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CASE REPORT
Year : 2022  |  Volume : 18  |  Issue : 2  |  Page : 587-589

The effect of afatinib and radiotherapy on a patient with lung adenocarcinoma with a rare EGFR extracellular domain M277E mutation and high PD-L1 expression


Cancer Center, Shandong Provincial Hospital, Cheeloo College of Medicine, Shangdong University, Jinan, Shangdong, China

Date of Submission11-Feb-2022
Date of Decision14-Feb-2022
Date of Acceptance26-Mar-2022
Date of Web Publication20-May-2022

Correspondence Address:
Hong Feng
Cancer Center, Shandong Provincial Hospital affiliated to Shandong University, Shandong University, 324 Jingwu Road, Jinan, Shandong - 250 021
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.jcrt_348_22

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 > Abstract 


In non-small cell lung cancer (NSCLC), about 15% of epidermal growth factor receptor (EGFR) mutations are rare. Herein, we report a 39-year-old male with stage IV NSCLC with a rare EGFR M277E mutation and high PD-L1 expression. The patient first underwent gamma-knife treatment for brain metastasis; then, he was started on 40 mg afatinib daily in combination with two cycles of chemotherapy. The clinical effect was stable disease (SD), so the patient underwent intensity-modulated radiation therapy guided by cone beam computed tomography on the lesion in the lower lobe of the right lung. A combination therapy with afatinib and chemotherapy was employed as the first-line therapy. A palliative radiotherapy to the primary pulmonary tumor was added, resulting in a significant response based on the next computerized tomography (CT) scan. To date, this is the first presented case of NSCLC with EGFR p.M277E mutation and its corresponding clinical outcome to combination therapies.

Keywords: Afatinib, EGFR extracellular domain M277E mutation, lung adenocarcinoma, radiotherapy


How to cite this article:
Lv D, Wang R, Wang X, Feng H. The effect of afatinib and radiotherapy on a patient with lung adenocarcinoma with a rare EGFR extracellular domain M277E mutation and high PD-L1 expression. J Can Res Ther 2022;18:587-9

How to cite this URL:
Lv D, Wang R, Wang X, Feng H. The effect of afatinib and radiotherapy on a patient with lung adenocarcinoma with a rare EGFR extracellular domain M277E mutation and high PD-L1 expression. J Can Res Ther [serial online] 2022 [cited 2022 Oct 1];18:587-9. Available from: https://www.cancerjournal.net/text.asp?2022/18/2/587/345543

Dongxiao Lv and Ruibin Wang contributed equally to this work





 > Introduction Top


Epidermal growth factor receptor (EGFR) mutations are present in nearly 22.5% and 52.5% of western and Asian patients with non-small cell lung cancer (NSCLC), respectively.[1],[2] More than 30,000 newly diagnosed patients with NSCLC have rare EGFR mutations.[3] They generally do not show consistent or favorable responses to EGFR-tyrosine kinase inhibitors (TKIs).[4]

This is the first reported patient with stage IV NSCLC with a rare EGFR M277E mutation and high PD-L1 expression. The patient was treated with afatinib and chemotherapy, and the clinical effect was stable disease (SD). Then, the patient was treated with radiotherapy, and the clinical effect was partial response (PR).


 > Case Report Top


A 39-year-old male presented to Shandong Provincial Hospital due to a lesion found in the lungs on September 9, 2021. An enhanced chest computerized tomography (CT) of the patient was done, showing soft tissue density nodules in the dorsal segment of the lower lobe of the right lung, with a size of about 1.9 × 1.8 cm, lobulation and burrs at the edge, oblique fissure and traction of the right posterior pleura, and uniform mild to moderate enhancement [Figure 1]a. On September 17, 2021, brain magnetic resonance imaging (MRI) showed an irregular mass with mixed T1 and T2 signal foci in the left frontal lobe and right parietal lobe. Fat-saturated T2 weighted imaging,FS-T2WI presented high and low mixed signal foci. Diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) showed a limited peripheral diffusion of the lesion, and the largest lesion with a diameter of about 2.1 cm was located in the left frontal lobe [Figure 2]a. Whole-body bone imaging showed no obvious abnormalities. The primary lesion was biopsied, and pathology showed adenocarcinoma, which was cT1N0M1 (stage IV according to American Joint Committee on Cancer 8th edition). The neoplastic cells were positive for CK7, NapsinA, TTF1, P53, and CEA and negative for P40, CgA, Syn, and CDX2. At the time of diagnosis, the tumor sample was sent to OrigiMed (CHINA) for next-generation sequencing (NGS). NGS identified an EGFR M277E mutation, where the codon methionine in position 277 of EGFR became glutamic acid in EGFR extracellular domain. NGS also identified EGFR amplification and KRAS G12C mutation. Notably, immunohistochemistry revealed that PD-L1–positive cells accounted for 60% of the tumor cells (22C3). Genetic testing showed very low tumor mutation burden values and microsatellite stability. This case was approved by Ethics Committee of Shandong Provincial Hospital Affiliated to Shandong First Medical University.
Figure 1: CT scan of the lungs before and after afatinib treatment. (a) Before afatinib treatment, September 2021. (b) After 2 months of afatinib treatment, November 2021. (c) After 2 months of radiation therapy, February 2022. CT = computerized tomography

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Figure 2: Brain MRI before and after gamma-knife treatment. (a) Before gamma-knife treatment, September 2021. (b) After 2 months of gamma-knife treatment, November 2021. MRI = magnetic resonance imaging

