Invasive mucinous adenocarcinoma harbored MET exon 14 skipping mutation: case report

Introduction

Mucinous adenocarcinoma is a tumor type of lung cancer, accounting for 3–10% of lung adenocarcinoma (1). Invasive mucinous adenocarcinoma (IMA) is often misdiagnosed as infectious pneumonia or interstitial lung disease because of imaging features such as ground glass opacity or consolidative lung infiltration. Regarding molecular characteristics, IMAs have specific genetic alteration compared to other adenocarcinoma types, the benefit of multiplex genetic testing in such patients. KRAS is frequently detected in genetic alteration (53.3%), followed by NRG1 fusion (6.0%), ALK fusion (2.2%), ERBB2 mutation (2.2%), and EGFR mutation (1.6%) (2). However, the clinical features of IMA with MET exon 14 skipping mutations have not been reported. Here, we describe the first reported case of IMA-harbored MET exon 14 skipping mutation and successful treatment with tepotinib. We present this article in accordance with the CARE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-449/rc).

Case presentation

A 68-year-old Japanese female patient visited her general practitioner with the chief complaint of persistent dry cough lasting for a month. She had no history of smoking. Chest computed tomography showed a 31-mm lung infiltration in her left upper lobe (Figure 1A) and she was referred to our university hospital. She was initially diagnosed with community-acquired pneumonia. The antibiotics she received after diagnosis were ineffective and the lung infiltration enlarged to 40 mm (Figure 1B), so we performed trans-bronchial lung biopsy at the left upper lobe. No specific pathological findings were obtained, and the culture of sputum collected by bronchoscopy was negative. We considered a possible diagnosis of cryptogenic organizing pneumonia and started prednisone 0.5 mg/kg. After 2 weeks of treatment, the patient’s left upper infiltration was expanded, and a new infiltration had emerged in the left-lower lobe (Figure 1C). Blood carcinoembryonic antigen had increased since her first visit (4.3 to 11.2 ng/mL). Positron emission tomography showed the uptake of ¹⁸F-fluorodeoxyglucose on the infiltration. Five months after her first visit, we performed a second trans-bronchial lung biopsy, and this allowed diagnosis of IMA of the lung, stage IVA (cT4N0M1a). Histopathology showed an atypical glandular epithelium papillary structure and atypical cells with hyperchromatic nuclei. Intracytoplasmic mucins were partially found (Figure 2). Histopathology showed mainly papillary pattern with no lepidic or solid pattern in a small biopsy specimen. Multiplex gene testing by next-generation sequencing revealed that her tumor harbored both MET exon 14 skipping and PIK3CA H1047L. Programmed cell death-ligand 1 (PD-L1) level using immunohistochemistry 22C3 was less than 1%. Tepotinib 500 mg was initiated, and her lung infiltration was slightly reduced in the area on chest radiography 1 week later. At 7 months, the lung infiltration was shown to be stable with this treatment and adverse events were generally mild (grade 2 edema and grade 1 maculopapular rash). At 10 months, however, the lung infiltration was expanded, so we diagnosed progressive disease.

Figure 1 Time course of the patient’s chest imaging. (A) CT of the chest at the first visit; (B) CT after 2 months; and (C) CT and positron emission tomography after 4 months. CT, computed tomography.

Figure 2 Hematoxylin-eosin staining (×40). Pathological imaging showed atypical glandular epithelium formed papillary structure. Atypical cells were shown to be hyperchromatic and showed nuclear swelling. Intracytoplasmic mucins were partially found.

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 Helsinki Declaration (as revised in 2013). Written informed consent for publication of this case report and accompanying images was not obtained from the patient or the relatives after all possible attempts were made.

Discussion

IMA tends to have specific genetic alteration patterns compared to other adenocarcinoma types. As mentioned above, KRAS mutation, ALK rearrangement, and EGFR mutation are more commonly detected. This is the first case report of a patient with advanced IMA harboring MET exon 14 skipping mutation. In the current era of precision oncology, multiplex genetic testing is thought to be the most suitable procedure in selection of an appropriate regimen when diagnosing patients with advanced IMA of the lung (3).

Generally, MET exon 14 skipping mutation represents 3–4% of advanced non-small cell lung cancer (NSCLC) (4). Skipping of the MET exon 14 region results in abnormal accumulation of MET proteins, which leads to continuous activation of MET signaling and ultimately enhances carcinogenesis (5). In the VISION study, the efficacy and safety of tepotinib 500 mg once daily was explored in patients with advanced or metastatic NSCLC with MET exon 14 skipping. Tepotinib had an objective response rate of 51.4%, and the median progression-free survival was 11.2 months (4).

