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

Yu, Helena A.; Arcila, Maria E.; Rekhtman, Natasha; Sima, Camelia S.; Zakowski, Maureen F.; Pao, William; Kris, Mark G.; Miller, Vincent A.; Ladanyi, Marc; Riely, Gregory J.

doi:10.1158/1078-0432.ccr-12-2246

Cited by 2,454Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchCancer Genomics and Diagnostics

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

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Yu, Helena A., Arcila, Maria E., Rekhtman, Natasha, Sima, Camelia S., Zakowski, Maureen F., Pao, William, Kris, Mark G., Miller, Vincent A. +2 more·2013·Clinical Cancer Research

DOI 10.1158/1078-0432.ccr-12-2246PMC PMC3630270

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Abstract

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.

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The T790M mutation is a well-characterized mechanism of acquired resistance to first- and second-generation TKIs, reported to occur in >60% of cases.
“The “gatekeeper” T790M mutation is a well-characterized mechanism of acquired resistance to first- and second-generation TKIs, which has been reported to occur in >60% of cases.”
From Afatinib for the treatment of EGFR mutation-positive NSCLC: A review of clinical findings (2020) · cites this paper as [46]
The Abstract Results report T790M in 98 of 155 acquired-resistance samples (63%), supporting the >60% figure. But the Methods specify that patients received erlotinib or gefitinib; this study does not establish the frequency after second-generation TKIs. (LLM, conf=0.90)
Experimental — accuracy not yet measured
The most common mechanism of resistance to first-generation EGFR TKIs is T790M, occurring in approximately 50-70% of patients.
“The most common mechanism of resistance to first-generation EGFR TKIs is the development of the gatekeeper T790M mutation, which occurs in approximately 50–70% of patients.”
From Afatinib for the treatment of EGFR mutation-positive NSCLC: A review of clinical findings (2020) · cites this paper as [46]
T790M is the most common acquired resistance mechanism in EGFR-mutant adenocarcinomas that progress on erlotinib, occurring in more than half of resistant biopsies.
“A secondary epidermal growth factor receptor (EGFR) mutation, T790M, is the most common resistance mechanism in EGFR mutant adenocarcinomas that have progressed on erlotinib.”
From The Allelic Context of the C797S Mutation Acquired upon Treatment with Third-Generation EGFR Inhibitors Impacts Sensitivity to Subsequent Treatment Strategies (2015) · cites this paper as [12]
A subset of resistant EGFR mutant non-small-cell lung cancers undergo histological transformation to small-cell lung cancer.
“A fundamental histological transformation from NSCLC to small-cell lung cancer (SCLC) is observed in a subset of the resistant cancers”
From RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer (2015) · cites this paper as [13]
5-15% of patient tumours undergo transformation to SCLC histology upon acquisition of resistance.
“One unexpected finding from these studies was the discovery that 5–15% of patient tumours undergo transformation to SCLC histology upon acquisition of resistance.”
From RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer (2015) · cites this paper as [13]

Repeat biopsy studies have consistently suggested that SCLC transformed cancers represent an evolution from the initial adenocarcinomas rather than a second coincident cancer, because the activating driver EGFR mutations are identical to the original adenocarcinomas in all cases.
“However, repeat biopsy studies have consistently suggested that the SCLC transformed cancers represent an evolution from the initial adenocarcinomas rather than a second coincident cancer, because the activating driver EGFR mutations are identical to the original adenocarcinomas in all cases.”
From RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer (2015) · cites this paper as [13]
After T790M emerges, median survival is under 2 years.
“The median survival is less than 2 years after the emergence of T790M.6”
From Rociletinib in EGFR-Mutated Non–Small-Cell Lung Cancer (2015) · cites this paper as [6]
The T790M EGFR mutation is present in approximately 50 to 60% of cases of acquired resistance to EGFR inhibitors.
“is most commonly due to the EGFR T790M mutation, present in approximately 50 to 60% of resistant cases.5,6”
From Rociletinib in EGFR-Mutated Non–Small-Cell Lung Cancer (2015) · cites this paper as [6]
The T790M EGFR mutation is the most common acquired resistance mechanism, found in about 60% of patients.
“The most common mechanism of acquired resistance, detected in 60% of patients, is a secondary mutation in EGFR at position T790 (T790M)(10).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [10]
The most frequent mechanism of acquired resistance is the T790M mutation, occurring in ~50-60% after rebiopsy.
“the most frequent mechanism of acquired resistance (~50–60% after rebiopsy) [69, 70]”
From A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives (2015) · cites this paper as [70]
The secondary mutation T790M accounts for approximately 50%-60% of acquired resistance to first-generation EGFR-TKIs.
“The secondary mutation T790M accounts for approximately 50%–60% of acquired resistance to 1G‐TKI.34, 35”
From Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy (2016) · cites this paper as [35]
At progression, about 60% of patients have T790M mutation in EGFR.
“At the time of progression, about 60% of patients (regardless of race or ethnic background) are found to have a p.Thr790Met point mutation (T790M) in the gene encoding EGFR.13–16”
From Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung Cancer (2017) · cites this paper as [14]
The T790M gatekeeper mutation caused disease progression in 60% of cases.
“in 60% of cases this was due to the acquisition of the T790M ‘gatekeeper mutation’34,35.”
From Advances in covalent drug discovery (2022) · cites this paper as [34]
The EGFR T790M somatic mutation is the most frequent alteration found in about half of tumors that progress on first- or second-generation EGFR TKIs.
“with the EGFR T790M somatic mutation being the most frequent alteration detected in approximately half of progressing tumors.[14][15][16]”
From The International Association for the Study of Lung Cancer Consensus Statement on Optimizing Management of EGFR Mutation–Positive Non–Small Cell Lung Cancer: Status in 2016 (2016) · cites this paper as [16]
Other resistance mechanisms include MET amplification (5-30%), HER2 amplification (12%), PIK3CA mutation (5%), and BRAF mutation (1%).
“Other resistance mechanisms involve bypass pathways such as MET proto-oncogene, receptor tyrosine kinase gene (MET) amplification (5%-30% depending on thresholds), erb-b2 receptor tyrosine kinase 2 (HER2) amplification (12%), phosphatidylinositol-4,5bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) mutation (5%), and B-Raf proto-oncogene, serine/threonine kinase gene (BRAF) mutation (1%)”
From The International Association for the Study of Lung Cancer Consensus Statement on Optimizing Management of EGFR Mutation–Positive Non–Small Cell Lung Cancer: Status in 2016 (2016) · cites this paper as [16]
The most common mechanism of acquired resistance, occurring in 49%-60%, is the T790M mutation in exon 20.
“The most common (49%-60%) mechanism of acquired resistance is the acquisition of a single recurrent missense mutation within exon 20, the T790M mutation [119, 120].”
From Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up (2016) · cites this paper as [119]

