Clinical Benefit for Patients When Treated Based on ctDNA Findings

CHICAGO —Nearly half of patients with advanced cancer treated with FDA-approved therapies had alterations in circulating tumor DNA (ctDNA), with 27% having actionable resistance to alterations, a study presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting has shown.¹

“Advanced cancers shed tumor DNA into the bloodstream,” explained Philip C. Mack, PhD, Director of molecular pharmacology at UC Davis Health System in California. “ctDNA can provide a global summary of tumor heterogeneity.”

Although next-generation sequencing of ctDNA enables non-invasive profiling of solid tumors, liquid biopsy studies to date have been limited by relatively small sample sizes and case studies. Researchers therefore sought to assess the clinical accuracy and utility of next-generation sequencing of ctDNA on a large population scale.

Investigators determined the somatic genomic profiles of more than 15,000 patients with advanced cancer, by using a highly accurate, deep-coverage ctDNA next-generation targeting sequence, which test targeted critical exons in 70 genes. Researchers then compared the frequencies of somatic ctDNA alterations per gene with those previously described in The Cancer Genome Atlas (TCGA).

Results showed that the cohort consisted of lung (37%), breast (14%), colorectal (10%) and other cancers (38%), with ctDNA clinical sensitivity of 86%, 83%, 85%, and 78%, respectively. There was a 94% to 100% positive predictive value for ctDNA next-generation sequencing across 6 key biomarkers, including TP53, KRAS, and PIK3CA.

“ctDNA alteration patterns were highly similar to TCGA tissue alteration patterns, with the exception of secondary resistance mechanisms, such as EGFR T790M, which was frequently found in the ctDNA cohort but was rare in the TCGA cohort.

Accuracy of ctDNA sequencing (positive predictive value) was then assessed by comparing the results with those of matched tissue tests for 386 patients. Researchers found that the overall accuracy of ctDNA sequencing in comparison with matched tissue tests was 87%, but when blood and tumor were collected less than 6 months apart, the accuracy increased to 98%.

When ctDNA utility was evaluated in under-genotyped non-small cell lung cancer (NSCLC), the study demonstrated that ctDNA next-generation sequencing increased biomarker yield by 42% in tissue insufficient/partially-genotyped NSCLC.   

Reference

1. Zill OA, Mortimer S, Banks KC, Nagy RJ, Chudova D, Jackson C, et al. Somatic genomic landscape of over 15,000 patients with advanced-stage cancer from clinical next-generation sequencing analysis of circulating tumor DNA. J Clin Oncol. 2016; 34 (suppl; abstr LBA11501).