Concurrent TP53 Mutations Facilitate Resistance Evolution in EGFR Exon 20 S768I Mutant Lung Adenocarcinoma: A Case Report and Review of the Literature

Overview

Journal Case Rep Oncol

Publisher Karger

Specialty Oncology

Date 2025 Feb 21

PMID 39980520

Authors

Huijuan Zhu

Hui Tang

Huizhen Peng

Wei Ding

Affiliations

Soon will be listed here.

Abstract

Introduction: Adenocarcinoma of the lung is the most common subtype of non-small cell lung cancer, and epidermal growth factor receptor (EGFR) mutations are the most common driver genes in the development of cancer (NSCLC). Among them, mutations in exons 18-21 are the most frequent, especially the deletion of exons 19 and 21, where L858R mutations are the most common. Other mutations such as S768I, G719X, and 20ins are relatively rare. In the population of lung adenocarcinoma patients with EGFR mutations, some common mutations may occur, especially TP53.

Case Presentation: Here, this study presents a retrospective analysis of neoadjuvant therapy for lung adenocarcinoma and reviews relevant literature. The patient was diagnosed with T4N3M1a, stage IVa. After 1 month of chemotherapy with 860 mg of pemetrexed and 480 mg of carboplatin, and immunotherapy with 200 mg of sintilimab, good response to conventional chemotherapy, but a follow-up CT scan showed disease progression. Next-generation sequencing showed EGFR exon 20 missense mutation (p.S768I and p.V774M) combined with tumor protein p53 (TP53) (p.Y220C) missense mutation, with mutation abundance of 48.6%/49.7% and 49.2%, respectively. Subsequently, chemotherapy with paclitaxel albumin 400 mg and treatment with pembrolizumab 200 mg were administered, followed by targeted treatment with oral afatinib (PFS: 12 months). And then, brain metastasis occurred, and targeted treatment with osimertinib was used instead (PFS: 9 months). The therapeutic effect is significant, but due to severe side effects, the patient stopped taking the medication on their own. Five months later, the patient became seriously ill again and CEA levels increased. Targeted treatment with furmonertinib (PFS: 3 months) and sunvozertinib (PFS: 3 months) was used instead. Three months later, the blood CEA level briefly decreased and then continued to increase, indicating the patient's critical condition.

Conclusion: The results indicate that targeted therapy with afatinib and osimertinib for EGFR S7688I/V774M and TP53 mutations has better PFS than targeted therapy with furmonertinib and sunvozertinib. Simultaneously, the combination of platinum-based chemotherapy and immunotherapy may be a potential neoadjuvant therapy for NSCLC IVa stage patients.

References

Wang M, Herbst R, Boshoff C . Toward personalized treatment approaches for non-small-cell lung cancer. Nat Med. 2021; 27(8):1345-1356. DOI: 10.1038/s41591-021-01450-2. View

Ding K, Peng Z, Liu D, Xu Y . Sunvozertinib overcoming resistance to afatinib and osimertinib in lung adenocarcinoma harboring an EGFR exon 18 DelE709_T710insD mutation. J Transl Med. 2024; 22(1):761. PMC: 11323653. DOI: 10.1186/s12967-024-05522-y. View

Zhang T, Wan B, Zhao Y, Li C, Liu H, Lv T . Treatment of uncommon mutations in non-small cell lung cancer: new evidence and treatment. Transl Lung Cancer Res. 2019; 8(3):302-316. PMC: 6626855. DOI: 10.21037/tlcr.2019.04.12. View

Bade B, Dela Cruz C . Lung Cancer 2020: Epidemiology, Etiology, and Prevention. Clin Chest Med. 2020; 41(1):1-24. DOI: 10.1016/j.ccm.2019.10.001. View

Zhu X, Bai Q, Lu Y, Qi P, Ding J, Wang J . Response to Tyrosine Kinase Inhibitors in Lung Adenocarcinoma with the Rare Epidermal Growth Factor Receptor Mutation S768I: a Retrospective Analysis and Literature Review. Target Oncol. 2016; 12(1):81-88. DOI: 10.1007/s11523-016-0455-4. View

Guven D, Erul E, Kaygusuz Y, Akagunduz B, Kilickap S, De Luca R . Immune checkpoint inhibitor-related hearing loss: a systematic review and analysis of individual patient data. Support Care Cancer. 2023; 31(12):624. DOI: 10.1007/s00520-023-08083-w. View

Wang Y, Goh K, Chen Z, Lee W, Choy S, Fong J . A Novel TP53 Gene Mutation Sustains Non-Small Cell Lung Cancer through Mitophagy. Cells. 2022; 11(22). PMC: 9688643. DOI: 10.3390/cells11223587. View

Brody H . Lung cancer. Nature. 2014; 513(7517):S1. DOI: 10.1038/513S1a. View

Hobor S, Al Bakir M, Hiley C, Skrzypski M, Frankell A, Bakker B . Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling. Nat Commun. 2024; 15(1):4871. PMC: 11176322. DOI: 10.1038/s41467-024-47606-9. View

10.

