Acquired L718V/TP53 co-mutation and discordant molecular pattern between plasmatic and cerebrospinal fluid in a bone and meningeal metastatic L858R+ non-small cell lung cancer: a case report

Introduction

Epidermal growth factor receptor (EGFR) mutations occur in 11% of patients with a non-small cell lung cancer (NSCLC) (1). First- and second-generation EGFR tyrosine kinase inhibitors (TKIs) are major treatments in this population. Acquired EGFR T790M mutation occurs in 60% of patients treated with those EGFR TKIs (2,3). Osimertinib, a third-generation TKI, demonstrated clinical activity in T790M-positive EGFR-mutated NSCLC (4). Osimertinib was approved as a first-line treatment for metastatic EGFR-positive NSCLC with a 38.6-month median overall survival (5). Preclinical data suggested several mechanisms of resistance to first-line osimertinib, such MET amplification or secondary EGFR mutations (6,7). Studies assessing specific therapeutic approaches such TKIs combination are ongoing (8). We describe a rare case of a patient with a bone and leptomeningeal metastatic NSCLC who developed an acquired EGFR L718V/TP53 V272M resistance co-mutation to osimertinib without sensibility to afatinib. Discordant molecular pattern in plasmatic and cerebrospinal fluid (CSF) is also described in this unique case. We present the following case in accordance with the CARE reporting checklist (available at https://atm.amegroups.com/article/view/10.21037/atm-22-3861/rc).

Case presentation

A 52-year-old female, never smoker and without previous medical history, was diagnosed with bone metastatic EGFR L858R-mutated NSCLC in July 2019. According to guidelines, gefitinib (250 mg daily), a first-generation TKI, was administered without any adverse event (Figure 1A). Eleven months later, in June 2020, the patient developed intracranial hypertension symptoms (headache, diplopia, vomiting). CSF analysis showed hyperproteinorachia (0.49 g/L) and adenocarcinomatous cells (4%). Bone metastases and primary lung lesion did not progress. Molecular analysis identified EGFR L858R mutation without acquired T790M mutation in plasmatic and CSF analysis. Osimertinib (80 mg daily), as a second-line treatment, was started in combination with nineteen intrathecal methotrexate injections (15 mg biweekly) (Figure 1B). This treatment was well tolerated and led to neurological improvement with disappearance of tumor cells in CSF and normalization of proteinorachia.

Figure 1 Timeline of therapeutic management and genotype data from each DNA analysis in plasmatic and cerebrospinal fluid according to the disease progression (A-C). NSCLC, non-small cell lung cancer; EGFR, epidermal growth factor receptor; CSF, cerebrospinal fluid.

Seventeen months later, in October 2021, neurological symptoms (cerebellar ataxia, diplopia, headaches and dysarthria) reappeared and CSF analysis confirmed progression of carcinomatous meningitis and high proteinorachia (8.66 g/L) while bone and lung lesion did not progress. Circulating plasmatic tumor cells DNA next-generation sequencing (NGS) analysis identified EGFR L718V (2152C>G) mutation [allelic frequency variation (AFV): 9%] and TP53 V272M (814G>A) mutation (AFV: 2%) in conjunction with EGFR L858R mutation (AFV: 10%). In CSF, EGFR L718V mutation was not found while EGFR L858R mutation (AFV: 40%) and TP53 V272M mutation (AFV: 33%) were found (Figure 1C).

Afatinib (40 mg daily), as a third-line treatment was started in December 2021 without any neurological clinical benefit. CSF analysis and thoracic CT-scan to evaluate afatinib effect could not be performed due to serious neurological degradation. The patient died in March 2022 of neurological progression.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki (as revised in 2013). Oral consent was obtained from the patient for publication of this case report and accompanying images.

Discussion

We report a rare case of an acquired EGFR L718V/TP53 V272M co-mutation in a patient with a bone and leptomeningeal metastatic L858R-mutated NSCLC. Preclinical data suggest that acquired EGFR L718V mutation confers resistance to osimertinib (9). Five cases are previously described in the literature, all with an acquired EGFR L718V resistance mutation to osimertinib and L858R+/T790M− status (10-13). The pathophysiological mechanisms remain unclear. In vitro studies suggested that L718V mutation induces a spatial conflict of EGFR that prevents osimertinib binding (9,11).

Resistance to osimertinib and sensitivity to afatinib were described in preclinical data and among the five patients treated with afatinib, four had clinical benefit with a disease stabilization (9,14). In this reported patient, afatinib had no efficacy against neurological progression. This could be explained by the absence of EGFR L718V mutation in CSF tumor cells. As observed by Zheng et al. liquid biopsy in CSF is more sensitive than in plasma to detect resistance alterations in leptomeningeal metastatic NSCLC with oncogenic driver mutation (15). As reported by Aredo et al. afatinib had a limited activity after progression under osimertinib (16). Also, Tamiya et al. observed low efficacy of afatinib for leptomeningeal carcinomatosis with a median progression-free survival of 2 months (17). The same authors described a low CSF penetration rate (1.7% compared to blood concentration rate) (18).

In this case, concomitant TP53 V272M (exon 7) mutation could also explained afatinib resistance. Mutation in exon 7 in TP53 is a negative survival prognostic factor in EGFR-mutated NSCLC, as reported in a phase III trial including 195 patients (19). No case of EGFR L718V/TP53 co-mutation was reported in literature.

This case reported a rare resistance co-mutation EGFR L718V/TP53 against osimertinib and a discordant molecular pattern between plasmatic and CSF. It suggested that EGFR TKI induced a molecular heterogeneity on metastases and discordant clinical evolution. In routine practice, biopsies of the metastases that progressed should be performed to adapt the therapeutic strategy.

There is currently no therapeutic guideline in case of EGFR L718V mutation resistance to osimertinib. Combination of chemotherapy-bevacizumab and atezolizumab (20,21), or amivantanab a bispecific antibody targeting EGFR and MET, or lazertinib a third generation EGFR TKI could be therapeutic options. Studies are needed to evaluate these therapies after progression under osimertinib.

Conclusions

Acquired EGFR L718V/TP53 co-mutation mediates resistance against osimertinib. Molecular pattern can be different between metastatic sites. Histologic analysis of progressive metastases is suggested to adapt the therapeutic strategy. Identify the resistance mechanisms against third-generation TKI and develop specific therapeutic approaches are a challenge in clinical routine.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://atm.amegroups.com/article/view/10.21037/atm-22-3861/rc

Peer Review File: Available at https://atm.amegroups.com/article/view/10.21037/atm-22-3861/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-3861/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki (as revised in 2013). Oral consent was obtained from the patient for publication of this case report and accompanying images.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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