Detection of T790M, the acquired resistance EGFR mutation, by tumor biopsy versus noninvasive blood-based analyses
A partir d'échantillons tumoraux et d'échantillons sanguins prélevés sur 40 patients atteints d'un cancer du poumon non à petites cellules présentant un gène EGFR muté, cette étude évalue les performances d'une méthode d'analyse des cellules tumorales circulantes et de l'ADN libre circulant pour détecter la muation T790M du gène EGFR associée à la résistance à une thérapie ciblée anti EGFR
Purpose: The T790M gatekeeper mutation in the Epidermal Growth Factor Receptor (EGFR) is acquired by some EGFR-mutant non-small cell lung cancers (NSCLC) as they become resistant to selective tyrosine kinase inhibitors (TKIs). As third generation EGFR TKIs that overcome T790M-associated resistance become available, noninvasive approaches to T790M detection will become critical to guide management.
Experimental Design: As part of a multi-institutional Stand-Up-To-Cancer collaboration, we performed an exploratory analysis of 40 patients with EGFR-mutant tumors progressing on EGFR TKI therapy. We compared the T790M genotype from tumor biopsies with analysis of simultaneously collected circulating tumor cells (CTC) and circulating tumor DNA (ctDNA).
Results: T790M genotypes were successfully obtained in 30 (75%) tumor biopsies, 28 (70%) CTC samples and 32 (80%) ctDNA samples. The resistance-associated mutation was detected in 47-50% of patients using each of the genotyping assays, with concordance among them ranging from 57-74%. While CTC- and ctDNA-based genotyping were each unsuccessful in 20-30% of cases, the two assays together enabled genotyping in all patients with an available blood sample, and they identified the T790M mutation in 14 (35%) patients in whom the concurrent biopsy was negative or indeterminate.
Conclusion: Discordant genotypes between tumor biopsy and blood-based analyses may result from technological differences, as well as sampling different tumor cell populations. The use of complementary approaches may provide the most complete assessment of each patient's cancer, which should be validated in predicting response to T790M-targeted inhibitors.
Clinical Cancer Research , résumé, 2015