Targeted therapy is efficient for patients with advanced non-small cell lung cancer (NSCLC) with related gene mutations, highlighting the importance of actively searching for mutations. Tyrosine receptor kinase ROS proto-oncogene 1 (ROS1) rearrangements occur in 1–2% of patients with non-small cell lung cancer (NSCLC) (1). Crizotinib is a tyrosine kinase inhibitor (TKI) that targets the anaplastic lymphoma kinase gene (ALK) or ROS1 kinase domain and is considered the standard of care for metastatic NSCLC who were positive for ROS1 fusion gene. Although the frequency of ROS1 rearrangements in lung cancers is low, the efficient determination of ROS1 status in patients with NSCLC is critical for directing patient care. Here we report the case of a patient with NSCLC harboring a rare HLA_A-ROS1 rearrangement, who showed a clinical response to crizotinib.

A 47-year-old Japanese woman with dyspnea for 2 months was referred to our hospital. She had no relevant history except for light smoking. Chest radiography analysis revealed a mass in the right upper lung field. Computed tomography (CT) analysis revealed a 7.0 cm mass in the right upper lobe with mediastinal invasion, contralateral mediastinal lymphadenopathy and a left adrenal gland tumor. Bronchoscopy analysis revealed a polypoid tumor at the orifice of the right upper lobe bronchus and a transbronchial biopsy was performed. Pathological examination showed primary lung adenocarcinoma with hepatoid cytology and signet cells (Fig. 1A and B). According to the 7th edition of TNM staging, the patient was classified as having stage IVB lung adenocarcinoma (T4aN3M1b). Mutation status was negative for EGFR, ALK, BRAF, and ROS1; the OncoGuide AmoyDx ROS1 gene fusion detection kit was used to detect ROS1 rearrangement. Programmed death-ligand 1 expression with a tumor proportion score of 5% was confirmed by immunohistochemistry analysis using 22C3 antibody. She was treated with radiation therapy for the primary lesion (50 Gy/20 Fr) as well as chemotherapy (carboplatin plus pemetrexed), which was followed by pemetrexed maintenance therapy. After 15 cycles of maintenance therapy, mediastinal lymphadenopathy was newly detected and pembrolizumab monotherapy was initiated as the second-line therapy. During the treatment, as the Oncomine CDx Target Test (Oncomine DxTT) was newly covered by insurance as a multigene panel assay for NSCLC in Japan, the residual specimen was subjected to Oncomine DxTT and HLA_A-ROS1 rearrangement was detected. After 21 cycles of pembrolizumab monotherapy (Fig. 2), the CT scan showed left supraclavicular lymphadenopathy (Fig. 3 A and B), and the patient was administered crizotinib therapy as the third-line therapy. She achieved a partial response as defined by the Response Evaluation Criteria in Solid Tumors version 1.1. Currently, cancer has been stable for over 16 months and patient follow up is ongoing (Fig. 3C and D).

This is the first case report of a patient with lung adenocarcinoma harboring an HLA_A-ROS1 rearrangement with a clinical course and response to crizotinib. To our knowledge, there is only one case report of HLA_A-ROS1 rearrangement in melanoma (2). HLA_A-ROS1 rearrangement was generated by the fusion of exon 34 of ROS1 located on the long arm of chromosome 6 with exon 7 of HLA_A located on the short arm of chromosome 6 (Fig. 4). ROS1-rearranged NSCLC was majorly observed in young females with no or light smoking history (3). Currently, more than 34 ROS1 fusion partner genes have been reported in NSCLC, including CD74, SDC4, EZR, and SLC34A2 (4). In Japan we previously often used the OncoGuide AmoyDx ROS1 gene fusion detection kit to detect ROS1 rearrangements including those in major partner genes (5,6); however, this single gene testing was unable to detect HLA_A-ROS1 rearrangement. Pathologically, ALK- and ROS1-rearranged lung adenocarcinomas often show a solid growth pattern and possess hepatoid cells and signet ring cells (7). These pathological features are the indicators of ALK and ROS1 rearrangement status in NSCLC. Hence, an additional multigene panel assay should be considered for patients suspected of carrying driver oncogenes based on patient background and pathological patterns even if single gene tests were negative.

Crizotinib is a potent TKI for ALK, ROS1, and mesenchymal-epithelial transition mutation-positive NSCLC. A previous study showed that crizotinib was associated with an overall response rate of 72% and a median progression-free survival of 19.3 months in advanced ROS1-rearranged NSCLC (8). The efficacy of crizotinib varies depending on ROS1 fusion partner (9). A previous study showed that the patients carrying non-CD74-ROS1 fusions could get better prognostic outcomes than those with CD74-ROS1 fusions by crizotinib treatment (10). Hicks et al reported that a patient with lung adenocarcinoma harboring a rare ZCCHC8-ROS1 fusion who responded to crizotinib showed progression-free survival of 7 months and total duration of treatment of 15 months (11). The dramatic response to crizotinib therapy in this case may be a reference for the treatment and prognosis for NSCLC with the same fusion partner.

In conclusion, this report describes a case of advanced lung adenocarcinoma harboring an HLA_A-ROS1 rearrangement with a dramatic response to crizotinib therapy. The information presented in our report highlights to oncologists and pulmonologists the importance of accurate multigene panel assays in detecting driver oncogenes for treating patients with NSCLC.