Utility of Genomic Assessment of Blood-Derived Circulating Tumor DNA (ctDNA) in Patients with Advanced Lung Adenocarcinoma

• Published in: Clinical cancer research 2017-09, Vol.23 (17), p.5101-5111
• Main Authors: Schwaederlé, Maria C, Patel, Sandip P, Husain, Hatim, Ikeda, Megumi, Lanman, Richard B, Banks, Kimberly C, Talasaz, AmirAli, Bazhenova, Lyudmila, Kurzrock, Razelle
• Format: Article
• Language: English
• Subjects: Aberration; Adenocarcinoma; Adenocarcinoma - blood; Adenocarcinoma - drug therapy; Adenocarcinoma - genetics; Adenocarcinoma - pathology; Adenocarcinoma of Lung; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor - blood; Biopsy; Blood; Blood circulation; Circulating Tumor DNA - blood; Clinical trials; Clinical Trials as Topic; Deoxyribonucleic acid; DNA; Epidermal growth factor receptors; Experimental design; Female; Genome, Human - genetics; Genomics; Genotype; Genotyping; High-Throughput Nucleotide Sequencing; Humans; K-Ras protein; Lung Neoplasms - blood; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Lungs; Male; Medical research; Middle Aged; Mutation; Neoplasm Staging; Non-small cell lung carcinoma; p53 Protein; Patients; Therapy
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-16-2497

Genomic alterations in blood-derived circulating tumor DNA (ctDNA) from patients with non-small cell lung adenocarcinoma (NSCLC) were ascertained and correlated with clinical characteristics and therapeutic outcomes. Comprehensive plasma ctDNA testing was performed in 88 consecutive patients; 34 also had tissue next-generation sequencing; 29, other forms of genotyping; and 25 (28.4%) had no tissue molecular tests because of inadequate tissue or biopsy contraindications. Seventy-two patients (82%) had ≥1 ctDNA alteration(s); among these, 75% carried alteration(s) potentially actionable by FDA-approved (61.1%) or experimental drug(s) in clinical trials (additional 13.9%). The most frequent alterations were in the (44.3% of patients), (27.3%), (14.8%), (13.6%), and (6.8%) genes. The concordance rate for alterations was 80.8% (100% vs. 61.5%; ≤1 vs. >1 month between ctDNA and tissue tests; = 0.04) for patients with any detectable ctDNA alterations. Twenty-five patients (28.4%) received therapy matching ≥1 ctDNA alteration(s); 72.3% ( = 16/22) of the evaluable matched patients achieved stable disease ≥6 months (SD) or partial response (PR). Five patients with ctDNA-detected T790M were subsequently treated with a third generation EGFR inhibitor; all five achieved SD ≥ 6 months/PR. Patients with ≥1 alteration with ≥5% variant allele fraction (vs. < 5%) had a significantly shorter median survival ( = 0.012). ctDNA analysis detected alterations in the majority of patients, with potentially targetable aberrations found at expected frequencies. Therapy matched to ctDNA alterations demonstrated appreciable therapeutic efficacy, suggesting clinical utility that warrants future prospective studies. .