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Mutations in TP53, PIK3CA, PTEN and other genes in EGFR mutated lung cancers: Correlation with clinical outcomes.

ABSTRACT: INTRODUCTION:The degree and duration of response to epidermal growth factor receptor (EGFR) inhibitors in EGFR mutated lung cancer are heterogeneous. We hypothesized that the concurrent genomic landscape of these tumors, which is currently unknown in view of the prevailing single gene assay diagnostic paradigm in clinical practice, could play a role in clinical outcomes and/or mechanisms of resistance. METHODS:We retrospectively probed our institutional lung cancer database for tumors with EGFR kinase domain mutations that were also evaluated by more comprehensive molecular profiling, and evaluated tumor response to EGFR tyrosine kinase inhibitors (TKIs). RESULTS:Out of 171 EGFR mutated tumor-patient cases, 20 were sequenced using at least a limited comprehensive genomic profiling platform. 50% harbored concurrent TP53 mutation, 10% PIK3CA mutation, 5% PTEN mutation, among others. The response rate to EGFR TKIs, the median progression-free survival (PFS) to TKIs, the percentage of EGFR-T790M TKI resistance and survival had higher trends in EGFR mutant/TP53 wild-type cases when compared to EGFR mutant/TP53 mutant tumors (all p >0.05 without statistical significance); with a significantly longer median PFS in EGFR-exon 19 deletion mutant/TP53 wild-type cancers treated with 1st generation EGFR TKIs (p=0.035). CONCLUSIONS:Concurrent mutations, specifically TP53, are common in EGFR mutated lung cancer and may alter clinical outcomes. Additional cohorts will be needed to determine if comprehensive molecular profiling adds clinically relevant information to single gene assay identification in oncogene-driven lung cancers.

SUBMITTER: VanderLaan PA

PROVIDER: S-EPMC5351777 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Mutations in TP53, PIK3CA, PTEN and other genes in EGFR mutated lung cancers: Correlation with clinical outcomes.

VanderLaan Paul A PA Rangachari Deepa D Mockus Susan M SM Spotlow Vanessa V Reddi Honey V HV Malcolm Joan J Huberman Mark S MS Joseph Loren J LJ Kobayashi Susumu S SS Costa Daniel B DB

Lung cancer (Amsterdam, Netherlands) 20170125

<h4>Introduction</h4>The degree and duration of response to epidermal growth factor receptor (EGFR) inhibitors in EGFR mutated lung cancer are heterogeneous. We hypothesized that the concurrent genomic landscape of these tumors, which is currently unknown in view of the prevailing single gene assay diagnostic paradigm in clinical practice, could play a role in clinical outcomes and/or mechanisms of resistance.<h4>Methods</h4>We retrospectively probed our institutional lung cancer database for tu ...[more]

PMID: 28285689

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Project description:In recent years, the incidence of non?small cell lung cancer (NSCLC) has become the highest lethal rate of cancer worldwide. Molecular assays of EGFR, KRAS, BRAF, NRAS, PIK3CA and Her?2 are widely used to guide individualized treatment in NSCLC patients. Somatic mutations in 112 NSCLC patients, including 7 oncogenic driver genes, were detected by Iontorrent personal genome machine (PGM). Sanger sequencing was used to test and verify the results of PGM. Apart from uncommon mutations of EGFR, 101 NSCLC specimens were tested by droplet digital PCR (ddPCR). According to NGS results, mutations were detected in EGFR (58/112, 51.79% of tumors), KRAS (10/112, 8.93%), BRAF (2/112, 1.79%), NRAS (2/112, 1.79%), Her?2 (2/112, 1.79%), PIK3CA (6/112, 5.36%) and TP53 (31/112, 27.69%). There were 27 samples without any somatic mutations in all genes while 24 samples harboured mutations in two or more genes. A total of 61 samples had one or more mutations in a single gene. All alterations of 7 genes were presented and the overall detection rate of NGS and Sanger sequencing was determined to be 51.79% (58/112) and 37.50% (42/112), respectively (?2=5.88, P=0.015). Compared with Sanger sequencing, the total sensitivity and specificity of NGS assays was 95.24% (40/42) and 77.14% (54/70), respectively. The overall detection rate of NGS and ddPCR was 45.54% (46/101) and 47.52% (48/101), respectively (?2=0.000598, P=0.98). Compared with ddPCR, the overall sensitivity and specificity of NGS assays was 95.83% (46/48) and 98.11% (52/53), respectively. The findings indicated that the positive mutation rate of EGFR tested by NGS was significantly lower than that by Sanger sequencing, but the difference between ddPCR and NGS was not statistically significant. The high degree of agreement of reportable variants is proposed in both NGS and ddPCR analysis, suggesting the performance of NGS assays in routine clinical detection may be useful in determining the treatment decisions in NSCLC patients.

Dataset Information

Mutations in TP53, PIK3CA, PTEN and other genes in EGFR mutated lung cancers: Correlation with clinical outcomes.

Publications

Mutations in TP53, PIK3CA, PTEN and other genes in EGFR mutated lung cancers: Correlation with clinical outcomes.

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