Editors' ChoiceCancer

Lung cancer: A sanguine approach

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Science Translational Medicine  28 Oct 2015:
Vol. 7, Issue 311, pp. 311ec187
DOI: 10.1126/scitranslmed.aad5503

Non–small cell lung cancer (NSCLC) with mutations in the gene encoding epidermal growth factor receptor (EGFR) is sensitive to small-molecule EGFR tyrosine kinase inhibitors (TKI). Although these agents are highly effective, acquired resistance almost invariably develops after a median of 9 to 13 months. The most common mechanism of acquired resistance is the EGFR T790M mutation, present in approximately 50 to 60% of cases. “Third-generation” EGFR inhibitors— for example, AZD9291 and rociletinib— have shown promising clinical activity in EGFR T790M-mutant cancers. However, identification of EGFR T790M in resistant tumors currently requires tumor biopsies.

Blood-based identification of resistance mechanisms would be useful to noninvasively select patients who are most appropriate candidates for treatment with third-generation EGFR inhibitors. In a prospective multi-institutional study, Sundaresan et al. concurrently sampled circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) from 40 patients undergoing tumor biopsy at the time of acquired treatment resistance. The authors compared the EGFR genotype from tumor biopsies with that of CTCs and ctDNA. T790M status was successfully determined in 70 to 80% of patients by one or more of the three methods, and nearly half of all the samples were positive for this mutation. Concordance between the blood-based and tumor-based assessment was observed for 60% of the tumors. Although CTC- and ctDNA-based genotyping were each unsuccessful in 20 to 30% of cases, the two assays together enabled genotyping for all patients with an available blood sample. Blood-based testing identified the T790M mutation in a third of the patients in whom the concurrent biopsy was negative or indeterminate.

Although these findings are only exploratory, they suggest that as genotyping technologies improve, clinicians will be able to increasingly apply blood-based testing to identify resistance mechanisms, relying on tumor rebiopsies when blood-based testing is unrevealing.

T. K. Sundaresan et al., Detection of T790M, the acquired resistance EGFR mutation, by tumor biopsy versus noninvasive blood-based analyses. Clin. Cancer Res. 10.1158/1078-0432.CCR-15-1031 (2015). [Abstract]

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