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Non-small cell lung cancer; ALK; LMO7; Rearrangement

Background

Anaplastic lymphoma kinase (ALK) gene rearrangement is presented as driving oncogenesis and crucially therapeutic biomarker in non-small cell lung cancer (NSCLC) since most patients harbouring typical ALK fusion responded well to ALK tyrosine kinase inhibitors (ALK-TKIs). The impact is constantly on the focus that of various fusion breakpoints and independent fusion partners perform on ALK-TKIs [1,2]. In the picture regarding the ALK fusion companies, the EML4 gene was the dominant one, with a total of 16 variant types detected and independently predicted various overall survivals in patients receiving ALK-TKIs [3,4]. Other fusion companies such as TFG, KIF5B, STRN, HIP1, and BIRC6 were screened and presented potential oncogenesis [5]. Partner LMO7 gene was a fibrous actinbinding protein widely expressed in normal bronchial and alveolar epithelial cells, which was lately found in patients with NSCLC fused to ALK gene as reported (L15: A20), (L16: A20) [6,7]. Compared with patients harbouring LMO7-ALK fusion with reported breakpoints, clinical prognosis in this case was totally different. Whether breakpoints in LMO7-ALK fusion play important part on enhancing or weakening therapeutic response needs more discussion. Since LMO7-ALK fusion is an extremely rare mutation among ALK fusion companies, it would be worthwhile to explore the importance of different breakpoints and the clinical conditions [8].

This paper reported a case with a novel breakpoint (L13: A20) of LMO7-ALK rearrangement in advanced NSCLC. Literature with ALK rearrangements identified from 2007 was comprehensively described. Based on this, we provide valuable information on ALK rearrangements in NSCLC to clinicians and scientists who concentrate on the field perpetually [9].

Methods

According to the Response Evaluation Criteria in Solid Tumors

version 1.1 (RECIST 1.1), evaluation of therapeutic responses to targeted therapy measured by computed tomography (CT) screen, were sorted to complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD). Progression-free survival (PFS) was calculated from the date of the initial treatment to a radiologic or clinical observation of the disease progression. Overall survival (OS) was calculated from a randomized date to death for any reason. Genomic DNA was extracted from formalin-fixed paraffin-embedded (FFPE) tumor tissue, analysed by next-generation sequencing (NGS) detection (Amoy Diagnostics, Xiamen, China) [10-15].

Case Presentation

A 59-year-old man with a 40-pack-year smoking history was hospitalized due to a nodule in the right inferior lobe of the lung that had an unknown potential for malignancy. One month before admission to this hospital, CT screen revealed the lung nodule (12.7mm×10mm) during his regular health check, without experiencing any specific symptom. Then 18F-FDG positron-emission tomography-CT (PETCT) was performed to further report that multiple lymph node metastases of the mediastinum (3P, 4R, 4L, 7, 10R) and left cervix (β,χ) developed. Furthermore, no brain metastasis was observed by cranial magnetic resonance [16]. He underwent a CT-guided transthoracic core needle biopsy (TNB) of the specific lung tissue after being admitted to our hospital in order to develop an effective treatment plan. TTF-1, Napsin A and ALK (D5F3) were shown to be expressed positively by immunohistochemistry (IHC) analysis, while CK5/6 and P40 were found to be negatively expressed. PD-L1 was detected to be positively expressed (Figure 1). Subsequently, gene mutation was performed on the biopsy sample by NGS test, whereby a novel LMO7- ALK fusion Breakpoint (L13: A20) was firstly signified (abundance: 3.07%) based on a 448-gene panel on Illumina Novaseq6000/Nextseq 500 (AMOYDX, Xia Men, China) (Figure 2A) [17-20].

Figure 1: The results of HE and Immunohistochemical staining of the CT-guided transthoracic core needle biopsy (TNB) of the right inferior lobe of lung. CT-guided transthoracic core needle biopsy (TNB) of the right inferior lobe of lung showed: (A) Adenocarcinoma cells (hematoxylin-eosin HE × 100); (B) Immunohistochemical staining revealed positive expression of TTF-1 (+++); (C) Immunohistochemical staining revealed positive expression of NapsinA (+++); (D) Immunohistochemical staining revealed negative expression of CK5/6; (E) Immunohistochemical staining revealed negative expression of P40.

Figure 2: LMO7-ALK fusion is clinically actionable. (A) The Integrative Genomics Viewer (IGV) snapshot of LMO7-ALK; (B) A schematic representation of the LMO7-ALK fusion protein domain structure, exon 13 of the LMO7 (blue) was fused to exon 20 of the ALK (yellow). LMO7: LIM-domain only protein 7. ALK: anaplastic lymphoma kinase. chr: chromosome.

The diagnosis was a poorly differentiated adenocarcinoma with a strong expression of the ALK fusion protein at stage IV A (cT1bN3M1b, 8thUICC/AJCC). The response of the fusion variant obtaining novel breakpoint (L13: A20) to ALK-TKIs remained unclear. the patient accepted Crizotinib orally at a dosage of 250mg twice daily as the standard first-line targeted treatment ever since disease identification in the real-world study. The target lesion was reduced after four weeks of Crizotinib treatment [21-24]. Since then, a chest CT scan was routinely evaluated and conducted every four weeks. The lung lesion and cervix lymph nodes decreased with a partial response (PR) 3 months later after Crizotinib therapy according to the RECIST1.1 (Figure 3). During the targeted treatment period, the patient suffered from diarrhea, which was finally cured by an antidiarrheic treatment, without any additional symptoms. However, significant disease progression on Chest CT scans was confirmed at the fourth follow-up five months later at a local hospital. Unfortunately, he developed severe obstructive pneumonia caused by pneumocystis jiroveci infection and lost his life [25-30].