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Research works printed but not linked: 2

[17]Pao W Miller VA Politi KA Riely GJ Somwar R Zakowski MF Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain PLoS Med 2005 2 225 35 PMC549606 15737014
[20]Bean J Brennan C Shih JH Riely G Viale A Wang L MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib Proc Natl Acad Sci 2007 104 20932 7 18093943 PMC2409244

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P11-7 Efficacy of afatinib following osimertinib in patients with EGFR mutation-positive non-small-cell lung cancer
Tamura, T., Okubo, H., Yamada, Y., et al. (2021) · Annals of Oncology · doi:10.1016/j.annonc.2021.05.691
Which of afatinib and gefitinib/erlotinib is the better EGFR-TKI to be followed by osimertinib?
Tamiya, M., Tamiya, A., Suzuki, H., et al. (2018) · Annals of Oncology · doi:10.1093/annonc/mdy292.081 · Cited by 8 · see citing works
Rechallenge of afatinib for EGFR-mutated non-small cell lung cancer previously treated with osimertinib: a multicenter phase II trial protocol (REAL study)
Araki, T., Kanda, S., Komatsu, M., Sonehara, K., Tateishi, K., Takada, M., Kato, A., Yamamoto, M., Nishie, K., Hama, M., et al. (2023) · Translational Lung Cancer Research · doi:10.21037/tlcr-23-12 · Cited by 6 · see citing works
Resolving Resistance to Osimertinib Therapy With Afatinib in an NSCLC Patient With EGFR L718Q Mutation
Yang, X., Huang, C., Chen, R., & Zhao, J. (2020) · Clinical Lung Cancer · doi:10.1016/j.cllc.2019.12.002 · Cited by 25 · see citing works

Authors: Yu, H. A., Arcila, M. E., Rekhtman, N., Sima, C. S., Zakowski, M. F., Pao, W., Kris, M. G., Miller, V. A., Ladanyi, M., & Riely, G. J.
Affiliations: Memorial Sloan Kettering Cancer Center (US)
Corresponding author: Riely, Gregory J.
ORCID: Yu, Helena A.
Arcila, Maria E.
Rekhtman, Natasha
Zakowski, Maureen F.
Pao, William
Kris, Mark G.
Miller, Vincent A.
Ladanyi, Marc
Riely, Gregory J.
Venue: Clinical Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2013-04-15
Volume: 19
Issue: 8
Pages: 2240-2247
ISSN: 1078-0432 (ISSN-L)
1557-3265
DOI: 10.1158/1078-0432.ccr-12-2246
PMC: PMC3630270
OpenAlex: W2154149901
Cited by: 2,454
References: 40
Citations by year: 2026: 91 · 2025: 122 · 2024: 138 · 2023: 167 · 2022: 221 · 2021: 241 · 2020: 261 · 2019: 230 · 2018: 257 · 2017: 277 · 2016: 187 · 2015: 137 · 2014: 89 · 2013: 32 · 2012: 1
FWCI: 120.83
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Clinical Cancer Research (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Cancer Institute (R01CA121210, P01CA129243, R21CA115051, P30CA008748, T32CA009207, R25CA020449)
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords: acquired resistance, EGFR tyrosine kinase inhibitors, EGFR-mutant lung cancer, lung adenocarcinoma, T790M mutation, MET amplification, HER2 amplification, erlotinib, gefitinib, repeat biopsy, molecular mechanisms of resistance
MeSH terms: Erlotinib Hydrochloride, Gefitinib, Adenocarcinoma, Adult, Aged, Aged, 80 and over, Biopsy, DNA Mutational Analysis, Female, Humans, Immunohistochemistry, Lung, Lung Neoplasms, Male, Middle Aged, Mutation, Quinazolines, In Situ Hybridization, Fluorescence, Erb-b2 Receptor Tyrosine Kinases, CD56 Antigen, Drug Resistance, Neoplasm, Ki-67 Antigen, Proto-Oncogene Proteins c-met, Protein Kinase Inhibitors, Kaplan-Meier Estimate, ErbB Receptors

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

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