Ahmed Z, Moatter T, Siddiqui A, Pervez S . Distribution of EGFR mutations commonly observed in primary lung adenocarcinomas in Pakistan as predictors for targeted therapy. Asian Pac J Cancer Prev. 2014; 15(17):7125-8. DOI: 10.7314/apjcp.2014.15.17.7125. View

11.

Kim S, Lee J, Kim D, Joo H, Yun M, Jung D . Patient-Derived Cells to Guide Targeted Therapy for Advanced Lung Adenocarcinoma. Sci Rep. 2019; 9(1):19909. PMC: 6934824. DOI: 10.1038/s41598-019-56356-4. View

12.

Rizzo A, Santoni M, Mollica V, Logullo F, Rosellini M, Marchetti A . Peripheral neuropathy and headache in cancer patients treated with immunotherapy and immuno-oncology combinations: the MOUSEION-02 study. Expert Opin Drug Metab Toxicol. 2022; 17(12):1455-1466. DOI: 10.1080/17425255.2021.2029405. View

13.

Wang Y, Liu Q, Chu C, Li L, Wang Z, Liu Q . Six first-line tyrosine kinase inhibitors reveal novel inhibition potential for the EGFR S768I mutation. Toxicol Appl Pharmacol. 2023; 461:116385. DOI: 10.1016/j.taap.2023.116385. View

14.

Sahin T, Ayasun R, Rizzo A, Guven D . Prognostic Value of Neutrophil-to-Eosinophil Ratio (NER) in Cancer: A Systematic Review and Meta-Analysis. Cancers (Basel). 2024; 16(21). PMC: 11545344. DOI: 10.3390/cancers16213689. View

15.

Villaruz L, Wang X, Bertino E, Gu L, Antonia S, Burns T . A single-arm, multicenter, phase II trial of osimertinib in patients with epidermal growth factor receptor exon 18 G719X, exon 20 S768I, or exon 21 L861Q mutations. ESMO Open. 2023; 8(2):101183. PMC: 10163152. DOI: 10.1016/j.esmoop.2023.101183. View

16.

Zhang Y, Wang Z, Hao X, Hu X, Wang H, Wang Y . Clinical characteristics and response to tyrosine kinase inhibitors of patients with non-small cell lung cancer harboring uncommon epidermal growth factor receptor mutations. Chin J Cancer Res. 2017; 29(1):18-24. PMC: 5348472. DOI: 10.21147/j.issn.1000-9604.2017.01.03. View

17.

Rizzo A . Identifying optimal first-line treatment for advanced non-small cell lung carcinoma with high PD-L1 expression: a matter of debate. Br J Cancer. 2022; 127(8):1381-1382. PMC: 9553978. DOI: 10.1038/s41416-022-01929-w. View

18.

Imyanitov E, Iyevleva A, Levchenko E . Molecular testing and targeted therapy for non-small cell lung cancer: Current status and perspectives. Crit Rev Oncol Hematol. 2020; 157:103194. DOI: 10.1016/j.critrevonc.2020.103194. View

19.

Wang J, Fu Y, Gao Y, Li X, Xiong Q, Li R . Unique characteristics of G719X and S768I compound double mutations of epidermal growth factor receptor (EGFR) gene in lung cancer of coal-producing areas of East Yunnan in Southwestern China. Genes Environ. 2022; 44(1):17. PMC: 9125819. DOI: 10.1186/s41021-022-00248-z. View

20.

Zhang C, Lin L, Zuo R, Wang Y, Chen P . Response to tyrosine kinase inhibitors in lung adenocarcinoma with the rare epidermal growth factor receptor mutation S768I and G724S: A case report and literature review. Thorac Cancer. 2020; 11(9):2743-2748. PMC: 7471019. DOI: 10.1111/1759-7714.13606. View