Figure 3: Radiological evaluation before and after therapy. (A) The CT scan images demonstrated reduction in pulmonary lesions, the evaluation of the status of disease was PR after 1 month and 4 months (7.56 mm × 3.2 mm) vs. therapy before (12.7 mm × 10 mm). (B) PET-CT showed the reduction of targeted lesion, including nodule in the right lung lobe and cervical lymph nodes. PR: partial response. PD: progressive disease.

Discussion

LIM-domain only protein 7 (LMO7), a fibrous actin-binding protein, is a member of PDZ and LIM domain-containing protein family, which is widely expressed in adults’ tissues including normal bronchial and alveolar epithelial cells. LMO7 gene is considered as a molecule that facilitates the formation and maintenance of epithelial architecture via remodelling of the actin cytoskeleton.6 LMO7 gene is located in chromosome 13q22 and circumferentially in the plasma membrane of adenocarcinoma cells [31]. The decreased expression of LMO7 was significantly correlated with tumor progression and a poor prognosis in patients with lung adenocarcinoma, but it remains unclear whether LMO7 may be a candidate for molecular-targeting therapy.5 More than 90 atypical non-EML4 ALK fusion partners have been reported in NSCLC since 2007. The effect that diverse fusion breakpoints have on ALK-TKIs is inconsistent [32].

In light of this, we have compiled a list of the many ALK fusion partners that have been reported since 2007 along with related occurrences, namely breakpoints during rearrangement, the reaction to ALK-TKIs, and observed PFS (Tables 1 and 2). ALK-rearranged information was provided as rich as possible to guide clinician prognosis and therapy. The ALK-rearranged information was made available as richly as possible to assist physician prognosis and treatment [33]. PFS of the table listed visibly showed remarkable therapeutic efficacy, where 45 cases (45/52, 86.54%) achieved six-month PFS at least, 26 cases (26/52, 50%) reached twelve-month PFS at least, and PFS over eighteen months reached the point of 16 cases (16/52, 30.77%) [34]. The PFS of the patients in the table clearly demonstrated the treatment efficacy: PFS over six months was obtained in 45 cases (45/52, 86.54%), PFS over twelve months was reached in 26 cases (26/52, 50%), and PFS over eighteen months was attained in 16 cases (16/52, 30.77%). ALK-TKIs significantly improved the survival of patients in NSCLC harbouring ALK rearrangements [35].

Table 1: Catalog of Fusion Partners in ALK+ NSCLC.

Table 2: Different LMO7-ALK fusion variants published till now.

ALK fusion partners identification and breakpoints discovery still play an important role. ALK kinase domain is activated through the autophosphorylation involving dimerization and the N-terminal fusion partner provided a promoter that causes constitutive expression of the ALK fusion protein When gene fusion happens.38 In previous reports, LMO7-ALK variants (L16: A20) were reported with PD to alectinib and PR to ensartinib separately. In this fusion variant, exon 13 of LMO7 (NM_015842) is fused to exon 20 of ALK (NM_004304) [36]. The patient showed a partial response to Crizotinib whereafter developed rapidly and lost his life 5 months later, which is never reported before (Figure 2B). The predicted LMO7-ALK protein product contained amino acids comprising the N-terminal amino acid of LMO7 and C-terminal amino acid of ALK, containing the entire tyrosine kinase domain presenting that the fusion variant responded to ALK-TKIs [37].

However, poor prognosis indicated the novel breakpoint (L13: A20) LMO7-ALK rearrangement may be a hyper-progressive marker. In conclusion, the LMO7-ALK rearrangement in advanced NSCLC is identified as a potentially sensitive fusion mutation. Poor prognosis, in this case, indicated the novel breakpoint (L13: A20) LMO7-ALK rearrangement may be a hyper-progressive marker and result in shorter survival time than other breakpoints in LMO7-ALK rearrangement and other ALK fusions. However, the rearrangement was rare that leads to more observation between molecular mechanism and survival prognosis in real world. To signify efficient rearrangements in the molecule aspect and supply more detailed information about ALK fusion variants in NSCLC, we reviewed the ALK fusion partners as well as the relative PFS, response to ALK-TKIs from 2007. According to this research, it is possible that more accurate recommendations for precision medicine will be provided by employing the NGS test to find more fusion partners with the ALK gene [38].

Data Availability Statement

The data that support the findings of this study are available from the corresponding author, upon reasonable request.

Funding

This work was supported by the This work has been strongly supported by the External Cooperation of Science and Technology Program of Fujian Province (No. 202210034) and the 900th Hospital of the Joint Logistic Support Force of China: National Science and Technology Fund Incubation Special Program(No. 2023GK04)..

Conflict of Interest Disclosure

The authors report no declarations of interest.

Consent Statement

The follow-up data and images included in this paper have been acquired with the patient’s consent.

Acknowledgment

Thank AMOYDX (Xia Men, China) for providing support in genetic analysis technology. Ping Lin drafted the manuscript and collected present illness. Wencui Kong supplied the clinical data. Ying Chen evaluated disease status and therapeutic response to ALKTKIs. Lijuan Qu identified the pathology of lung cancer. Zongyang Yu modified the manuscript critically for important intellectual content and confirmed final approval of the version to be published. All authors confirmed to be 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.

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