1 Introduction
Tumors characterized by SMARCA4 deficiency typically show primitive differentiation and an unfavorable prognosis, with a relatively low overall incidence in various human tissues [
1]. The occurrence of SMARCA4 loss in lung cancer is approximately 4%–8% [
2,
3]. Prior studies indicate that SMARCA4-dNSCLC rarely presents with the most common targetable oncogenes, namely,
EGFR, ALK, and
ROS1 [
4]. Given the rarity of SMARCA4 deficiency in NSCLC, occurrences with concurrent uncommon
EGFR mutations are even more exceptional than others. We report the first instance of a nonsmoking middle-aged female patient with SMARCA4-dNSCLC coinciding with mutations of
EGFR exon 20 S768I and exon 18 G719X. With afatinib as the initial targeted treatment, the patient achieved notable tumor remission after only one month of therapy and the complete resolution of brain metastases. Moreover, she sustained a progression-free survival (PFS) of 17 months.
2 Case report
In March 2022, a 53-year-old nonsmoking female was admitted to Sir Run Run Shaw Hospital, Zhejiang University School of Medicine for hoarseness lasting one month. The patient had no familial history of cancer and no remarkable past medical history. Physical examination revealed dyspnea and numerous enlarged bilateral lymph nodes in the supraclavicular and submandibular regions alongside axillary nodes. The latter was palpably tumorous. Notably, a right thoracic mass, characterized by irregular borders and dense shadows, was detected on computed tomography (CT).
Positron emission tomography/CT imaging at our institution revealed a heterogeneous increase in fluorodeoxyglucose (FDG) metabolism in a soft tissue mass in the right lower pulmonary lobe with lobulated edges and pleural entrapment. The mass had the largest diameter of approximately 4.95 cm and a SUVmax of 8.59. Multifocal lymph node metastases were seen in the bilateral cervical, mediastinal, and left axillary regions; a left parietal lobe cerebral metastatic tumor was also observed (Fig.1). Cranial magnetic resonance imaging (MRI) corroborated these findings. The patient underwent a lung tumor percutaneous biopsy. The tumor stage was classified as cT2bN3M1c, stage IVB. Immunohistochemistry showed the absence of BRG1 and SALL4 and the positive expression of CK5/6 and CK7. The pathology diagnosed was SMARCA4-dNSCLC. The tumor proportion score of programmed death-ligand 1 was 12% with 22C3 antibody (Fig.2). Mutations of exon 20 S768I and exon 18 G719X of the EGFR gene were identified through ARMS genetic testing (supplemental material).
Given the identification of rare EGFR mutations, the patient immediately commenced targeted therapy with the oral administration of 40 mg of afatinib once daily. Chest CT and cranial MRI were reassessed after one month, revealing considerable reduction in the right lower lobe pulmonary lesion, left parietal lobe metastasis, and all metastatic lymph nodes compared with the chest CT and cranial MRI at baseline. A subsequent chest CT after afatinib treatment was continued for another two months confirmed the above remarkable response, and a follow-up cranial MRI showed the complete response of the brain metastasis (Fig.3). The patient maintained a PFS of 17 months. In August 2023, when tumor progression was evident, a repeat lung biopsy was conducted, revealing persistent SMARCA4 poorly differentiated carcinoma. Additionally, ARMS testing once again confirmed the absence of T790M mutations. Subsequently, the patient opted to discontinue chemotherapy in favor of palliative care and passed away in September 2023.
3 Discussion
The
SMARCA4 gene is located on the short arm of chromosome 19 and encodes the BRG1 protein, a catalytic subunit of the heterodimeric switch/sucrose nonfermenting complex that facilitates cellular differentiation to exert its tumor suppressor function [
5]. Mutations in SMARCA4 result in the loss of BRG1, thereby promoting tumorigenesis, metastasis, and growth [
6]. SMARCA4-dNSCLC rarely presents in conjunction with
EGFR mutations. However, the present case report describes a case with concurrent rare
EGFR mutations.
Studies have shown that chemotherapy combined with immunotherapy is the conventional treatment approach for patients with SMARCA4 deficiency who lack actionable oncogene mutations [
7,
8]. According to research by Shi
et al., SMARCA4/BRG1-deficient undifferentiated tumors generally exhibit resistance to chemotherapy but are responsive to chemotherapy combined with immunotherapy (median PFS: 3.5 months vs. 7.5 months,
P < 0.001). Among combination therapies, paclitaxel led to a longer median PFS than pemetrexed (10.0 months vs. 7.3 months,
P = 0.028) [
8]. Targeted therapy may offer good outcomes for SMARCA4-deficient patients harboring actionable oncogene mutations (including
EGFR, ALK, and
ROS1). Our institution previously reported a SMARCA4-dNSCLC case coinciding with
ALK rearrangement; in this case, the patient, when treated with alectinib as a first-line therapy, achieved remarkable tumor remission [
9].
Prior cases included those with concurrent
EGFR mutations, such as one case with the common
EGFR L858R mutation; this case did not undergo follow-up after osimertinib treatment, leaving its prognosis unknown [
10]. Our case is the first to exhibit remarkable tumor remission, including the disappearance of brain metastases one month after commencing first-line targeted therapy with afatinib, in the presence of rare mutations of
EGFR exon 20 S768I and exon 18 G719X, leading to a PFS of 17 months. The patient passed away one month after treatment discontinuation due to disease progression, illustrating the rapid progression and poor prognosis characteristic of this tumor type. However, the mechanism underlying concurrent
EGFR mutations with SMARCA4-dNSCLC remains unclear and requires further study.
In summary, the precise treatment strategy for SMARCA4-dNSCLC remains elusive. This case highlights the critical role of EGFR identification in refining the therapeutic potential of SMARCA4-dNSCLC.
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