There are few reports on the efficacy of molecular targeted drugs in IMA. In this context, it is relevant to report that our patient had clinically meaningful benefit of taking tepotinib. Although the patient’s lung infiltration did not significantly decrease, the duration of response obtained was comparable with the progression-free survival observed in the VISION study (4). Additionally, considering the mild adverse events and the tolerability, we suggest the appropriateness of treatment with tepotinib, even in patients with IMA with MET 14 skipping. If molecular targeted drugs are not effective, chemotherapy or immunotherapy is considered according to performance status and PD-L1 expression, as NSCLC. However, there are no reports on the efficacy of these therapies for invasive mucinous adenocarcinoma harbored MET exon 14 skipping.

Conclusions

We report the first case of IMA of the lung harbored MET exon 14 skipping mutation. Tepotinib was thought to be an appropriate treatment for this patient. We recommend aggressive multiplex genetic testing in patients with IMA and subsequent treatment with molecular targeted drugs.

Acknowledgments

We acknowledge Benjamin Phillis from the Clinical Study Support Center at Wakayama Medical University for proofreading and editing.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-449/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-449/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-449/coif). H.A. received research grants from Amgen Inc., Chugai Pharmaceutical Co., Ltd., and MSD K.K.; received honoraria from Amgen Inc., AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Bristol-Myers Squibb, Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., MSD K.K., Nippon Kayaku Co., Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Pfizer Inc., Takeda Pharmaceutical Co., Ltd., and Taiho Pharmaceutical Co., Ltd.; and has advisory roles at Amgen Inc., Janssen Pharmaceutical K.K., and Sandoz K.K. N.Y. received research grants from AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., MSD K.K., Taiho Pharmaceutical Co., Ltd, Boehringer Ingelheim Japan Inc., Novartis Pharma K.K., AbbVie Inc., Amgen Inc., Asahi Kasei Co., Janssen Pharmaceutical K.K., Bristol-Myers Squibb K.K., IQVIA Services Japan K.K., EPS Co., Ltd., A2 Healthcare Corp., Mebix, Inc., and Ono Pharmaceutical Co., Ltd.; received consulting fees from AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., MSD K.K., Eli Lilly Japan K.K., Amgen Inc., Novartis Pharma K.K., and Ono Pharmaceutical Co., Ltd.; received honoraria for lectures, presentations, speaking, for bureaus, manuscript writing or educational evens from AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., MSD K.K., Takeda Pharmaceutical Co., Ltd., Accuray Japan K.K., AbbVie Inc., Amgen Inc., Ono Pharmaceutical Co., Ltd., Guardant Health Japan Corp., Kyorin Pharmaceutical Co., Ltd., Daiichi Sankyo Healthcare Co., Ltd., Taiho Pharmaceutical Co., Ltd., Tsumura & Co., Terumo Corp., Eli Lilly Japan K.K., Boehringer Ingelheim Japan Inc., Novartis Pharma K.K., Pfizer Inc., Miyarisan Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., and Janssen Pharmaceutical K.K.; and has an advisory role at AstraZeneca K.K. The other 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 Helsinki Declaration (as revised in 2013). Written informed consent for publication of this case report and accompanying images was not obtained from the patient or the relatives after all possible attempts were made.

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/.

References

1. Nicholson AG, Tsao MS, Beasley MB, et al. The 2021 WHO Classification of Lung Tumors: Impact of Advances Since 2015. J Thorac Oncol 2022;17:362-87. [Crossref] [PubMed]
2. Chang WC, Zhang YZ, Nicholson AG. Pulmonary invasive mucinous adenocarcinoma. Histopathology 2024;84:18-31. [Crossref] [PubMed]
3. Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 2014;311:1998-2006. [Crossref] [PubMed]
4. Mazieres J, Paik PK, Garassino MC, et al. Tepotinib Treatment in Patients With MET Exon 14-Skipping Non-Small Cell Lung Cancer: Long-term Follow-up of the VISION Phase 2 Nonrandomized Clinical Trial. JAMA Oncol 2023;9:1260-6. Erratum in: JAMA Oncol 2023;9:1300. [Crossref] [PubMed]
5. Fujino T, Suda K, Mitsudomi T. Emerging MET tyrosine kinase inhibitors for the treatment of non-small cell lung cancer. Expert Opin Emerg Drugs 2020;25:229-49. [Crossref] [PubMed]