BARCELONA, Spain—Anti-EGFR monoclonal antibodies should only be considered for treatment of metastatic colorectal cancer patients whose tumors are wild type, but determining which patients are eligible by biopsy analysis is time consuming and invasive.
In a retrospective study using data from 150 patients with colorectal cancer, RAS testing of circulating tumor DNA (ctDNA) in plasma showed a strong overall agreement with standard of care testing for EGFR markers for RAS, with an overall concordance of 89.8 percent in patients who had responded to anti-EGFR therapy.
Liquid biopsy of ctDNA “may translate into a significant impact in clinical practice for anti-EGFR treatment selection,” said Julieta Grasselli, MD, Attending Physician and Clinical Investigator, Department of Medical Oncology, Vall d'Hebron Institute of Oncology, Barcelona, in her presentation at the recent European Society of Medical Oncology World Congress on Gastrointestinal Cancer.
The tissue for RAS testing was obtained at the time of diagnosis, 85 percent from primary tumors and 15 percent from metastatic biopsies. The group of patients treated with an anti-EGFR monoclonal antibody had plasma ctDNA analysis performed before their treatment.
The testing was done “in house, in a real-world setting,” Grasselli said.
According to Grasselli, FFPE (formaldehyde fixed-paraffin embedded) tumor tissue is currently the standard of care for RAS testing, but recent studies have shown the possibility of RAS status determination based on ctDNA (J Clin Oncol 2015;33:692-700).
The main benefits of ctDNA analysis are safety and convenience. “The technique is minimally invasive, gives accurate information, is accessible at any time, and confers a limited selection bias for heterogeneity,” Grasselli explained.
The primary objective of the retrospective trial was a concordance analysis of plasma-based RAS mutation testing and tissue-based RAS mutation testing to establish eligibility for anti-EGFR therapy. The secondary objective was progression-free survival in patients who received anti-EGFR therapies, and also overall survival.
The 150 patients on whom data were collected had confirmed metastatic colorectal cancer, had FFPE tissue available for mutational analysis, were anti-EGFR naïve before plasma collection, and showed evidence of measurable disease.
The median age of patients was 65 years, 73 percent were male, and 68 percent had been diagnosed with advanced disease. Prior to plasma extraction, 41 percent were treatment-naïve, 31 percent had received frontline metastatic chemotherapy, 24 percent second-line, and 4 percent third-line and beyond. Median overall survival in the metastatic setting was 35.9 months, with a range of 29.7-42.9 months.
Identical Progression-Free Survivals
In the subset of patients who received anti-EGFR monoclonal antibody treatment plus irinotecan in second- or third-line, those with RAS wild type by standard of care analysis (51 patients) had a median progression-free survival of 8.7 months, with a range of 6.4-10.2 months.
Those with RAS wild type by ctDNA (47 patients) had progression-free survival of 8.7 months, with a range of 6.7-11.2 months.
According to Grasselli, ctDNA RAS determination also identified 10 cases of low frequency RAS mutations that were not detected in tissue. “This could be explained due technical sensitivity, temporal or spatial heterogeneity or procedural errors,” she noted.
On the other hand, in five cases no RAS mutations were detected in plasma. This could have been due to low tumor burden or ctDNA shedding, Grasselli said. “Validation of a concordance between plasma and tissue determination is critical to move ctDNA forward as a surrogate testing in clinical practice.”
“Stethoscope for the Next 200 Years”
The discussant for this paper, Fortunato Ciardiello, MD, PhD, Professor and Head of the Division of Medical Oncology, Seconda Università degli Studi di Napoli, Naples, Italy, was very enthusiastic about this study.
Liquid biopsy will be the “stethoscope for the next 200 years,” he said. “Analysis by ctDNA is highly compliant, minimally invasive, and always accessible, while tumor tissue is not always accessible.
“And it proffers a fresh DNA profile, while archival tissue can have a different mutation profile no selection bias,” he continued.
Furthermore, liquid biopsy accounts for tumor heterogeneity at both primary and metastatic sites, monitoring is possible, and turnaround time is reduced compared with tissue biopsy.
Robert H. Carlson is a contributing writer.