Blood Samples Reflect Info From Tumor Biopsies in NSCLC

Alexander M. Castellino, PhD

March 02, 2015

New findings show that it is feasible to determine epidermal growth-factor receptor (EGFR) mutations from the blood samples of patients with advanced non-small cell lung cancer (NSCLC) and correlate them to clinical outcomes. The information is similar to that obtained from tumor tissue biopsies, but blood samples are obviously easier to obtain.

The findings, from an analysis of the phase 3 European Erlotinib Versus Chemotherapy (EURTAC) study, were published online February 26 in JAMA Oncology.

The blood samples were used to determine the circulating free (cf)DNA shed into the blood through one of several mechanisms: release from macrophages or tumors; metastases; or circulating tumor cells.

cfDNA analysis ("liquid biopsy") was a prespecified secondary end point of the EURTAC study, which had previously shown longer progression-free survival in NSCLC patients receiving erlotinib whose their tumors harbor EGFR mutations. That finding was the basis for the approval of erlotinib for the treatment of advanced NSCLC in patients with EGFR-positive tumors.

The idea that cfDNA in blood can accurately predict tumor mutations is attractive because it could eliminate the need for tumor tissue biopsy, which is not always easily available, especially for tumors such as NSCLC.

Liquid biopsy can be used as a surrogate for tumor biopsy, the EURTAC investigators suggest.

Erlotinib Prolongs Survival

TheEURTAC study was conducted by Rafael Rosell, MD, from the Hospital Germans Trias I Pujol in Badalona, Spain, and his colleagues in the Spanish Lung Cancer Group.

They examined baseline EGFR mutations isolated from 97 blood samples taken from patients before treatment with erlotinib.

EGFR mutations were detected in 76 of these samples. Overall survival data were similar when the mutations were detected with cfDNA or with tissue biopsies.

Progression-free survival outcomes were similar to those reported for overall survival. Generally, for patients with EGFR mutations detected with cfDNA, only erlotinib treatment was an independent predictor of longer progression-free survival.

Focusing on Specific Mutations

The EURTAC investigators looked specifically at EGFR mutations with exon 19 deletions or with L858R mutations in exon 21.

They found that overall survival was longer for patients with exon 19 deletions than with L858R mutations detected with cfDNA (30.0 vs 13.7 months) and tissue biopsy (24.9 vs 17.7 months).

For patients receiving erlotinib, overall survival was also longer in those with exon 19 deletions detected with cfDNA than in those with L858R mutations (34.4 vs 13.7 months).

In addition, for patients with L858R mutation in tumor tissue, overall survival was longer when cfDNA analysis did not reveal the L858R mutation (27.7 vs 13.7 months for L858R in tumor tissue); for patients with exon 19 deletion in tumor tissue, overall survival was longer when cfDNA also showed exon 19 deletion (30.0 vs 14.4 months for exon 19 deletion in tumor tissue).

"L858R mutations have significantly worse prognosis than exon 19 deletions, either in the tumor or in the serum, Dr Rosell told Medscape Medical News in an email. The study highlights, "for the first time, that even in the subgroup of patients with EGFR L858R mutations, the coexistence of L858R mutations in the serum leads to significantly poorer prognosis," he added.

More Studies Underway

Dr Rosell reported that two trials — BELIEF and GOAL — are analyzing EGFR mutations in the serum of patients. In these studies, cfDNA analysis is being conducted before treatment, at the time of response, and when disease progresses.

However, he emphasized that in these studies, EGFR tyrosine kinase inhibitors (TKIs) are being used in combination with other drugs. For example, BELIEF is using erlotinib in combination with bevacizumab (Avastin) in patients with EGFR-positive NSCLC (NCT01562028).

"One point of complexity is that single EGFR TKIs are becoming recognized as incomplete treatment in lung cancer patients with EGFR mutations. Both trials could pave the way to improve treatment and could be the first in monitoring EGFR mutations in cfDNA," Dr Rosell explained.

He indicated that the team is planning on closely monitoring for T790M mutations in cfDNA samples. "This can obviate the need for rebiopsy and even anticipate clinical progression," he said.

However, he noted, additional protocols are required to convince the scientific community and health authorities about the need for the routine use of blood testing throughout the course of the disease.

In clinical practice, the "testing of tumor tissue remains the recommended method for detecting the presence of oncogenic EGFR mutations," the EURTAC investigators note.

However, the "amount of tumor tissue obtained by biopsy is often insufficient, especially in advanced NSCLC, raising the question of whether cfDNA may be used as a surrogate liquid biopsy for the noninvasive assessment of EGFR mutations," they add.

Better Evaluation of Tumor Genome Landscape

"The updated EURTAC study demonstrates that mutations detected in cfDNA are prognostic and consistent with data obtained from tumor biopsies," write Roy S. Herbst, MD, PhD, from the Yale School of Medicine in New Haven, Connecticut, and colleagues in an accompanying editorial.

"The potential benefits of liquid biopsies include a better evaluation of the tumor genome landscape with the identification of a comprehensive set of targetable mutations and the serial noninvasive monitoring, which may allow the detection of additional mutations from emerging subclones, including those involved in the development of acquired resistance," the editorialists write.

"Finally, the presence of specific mutations in cfDNA may help identify populations of patients who are likely to have worse (or better) outcomes and who may require alternative treatments," they conclude.

Dr Rosell has disclosed no relevant financial relationships. Two of the study coauthors and all three of the editorialists report financial relationships with pharmaceutical companies.

JAMA Oncol. Published online February 26, 2015. Abstract, Editorial

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