turnaround time.[1–4] For patients with advanced cancers, specifically those who have either exhausted their solid tumor block or have quickly progressed on compelling intervening therapy, repeat invasive tissue biopsy is necessary to identify driver mutations and/or resistance mechanisms that arise in response to treatment or natural tumor evolution/progression.[3,5] In addition, a single sample can serve as a global representation of the mutational landscape across multiple metastatic lesions.[6–8] Together, these attributes make cfDNA testing especially attractive for patients with advanced cancer where a quick clinical decision is necessary to identify genomically relevant clinical trials.

However, approaches are needed to discern truncal driver alterations from those that later evolve[3] and to prioritize variants for actionability through variant functional annotation, assignment of potential for clinical actionability, and clinical trial matching to guide clinical decision making on the basis of cfDNA testing. In this prospective study of 575 patients with advanced cancers, we provided such postprocessing to evaluate the clinical utility of cfDNA testing in identifying clinically actionable genomic alterations. This entailed the delivery of personalized annotation reports, including functional interpretation of variants and retrieval of genomically relevant clinical trials. However, physicians were allowed to order testing and initiate treatments without waiting for results, as appropriate. We retrospectively reviewed clinical management after cfDNA testing and provide end-to-end evaluation of the clinical potential utility against the true utility of cfDNA testing.

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