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.

Keywords: Adenocarcinoma; EGFR; Erlotinib; Kinase inhibitor; Lung cancer; Mutation; PIK3CA; PTEN; TP53.

Figure 1. Concurrent mutations identified in EGFR mutated lung cancers analyzed by focused comprehensive genomic profiling panels

A Type of EGFR mutation and concurrent mutation profile of tumors. The graphic representation highlights indel/truncating mutation or missesense mutation types. B. Frequency of co-occurring EGFR-exon 19 deletion or L858R with TP53, PIK3CA and PTEN in the BIDMC and TCGA cohorts.

Figure 2. TP53 mutations and how they affect clinical outcomes or resistance to EGFR kinase inhibitors

A. Graphic representation of the spectrum of EGFR and TP53 mutations identified in the 2014 TCGA lung adenocarcinoma cohort (data obtained using cBioPortal). B. Response (ORR, median PFS, median OS and rebiopsy results) of EGFR TKI-treated patients whose tumors harbored or not a concurrent TP53 mutation. C. Kaplan-Meier PFS curve of patients with EGFR mutated tumors with or without TP53 mutations and treated with 1^st/2^nd generation EGFR TKIs. D. Kaplan-Meier PFS curve of patients with EGFR-exon19 deletion mutated tumors with or without TP53 mutations treated with 1^st generation EGFR TKIs. *, p-value calculated using Fisher’s exact test. ^, p-values obtained using the log-rank test.

Figure 3. Spatial-temporal heterogeneity of molecular alterations in one case of recurrent EGFR-L858R mutated lung adenocarcinoma prior to EGFR inhibitor therapy

In this case of EGFR mutated lung cancer, the original right upper lobectomy for a 2.0 cm invasive lung adenocarcinoma demonstrated a mixture of acinar (tumor section 1) and lepidic (tumor section 2) patterns. Both harbored the same EGFR mutation (L858R) as well as shared proposed germline mutations (also observed in a section of adjacent uninvolved lung parenchyma); however, significant heterogeneity was observed in branch-type mutations, including TP53 only on tumor section 1 but not section 2. The recurrent metastatic adenocarcinoma found in two separate supraclavicular lymph nodes (lymph node 1 and 2) were morphologically similar and once again demonstrated the same driver EGFR-L858R mutation and shared germline mutations, but displayed significant heterogeneity in the branch-type mutations.