Clinical implications of genomic variants identified in over 30,000 advanced-stage cancer patients by next-generation sequencing of circulating tumor DNA

Abstract

Background: Next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) enables non-invasive profiling of solid tumor cancers. Over the past few years, research and clinical practice guidelines have highlighted a role for liquid biopsy in patient care; however, few large datasets on clinical use have been published. Methods: Somatic genomic profiles of 35,492 plasma samples from 30,024 advanced cancer patients were determined by a ctDNA NGS test targeting up to 73 genes (Guardant360VR ). Accuracy of ctDNA-detected driver alterations (PPV) was assessed by comparing to available matched tissue tests for 646 patients (lung, colon, and other cancer types). A pooled response rate analysis was performed across published/in press datasets presenting response data to alterations detected by Guardant360VR . Results: The full cohort consisted of non-small cell lung cancer (NSCLC) (39%), breast (16%), colorectal (CRC) (10%) and multiple other solid cancer types (35%), with ctDNA alterations detected in 88%, 86%, 88%, and 82%, respectively (86% overall). 19% of patients had 1 or more ctDNA alterations associated with an FDA-approved therapy. Resistance variants were identified in 18% of NSCLC, breast, CRC, prostate, melanoma and GIST patients. PPV ranged from 92-100% for EGFR L858R/E19del/ E20ins (98%), ALK/RET/ROS1 fusions (92%), BRAF V600E (95%), KRAS G12/G13/ Q61 (94%), and MET E14 skipping mutations (100%). Pooled response rate to 1st line EGFR TKIs (n=43 NSCLC): 86% [95% CI: 71-94%]; to osimertinib (n=19 NSCLC): 94% [72-99%]; to rociletinib (n=63 NSCLC): 54% [41-67%]; to crizotinib (n=11 NSCLC): 82% [48-97%]; to anti-HER2 agents (n=7 breast): 86% [49-97%]; (n=5 gastric): 80% [37-96%]. Conclusions: Use of liquid biopsies is increasing in clinical care, providing an option of obtaining genomic information non-invasively. This dataset, derived from liquid biopsy use in clinical practice, highlights the clinical impact of identifying alterations that are targetable by drugs with regulatory approval, including emergent resistance alterations.