PMC9582288_01
Timeline of the 5' NOK ALK fusion clinical diagnosis and treatment and MRI/X-ray computed tomography of lesions of the brain and mediastinal lymph node (station 7) of the patient. (A) Timeline of patient clinical diagnosis and treatment. (B,C) Baseline: brain lesion (24*21 mm) and lymphadenopathy in the mediastinum (station 7) (short diameter, 10 mm). (D,E) One month after ensartinib treatment: brain lesion reduction (18*14 mm) and the lesion in the mediastinum (station 7) was reduced (short diameter, 4 mm). (F,G) Four months after ensartinib treatment: brain lesion reduction (16*15 mm) and the lesion in the mediastinum (station 7) disappeared. (H,I) Twenty-three months after ensartinib treatment: the brain lesion shrank again (15.8*13.8 mm), and there was no lesion in the mediastinal region (station 7). (J,K) Twenty-nine months after ensartinib treatment: the brain lesion progressed (28*21 mm), but the mediastinal region (station 7) was still responding. The white arrow indicates the lesion. ASC: adenosquamous carcinoma; PR: partial response; PD: progressive disease.
fmed-09-979032-g001.jpg
PMC9582288_01_fmed-09-979032-g001.jpg
F1
The postoperative pathology indicated lung adenosquamous carcinoma, and the pathologic stage was IIIA; thus, she accepted pemetrexed plus carboplatin as standard adjuvant chemotherapy (Figure 1A). The brain MRI revealed a nodule in the left basal ganglia with edema, compression of the ventricle, and right midline shift (Figure 1B). The chest CT showed lymphadenopathy in the mediastinum (station 7) (Figure 1C). The ALK fusion was validated by another DNA panel, Oncofocus  (Genetron Health) (Supplementary Figure 1 and Supplementary Data 1). The brain and mediastinal lesions (station 7) were significantly reduced after 1 month of medication (Figures 1D,E; December 2019). The chest lymph node disappeared after an additional 3 months of ensartinib treatment (Figures 1F,G; March 2020). The brain lesion shrank again after 23 months of ensartinib treatment (Figures 1H,I; October 2021). When the patient had been using ensartinib for 29 months, the brain lesion began to progress, while mediastinal lesions (station 7) continued to respond (Figures 1J,K, April 2022).
Multiple methods were used to detect ALK fusions in the surgical tissue. (A)
ALK-CYP27C1 fusion was detected by DN ANGS; (B)
ALK protein expression was detected by IHC. (C)
EML4-ALK fusion was detected by RNA NGS.
fmed-09-979032-g002.jpg
PMC9582288_01_fmed-09-979032-g002.jpg
F2
A 5' NOK fusion ALK-CYP27C1 (A19:C5) was identified in DNA level, of which a breakpoint occurred in chromosome 2: 29,446,807 (intron 19-ALK) and chromosome 2: 127,956,210 (intron 4-CYP27C1) (Figure 2A). ALK protein was expressed, IHC was further performed on a Ventana platform, and ALK protein expression was positive (Figure 2B). According to the positive results of ALK IHC, the patient was enrolled in a donation project about a new ALK inhibitor, ensartinib, on 19 November 2019, and received 225 mg orally once daily. Intriguingly, the result showed EML4-ALK (V1, E13:A20) instead of ALK-CYP27C1 (Figure 2C).