Analysis of Tumor Specimens at the Time of Acquired Resistance to EGFR-TKI Therapy in 155 Patients with EGFR-Mutant Lung Cancers

Abstract

Purpose All patients with EGFR mutant lung cancers eventually develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Smaller series have identified various mechanisms of resistance, but systematic evaluation of a large number of patients to definitively establish the frequency of various mechanisms has not been performed. Experimental Design Patients with lung adenocarcinomas and acquired resistance to erlotinib or gefitinib enrolled onto a prospective biopsy protocol and underwent a re-biopsy after the development of acquired resistance. Histology was reviewed. Samples underwent genotyping for mutations in EGFR, AKT1, BRAF, ERBB2, KRAS, MEK1, NRAS and PIK3CA, and FISH for MET and HER2. Results Adequate tumor samples for molecular analysis were obtained in 155 patients. Ninety-eight had second-site EGFR T790M mutations (63%, 95% CI 55-70%) and four had small cell transformation (3%, 95% CI 0-6%). MET amplification was seen in 4/75 (5%, 95% CI 1-13%). HER2 amplification was seen in 3/24 (13%, 95% CI 3-32%). We did not detect any acquired mutations in PIK3CA, AKT1, BRAF, ERBB2, KRAS, MEK1, or NRAS. (0/88, 0%, 95% CI 0-4%). Overlap among mechanisms of acquired resistance was seen in 4%. Conclusions This is the largest series reporting mechanisms of acquired resistance to EGFR TKI therapy. We identified EGFR T790M as the most common mechanism of acquired resistance, while MET amplification, HER2 amplification, and small cell histologic transformation occur less frequently. More comprehensive methods to characterize molecular alterations in this setting are needed to improve our understanding of acquired resistance to EGFR TKIs.

Mutation and prognostic analyses of PIK3CA in patients with completely resected lung adenocarcinoma

“…The incidence of PIK3CA mutation was around 3% in lung adenocarcinoma and 5–10% in squamous cell carcinoma 12, 13, 14, 15. In this study, the frequency of PIK3CA mutation at 2.8% was consistent with that of previous studies.…”

“…With a frequency of 2–7% in NSCLC, it is more frequent in lung squamous cell carcinoma than in lung adenocacinoma 12, 13, 14. PIK3CA mutation was found both in patients without EGFR‐TKIs dosing and those resistance to targeted therapy 14, 15. However, because of heterogeneity and insufficient data of previous studies, no conclusion was observed for the frequency and prognosis of lung adenocarcinoma patients with PIK3CA mutation.…”

EGFR and NF-κB: partners in cancer

“…Virtually all patients who initially respond to EGFR inhibitors become resistant to these drugs as a result of acquired EGFR mutations [18]. The most clinically relevant EGFR mutation found in 50% of the cases showing acquired resistance to EGFR inhibitors (gefitinib and erlotinib) is the T790M mutation located in exon 20 ( Figure 1) [19]. This mutation, which is located within the ATP-binding site of the kinase domain, causes steric hindrance for access of the inhibitor to the cleft owing to the bulkiness of the methionine sidechain [20].…”

EGFR inhibition in NSCLC: New findings…. and opened questions?

“…The CAPP-Seq ctDNA analysis confirmed a single T790M mutation in 54% of patients, while revealed additional molecular alterations in 46% of them, including 34% MET or HER2 increased gene copy number (GCN), 7% single nucleotide variations (SNVs) in EGFR, PIK3CA, or Rb1, and 5% both MET GCN and PIK3CA or Rb1 SNVs (Chabon et al, 2016). Thus ctDNA genotyping allows to more accurately identify the presence of potential multiple mechanisms of resistance emerging during TKI therapy revealing a higher frequency (46%) of intra-tumor heterogeneity than that (5-15%) reported in previous studies (Sequist et al, 2011;Yu et al, 2013). Since the co-occurrence of different molecular alterations has been associated with inferior outcomes to subsequent third-generation TKI therapy, ctDNA analysis could represent a useful tool to guide the clinicians in the selection of the best treatment strategy for each patient.…”