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The patient first underwent gamma-knife treatment for brain metastasis under general anesthesia at Shandong Provincial Hospital on September 18, 2021. Plan: left frontal lobe metastasis, lesion volume: 6.0 cm3, central dose: 38 Gy, marginal dose: 19 Gy, isodose line: 50%, collimator: 8 mm*27, V 98% ≥20 Gy; metastatic tumor of the right parietal lobe, lesion volume: 4.2 cm3, central dose: 38 Gy, edge dose: 19 Gy, isodose line: 50%, collimator: 8 mm*17, V 98% ≥20 Gy; and small lesion at the pressor of the left corpus callosum, volume: 46 mm3, central dose: 22.5 Gy, edge dose: 13.5 Gy, isodose line: 60%, collimator: 8 mm*27, V 98% ≥20 Gy. Then, the patient was started on 40 mg afatinib daily on September 30, 2021, in combination with two cycles of chemotherapy on October 10, 2021 and December 21, 2021, with pemetrexed disodium 950 mg and carboplatin 700 mg intravenous (IV) drip on the first day of each cycle. During this period, the patient encountered prolonged chemotherapy cycle intervals due to impaired liver function.

Repeated chest CT imaging on November 22, 2021 showed no significant changes in the primary lung lesion [Figure 1]b, and brain MRI showed a significant remission of intracranial metastasis [Figure 2]b. The clinical effect was SD, indicating that the primary lesion in the lungs was not sensitive to the treatment. Therefore, the patient underwent intensity-modulated radiation therapy (60 Gy in 10 fractions) guided by cone beam CT on the lesion in the lower lobe of the right lung on November 30, 2021. A plain chest CT on February 11, 2021 showed that the primary lung lesion became smaller [Figure 1]c.


 > Discussion Top


EGFR p.M277E (c. 829_830delinsGA) mutation is located on exon 7 of EGFR gene and encodes an amino acid of the extracellular domain of EGFR protein. According to an update of the Catalogue of Somatic Mutations in Cancer database, the p.M277E mutation accounts for only 0.0065% of EGFR mutations (2/30,884), and its clinical significance is unclear. To date, the function of p.M277E mutation has been reported in only one study, which used adenocarcinoma cell line BaF3 and xenograft mouse models.[5] This is the first clinical report of p.M277E mutation in a patient with NSCLC, demonstrating the clinical responses to various therapies, including afatinib, chemotherapy, and radiotherapy.

Patients with EGFR mutations show various responses to EGFR-TKIs. Classical mutations, such as Del19 and L858R mutations, exhibit good responses to all TKIs. Major uncommon EGFR mutations, such as S768I and L861Q mutations, respond well to afatinib, while T790M mutation is sensitive to ositinib.[6] However, the sensitivity of EGFR extracellular domain mutations to TKIs has rarely been reported. A previous report demonstrated a patient with NSCLC with p.A289V mutation, which was also located on exon 7, encoding the amino acids of extracellular domain, that responded to icotinib, suggesting that certain mutations in the EGFR extracellular domain may be TKI sensitive, similar to common kinase domain mutations, especially in NSCLCs.[7] In this case, considering the results presented by Yu et al. that demonstrated the carcinogenicity of EGFR p.M277E and sensitivity of p.M277E mutations to TKI, we suggested afatinib as a first-line therapy due to its broad-spectrum inhibition of uncommon EGFR mutations. This patient also had KRAS G12C mutation and high PD-L1 expression, which are both related to primary resistance to EGFR-TKIs.[5],[8] Thus, to prevent drug resistance, a combination therapy with afatinib and chemotherapy was employed as the first-line therapy. As expected, the tumor in the lungs did not show significant shrinkage based on chest CT images after 2 months. Therefore, palliative radiotherapy to the primary pulmonary tumor was added, which exhibited a significant response in the next CT scan. To date, the patient has achieved a progression-free survival (PFS) of 5 months, which will prolong.

In conclusion, to the best of our knowledge, this is the first presented case of NSCLC with EGFR p.M277E mutation and its corresponding clinical outcome to combination therapies. Our findings need to be confirmed in more patients at a larger scale.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initial s will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Vargas AJ, Harris CC. Biomarker development in the precision medicine era: Lung cancer as a case study. Nat Rev Cancer 2016;16:525-37.  Back to cited text no. 1
    
2.
Harrison PT, Vyse S, Huang PH. Rare epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer. Semin Cancer Biol 2020;61:167-79.  Back to cited text no. 2
    
3.
da Cunha Santos G, Shepherd FA, Tsao MS. EGFR mutations and lung cancer. Annu Rev Pathol 2011;6:49-69.  Back to cited text no. 3
    
4.
Sari M, Aydiner A. Rare mutations of epidermal growth factor receptor in epidermal growth factor receptor-tyrosine kinase inhibitor-naive non-small cell lung carcinoma and the response to erlotinib therapy. J Cancer Res Ther 2020;16:132-8.  Back to cited text no. 4
    
5.
Yu S, Zhang Y, Pan Y, Cheng C, Sun Y, Chen H. The non-small cell lung cancer EGFR extracellular domain mutation, M277E, is oncogenic and drug-sensitive. Onco Targets Ther 2017;10:4507-15.  Back to cited text no. 5
    
6.
Kobayashi Y, Mitsudomi T. Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy. Cancer Sci 2016;107:1179-86.  Back to cited text no. 6
    
7.
Dai L, Su X, Lu L, Lv D. Nonsmall cell lung cancer with rare exon 7 p.A289V mutation in the EGFR gene responds to Icotinib treatment: A case report. Medicine (Baltimore) 2018;97:e13809. doi: 10.1097/MD.0000000000013809.  Back to cited text no. 7
    
8.
Fiala O, Pesek M, Finek J, Benesova L, Belsanova B, Minarik M. The dominant role of G12C over other KRAS mutation types in the negative prediction of efficacy of epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Cancer Genet 2013;206:26-31.  Back to cited text no. 8
    


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