Identification of Actionable Genomic Alterations Using Circulating Cell-Free DNA

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.

FIG 1.

Flow diagram that depicts the overall utility of cell-free DNA (cfDNA) in identifying actionable alterations in patients with advanced cancers. A total of 575 patients was enrolled, of whom 76.2% (n = 438) had at least one alteration reported. Of these 438, 81.5% (n = 357) had at least one alteration reported within an actionable gene, of whom in turn, 54.7% (n = 205) had at least one high potential for clinical action alteration. Hence, of the original 575 patients tested, 35.6% (n = 205) had at least one alteration classified as having a high potential for clinical action.

FIG 2.

Landscape of molecular alterations identified. (A) Commonly reported alterations by gene and alteration type. (B) Amplification levels of genes with copy number alterations. (C) Most frequently altered genes with consideration of each variant’s potential for clinical action. Shown are the most frequently altered genes in 205 patients with at least one alteration classified as high potential for clinical action. Indel, insertion/deletion alteration; SNV, single nucleotide variant.

FIG 3.

Identification of clinically actionable alterations and clinical trials by disease type. (A) Distribution of clinically actionable alterations by disease type. (B) Identification of clinical trials across all disease types in the context of variant’s potential for clinical action.

FIG 4.

(A) Clinical management outcomes of patients with at least one variant of high potential for clinical action identified. (B) Reasons why genomic alterations were not acted upon in patients with at least one variant of high clinical potential identified. ^a2. ^b3. ^c5. ^d6. ^e7. ^f11. ^g26. ^h27. Mets, metastases; PS, performance status.