ESMO 2017: Large Dataset of Targetable Genomic Alterations Created Using Liquid Biopsy

Genomic variants identified by NGS of ctDNA that have clinical implications regarding choice of treatment

Liquid biopsies of cell free circulating tumour DNA (ctDNA) represent a non-invasive means of obtaining genomic information and identifying alterations that can help optimize treatment for patients with advanced cancer, according to findings from a large series presented during the ESMO 2017, the Annual Congress of the European Society for Medical Oncology in Madrid, Spain.

Sumanta Kumar Pal, MD, Medical Oncologist at City of Hope, Duarte, USA and colleagues performed liquid biopsies consisting of next-generation sequencing (NGS) of ctDNA to create a large dataset encompassing samples from patients with non-small cell lung cancer (NSCLC), breast cancer, colorectal cancer (CRC), and several other types of solid tumours.

The investigators determined the somatic genomic profiles in 35,492 plasma samples that were obtained from 30,026 patients with advanced cancer using a ctDNA NGS test that targeted up to 73 genes (the Guardant360® assay). The positive predictive value (PPV) of ctDNA-detected driver alterations was assessed by comparing the PPV to available matched tissue tests in 646 patients having lung, colon, and other cancer types.

The series comprised 36.6% of NSCLC samples, 15.6% of breast, 9.2% of CRC, and 38.6% of multiple other solid cancer types, which had detectable ctDNA alterations in 86.7%, 81.8%, 86.4%, and 82%, of samples, respectively. 

Overall, alterations were detected in 83.7% of samples that revealed 19% of patients had one or more ctDNA alterations associated with an FDA-approved therapy.

Resistance to approved drugs also detected in ctDNA samples

Additionally, the investigators identified resistance variants in samples from patients with NSCLC, breast and prostate cancers, CRC, melanoma, and gastrointestinal stromal tumours.

PPV ranged from 92% to 100% across certain driver alterations; PPV was 98% to 100% for EGFR L858R/E19del/E20ins, 92% for ALK/RET/ROS1 fusions, 95% for BRAF V600E, 94% for KRAS G12/G13/Q61, and 100% for MET E14 skipping mutations.

Alterations linked to response to approved drugs

A response rate analysis was performed across published/in press datasets presenting response data to alterations detected by the Guardant360 assay.  It revealed high response rates to ALK inhibitors as well as first-line and second-line EGFR tyrosine kinase inhibitors (TKIs) in NSCLC, and anti-HER2 agents in patients with breast and gastric tumours.

Conclusions

The authors noted that the use of liquid biopsies is increasing in clinical care, which provides an option for obtaining genomic information non-invasively.

This dataset, derived from liquid biopsy use in clinical practice, highlights the utility of identifying alterations that are targetable by drugs with regulatory approval, and the clinical impact of detecting emergent resistance alterations.

Disclosure

No funding was reported.

Reference

1702O – Pal SK, et al. Clinical implications of genomic variants identified in over 30,000 advanced-stage cancer patients by next-generation sequencing of circulating tumor DNA.