Allelic Context of EGFR C797X-Mutant Lung Cancer Defines Four Subtypes With Heterogeneous Genomic Landscape and Distinct Clinical Outcomes
Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved..
INTRODUCTION: EGFR C797X (C797S or C797G) mutation is the most frequent on-target mechanism of resistance to osimertinib. The hypothesis that the allelic context of C797X/T790M has implications for treatment is on the basis of sporadic reports and needs validation with larger cohorts.
METHODS: We identified patients with EGFR C797X-mutant NSCLC from nine centers who progressed on osimertinib, all analyzed in a single laboratory through next-generation sequencing. We analyzed genomic profiles and assessed associations between clinical outcomes and C797X status.
RESULTS: A total of 365 EGFR C797X-mutant cases were categorized into four subtypes on the basis of allelic context: in cis (75.3%), in trans (6.4%), cis&trans (10.4%), and C797X-only (7.9%). Genomically, the cis&trans subtype displayed the highest frequency of concurrent alterations at osimertinib resistance sites (21.1%), while the in cis subtype had the lowest (8.4%). Clinically, cis&trans patients exhibited the worst progression-free survival (PFS) on both previous (median 7.7 mo) and subsequent treatment (median 1.0 mo) and overall survival (median 3.9 mo). In subsequent treatments, in cis patients exhibited superior PFS with combined brigatinib and cetuximab (median 11.0 mo) compared with other regimens (p = 0.005), while in trans patients exhibited variable outcomes with combined first or second- and third-generation EGFR inhibitor (PFS range: 0.7-8.1 mo, median 2.6 mo). Notably, subtype switching was observed after subsequent treatments, predominantly toward the in cis subtype.
CONCLUSIONS: Allelic context could define four EGFR C797X-mutant NSCLC subtypes with heterogeneous genetic landscapes and distinct clinical outcomes. Subsequent treatments further complicate the scenario through subtype switching.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:19 |
|---|---|
| Enthalten in: |
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer - 19(2024), 4 vom: 01. Apr., Seite 601-612 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Lu, Chang [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 08.04.2024 Date Revised 18.04.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.jtho.2023.11.016 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM364727454 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM364727454 | ||
| 003 | DE-627 | ||
| 005 | 20240419232136.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.jtho.2023.11.016 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1380.xml |
| 035 | |a (DE-627)NLM364727454 | ||
| 035 | |a (NLM)37981218 | ||
| 035 | |a (PII)S1556-0864(23)02372-9 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Lu, Chang |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Allelic Context of EGFR C797X-Mutant Lung Cancer Defines Four Subtypes With Heterogeneous Genomic Landscape and Distinct Clinical Outcomes |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 08.04.2024 | ||
| 500 | |a Date Revised 18.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a INTRODUCTION: EGFR C797X (C797S or C797G) mutation is the most frequent on-target mechanism of resistance to osimertinib. The hypothesis that the allelic context of C797X/T790M has implications for treatment is on the basis of sporadic reports and needs validation with larger cohorts | ||
| 520 | |a METHODS: We identified patients with EGFR C797X-mutant NSCLC from nine centers who progressed on osimertinib, all analyzed in a single laboratory through next-generation sequencing. We analyzed genomic profiles and assessed associations between clinical outcomes and C797X status | ||
| 520 | |a RESULTS: A total of 365 EGFR C797X-mutant cases were categorized into four subtypes on the basis of allelic context: in cis (75.3%), in trans (6.4%), cis&trans (10.4%), and C797X-only (7.9%). Genomically, the cis&trans subtype displayed the highest frequency of concurrent alterations at osimertinib resistance sites (21.1%), while the in cis subtype had the lowest (8.4%). Clinically, cis&trans patients exhibited the worst progression-free survival (PFS) on both previous (median 7.7 mo) and subsequent treatment (median 1.0 mo) and overall survival (median 3.9 mo). In subsequent treatments, in cis patients exhibited superior PFS with combined brigatinib and cetuximab (median 11.0 mo) compared with other regimens (p = 0.005), while in trans patients exhibited variable outcomes with combined first or second- and third-generation EGFR inhibitor (PFS range: 0.7-8.1 mo, median 2.6 mo). Notably, subtype switching was observed after subsequent treatments, predominantly toward the in cis subtype | ||
| 520 | |a CONCLUSIONS: Allelic context could define four EGFR C797X-mutant NSCLC subtypes with heterogeneous genetic landscapes and distinct clinical outcomes. Subsequent treatments further complicate the scenario through subtype switching | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a EGFR C797S mutation | |
| 650 | 4 | |a Non–small cell lung cancer | |
| 650 | 4 | |a Osimertinib | |
| 650 | 4 | |a Resistance mechanism | |
| 650 | 7 | |a Acrylamides |2 NLM | |
| 650 | 7 | |a Aniline Compounds |2 NLM | |
| 650 | 7 | |a EGFR protein, human |2 NLM | |
| 650 | 7 | |a EC 2.7.10.1 |2 NLM | |
| 650 | 7 | |a ErbB Receptors |2 NLM | |
| 650 | 7 | |a EC 2.7.10.1 |2 NLM | |
| 650 | 7 | |a Indoles |2 NLM | |
| 650 | 7 | |a osimertinib |2 NLM | |
| 650 | 7 | |a 3C06JJ0Z2O |2 NLM | |
| 650 | 7 | |a Protein Kinase Inhibitors |2 NLM | |
| 650 | 7 | |a Pyrimidines |2 NLM | |
| 700 | 1 | |a Wei, Xue-Wu |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Zhen |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Zhen |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Yu-Tao |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Di |e verfasserin |4 aut | |
| 700 | 1 | |a He, Yong |e verfasserin |4 aut | |
| 700 | 1 | |a Xie, Zhan-Hong |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yong |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yi-Chen |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Zi-Jian |e verfasserin |4 aut | |
| 700 | 1 | |a Mei, Shi-Qi |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Jia-Qi |e verfasserin |4 aut | |
| 700 | 1 | |a Guan, Xu-Hui |e verfasserin |4 aut | |
| 700 | 1 | |a Deng, Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Zhi-Hong |e verfasserin |4 aut | |
| 700 | 1 | |a Tu, Hai-Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Chong-Rui |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Hua-Jun |e verfasserin |4 aut | |
| 700 | 1 | |a Zhong, Wen-Zhao |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Jin-Ji |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xu-Chao |e verfasserin |4 aut | |
| 700 | 1 | |a Mok, Tony S K |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Yi-Long |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Qing |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer |d 2006 |g 19(2024), 4 vom: 01. Apr., Seite 601-612 |w (DE-627)NLM169435504 |x 1556-1380 |7 nnns |
| 773 | 1 | 8 | |g volume:19 |g year:2024 |g number:4 |g day:01 |g month:04 |g pages:601-612 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.jtho.2023.11.016 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 19 |j 2024 |e 4 |b 01 |c 04 |h 601-612 | ||