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Liquid biopsy identifies mechanisms of acquired drug resistance in GI cancers

Christina Lau
17 Jul 2017

Liquid biopsy at disease progression effectively identifies novel and heterogeneous mechanisms of acquired resistance to targeted therapies in patients with a range of gastrointestinal (GI) cancers, which may help guide subsequent therapy.

In a study presented at the European Society for Medical Oncology (ESMO) 19th World Congress on Gastrointestinal Cancer (WCGC 2017) held in Barcelona, Spain, researchers found that systematic analysis of circulating tumour DNA (ctDNA) at disease progression more effectively captured the heterogeneity of mechanisms of acquired resistance to targeted therapies than parallel tumour biopsies. [WCGC 2017, abstract O-001]

The researchers collected plasma from 35 patients with GI cancers (colorectal cancer [CRC], n=24; biliary cancer, n=8; gastro-oesophageal cancer, n=3) who had initially achieved response or prolonged stable disease with targeted therapies. Plasma was collected at disease progression for next-generation sequencing of ctDNA to identify mechanisms of acquired resistance.

A total of 72 resistance alterations were identified from ctDNA analysis at disease progression. Twenty-eight patients (80 percent) had at least one molecular mechanism of acquired resistance, while 15 patients (43 percent) had more than one resistance alteration.

Among 14 patients with matched progression tumour biopsies, resistance alternations were identified in nine patients (61 percent), all of which were also detected in matched ctDNA. “Of note, in 64 percent of these patients, ctDNA analysis identified additional resistance mechanisms that were not detected in matched tumour biopsies,” reported investigator Dr Aparna Parikh of the Massachusetts General Hospital Cancer Center in Boston, Massachusetts, US.

“In seven patients with multiple progression tumour biopsies available, different resistance alterations were found in distinct metastases. All of the resistance alterations were detected in ctDNA,” she continued. “However, in six patients [86 percent], ctDNA analysis revealed additional resistance alterations not found in multiple tumour biopsies, which reflects extensive heterogeneity in the mechanisms of acquired resistance.”

The researchers also identified critical and/or novel resistance alterations in patients with various tumour types treated with a range of targeted therapies. In 14 of 17 patients with RAS wild-type CRC treated with EGFR antibodies, for example, they detected a total of 28 resistance alterations (13 distinct) affecting KRAS, EGFR extracellular domain, MEK1, MET and ERBB2. In three of five patients with BRAF-mutant CRC treated with BRAF inhibitor combinations, a total of 10 resistance alterations (nine distinct) affecting KRAS, NRAS, BRAF, MEK1 and MEK2 were detected.

In addition, all five patients with FGFR2 fusion-positive biliary cancer treated with an FGFR inhibitor were found to have novel secondary FGFR2 kinase mutations (13 total, eight distinct), with two patients having five concurrent mutations and one having two concurrent mutations. In a patient with MET-amplified gastro-oesophageal cancer treated with a MET inhibitor, the researchers identified two novel secondary mutations in the MET kinase domain.

“Our results suggest that ctDNA analysis at disease progression may be important to guide subsequent therapy in patients with GI cancers,” said Parikh. “Real-time monitoring of ctDNA levels may be a potential approach to predict response and resistance to therapy, as decrease in ctDNA levels by week 4 was found to correlate with response and treatment outcome.”  

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