Liquid Biopsy Improves Detection of Secondary GIST Mutations Causing Drug Resistance

Charles Bankhead

May 2013, Vol 4, No 4 - Personalized Medicine

Washington, DC—Analysis of circulating DNA provides information about secondary mutations that cause drug resistance in patients with previously treated gastrointestinal stromal tumors (GISTs), reported George D. Demetri, MD, Director of the Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston, at the 2013 American Association for Cancer Research meeting.

Mutations associated with resistance to tyrosine kinase inhibitors (TKIs) were detected in 47% of plasma samples compared with 12% in tissue specimens. The “liquid biopsies” demonstrated high concordance with mutations identified by DNA analysis of tumor specimens.

Most of the KIT resistance mutations occurred in the difficult-to-treat activation loop domain, which has implications for future drug development. “KIT mutations associated with TKI resistance were more readily detected in the plasma than by looking at archival tumor samples.”

More than 90% of GISTs arise from a single-gene mutation that triggers uncontrollable signaling by KIT or PDGFRA. Therapies that target the activated signaling kinase have dramatically improved median survival in patients with GISTs from a few months to more than 5 years.

The use of targeted therapies for GIST shows that secondary mutations can render standard therapies ineffective. The ability to detect and target drug-resistance mutations is essential to the development of effective targeted therapy.

As tumor cells die, their DNA leaks into the bloodstream, possibly providing opportunities to identify most or all of the tumor mutations in a given patient. Liquid biopsies could offer a means to overcoming the limitations of conventional tissue-based biopsies, according to Dr Demetri.

In a recent study by Dr Demetri and colleagues (Demetri GD, et al. Lancet. 2013;381:295-302), comparison of 2 biopsy techniques showed 89% to 100% concordance for primary KIT exon 9 mutations, 79% for primary KIT exon 11 mutations, and 84% overall concordance for the 2 mutations combined.

Mutational analysis also showed that regorafenib resulted in superior disease control versus placebo, irrespective of mutation type, Dr Demetri reported.