Detection of T790M, the Acquired Resistance EGFR Mutation, by Tumor Biopsy versus Noninvasive Blood-Based Analyses

Abstract

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.

Biophysical technologies for understanding circulating tumor cell biology and metastasis

“…The EGFR T790M mutation was 74% concordant between CTCs and tumor biopsies, whereas the ctDNA was concordant with tumor biopsies in 61% of cases. When CTC and ctDNA genotyping were combined, the T790M mutation was detected in 100% of cases, with 35% detection in in patients that had a negative or indeterminate concurrent biopsy (52). While this study showed that using CTC for detection of the T790M mutation was feasible, the yield may be increased by the combination of multiple genotyping modalities.…”

Plasma T790M and HGF as potential predictive markers for EGFR-TKI re-challenge

“…It was not possible to confirm concordance between plasma and re-biopsy. However, a previous study has reported the concordance between liquid biopsy (cell free plasma DNA and circulating tumor cell) and concurrent re-biopsy was ~60% (42). Considering this result, it is difficult to discuss the validity of liquid biopsy in comparison with re-biopsy.…”

Neueste technologische Entwicklungen für die Analyse von zirkulierender Tumor-DNA

“…Ein überaus wichtiger Punkt ist zudem, dass Resistenzmutationen im Plasma auch dann nachgewiesen werden können, wenn eine zeitgleiche Biopsie nicht möglich ist oder ein negatives Ergebnis liefert [96,97] …”