Detection of T790M, the Acquired Resistance EGFR Mutation, by Tumor Biopsy versus Noninvasive Blood-Based Analyses
Tilak K Sundaresan1, Lecia V Sequist1, John V Heymach2
1Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
Purpose:
The T790M gatekeeper mutation in the EGFR is acquired by some EGFR-mutant non-small cell lung cancers (NSCLC) as they become resistant to selective tyrosine kinase inhibitors (TKI). 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% to 50% of patients using each of the genotyping assays, with concordance among them ranging from 57% to 74%. Although CTC- and ctDNA-based genotyping were each unsuccessful in 20% to 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.
Conclusions:
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.
Insights
Detecting the T790M mutation in EGFR-mutant NSCLC is crucial for guiding treatment. Blood tests using circulating tumor DNA (ctDNA) and cells (CTC) show promise for identifying this resistance mutation when biopsies are inconclusive.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) is often mediated by the T790M gatekeeper mutation.
- The advent of third-generation EGFR TKIs necessitates reliable methods for detecting T790M to guide patient management.
Purpose of the Study:
- To evaluate the utility of noninvasive blood-based assays for T790M mutation detection in EGFR-mutant NSCLC patients progressing on TKI therapy.
- To compare the accuracy and concordance of T790M genotyping from tumor biopsies versus circulating tumor cells (CTC) and circulating tumor DNA (ctDNA).
Main Methods:
- An exploratory analysis of 40 patients with EGFR-mutant NSCLC was conducted.
- T790M genotyping was performed on tumor biopsies, simultaneously collected CTCs, and ctDNA.
- Genotyping success rates and concordance between methods were assessed.
Main Results:
- Successful T790M genotyping was achieved in 75% of tumor biopsies, 70% of CTC samples, and 80% of ctDNA samples.
- The T790M mutation was detected in 47-50% of patients across all tested sample types, with concordance ranging from 57% to 74%.
- Combined CTC and ctDNA analysis enabled genotyping in all patients and identified T790M in 35% of cases where biopsy results were negative or indeterminate.
Conclusions:
- Blood-based assays (CTC and ctDNA) offer a promising noninvasive approach for T790M detection in NSCLC.
- Discordant results between biopsy and blood tests may reflect technological differences or tumor heterogeneity.
- Complementary use of tumor biopsy and blood-based analyses may provide a comprehensive assessment for guiding T790M-targeted inhibitor therapy.
