Analysis of Tumor Specimens at the Time of Acquired Resistance to EGFR TKI therapy in 155 patients with EGFR mutant Lung Cancers

By H. Yu, M. Arcila, N. Rekhtman, C. Sima, M. Zakowski, William Pao, M. Kris, Vincent A. Miller, Marc Ladanyi, Gregory Riely. Clinical Cancer Research, 2013

2,352 citations recorded by the source corpus.

Purpose: All patients with EGF receptor (EGFR)–mutant lung cancers eventually develop acquired resistance to EGFR tyrosine kinase inhibitors (TKI). 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 conducted. Experimental Design: Patients with lung adenocarcinomas and acquired resistance to erlotinib or gefitinib enrolled onto a prospective biopsy protocol and underwent a rebiopsy 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% confidence interval (CI), 55%–70%] and four had small cell transformation (3%, 95% CI, 0%–6%). MET amplification was seen in 4 of 75 (5%; 95% CI, 1%–13%). HER2 amplification was seen in 3 of 24 (13%; 95% CI, 3%–32%). We did not detect any acquired mutations in PIK3CA, AKT1, BRAF, ERBB2, KRAS, MEK1, or NRAS (0 of 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, whereas 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. Clin Cancer Res; 19(8); 2240–7. ©2013 AACR.

Subfields: Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/0d033e354ebc8e63cc5542cb8b76e77987f1dd6c

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In Oncology

1. Walter Kolch
2. Carlos L. Arteaga
3. K. Kerr
4. Z. Du
5. M. Hellmann
6. Christine Lovly
7. J. Engelman

In Pulmonary and Respiratory Medicine

1. Carlos L. Arteaga
2. B. Hughes
3. B. Chan
4. Z. Du
5. Christine Lovly
6. J. Engelman

Citations in the corpus

• Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity (2020, background): “, MET and HER2) [34,35]; Loss of NF1 [36]; BRAF mutation [37]”
• Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. (2018, background): “About half of the resistance is explained by the acquired EGFR exon 20 T790M mutations [194].”
• Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer (2023, background): “The histologic transformation of lung cancers harboring epidermal growth factor receptor (EGFR) mutations from adenocarcinoma to aggressive neuroendocrine cancer is a notable example of lineage plasticity in cancer.(161,162) Numerous lines of evidence suggest that JAK-STAT signaling is tightly conne”
• Osimertinib in Untreated EGFR‐Mutated Advanced Non–Small‐Cell Lung Cancer (2018, background): “No mutation detected, invalid test, or no or inadequate sample 24 (9) 32 (12) Table 1.”
• Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. (2015, background): “Unfortunately a wide variety of mechanisms are being discovered including; ALK amplification, EGFR/HER1, HER2 and HER3 up-regulation, cKIT amplification and various ALK mutations including L1196M (analogous to T790M for EGFR) (107-110).”
• ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics (2014, background): “These efforts have also been coupled to biopsy programs, in which cancers are systematically biopsied upon the development of resistance to interrogate acquired molecular changes upon treatment pressures (Sequist et al., 2011; Yano et al., 2011; Yu et al., 2013).”