PMC9677532_01
Pathological and molecular analysis of tumor samples. (A, B). Hematoxylin and eosin (HE) staining shows neoplastic cells with morphological characteristics of lung adenocarcinoma. (A)
Picture magnification: 5x; scale bar: 50 microm.
(B)
Picture magnification: 10x; scale bar: 50 microm.
(C) Fluorescent in situ hybridization (FISH) reveals an ALK rearrangement (IQFISH break apart DAKO (Omnis)). ALK break-apart FISH utilizes DNA probes that hybridize to the 3' (red signal) and 5' (green signal) regions of the common fusion breakpoint in ALK gene. ALK rearrangement is identified by splitting of the red and green signals in the nuclei (white arrows) or isolated red signals, as opposed to fused adjacent red and green signals (yellow arrows). Picture magnification: 1000x.
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While there was no oncogenic driver found by a DNA Next Generation Sequencing (NGS) panel (Ion Torrent, ThermoFisher) targeting 22 genes ( Supplementary Table 1 ), further molecular analyses revealed an ALK rearrangement (score 2+ ALK expression by immunohistochemistry, confirmation by fluorescent in situ hybridization (FISH) (38% of analyzed tumor cells were positive) and by RNA NGS (11.115 reads), which revealed an Echinoderm microtubule-associated protein-like 4 (EML4) -ALK fusion) ( Figure 1 ).
Chest imaging evolution. (A) Computed tomography (CT) at diagnosis: presence of a left-lower lobe primary tumor (red arrow). (B) CT after three cycles of cisplatin and pemetrexed in first-line: partial tumor response with decreased size of the primary tumor (red arrow). (C) CT after 7 cycles of pemetrexed in maintenance and then 2.5 months without systemic treatment: tumor progression with increased size of the primary tumor (red arrow). (D) CT after two months on crizotinib in second-line: partial tumor response with decreased size of the primary tumor (red arrow). (E) CT after 5.5 months on crizotinib in second-line: progression of the primary tumor (red arrow), appearance of ground glass opacities (blue arrow), a retro-obstructive condensation in the left lower lobe (red cross), and a nodular lesion in the lingula (green arrow). (F) CT after two months on alectinib in third-line: partial tumor response with decreased size of the left lower lobe primary tumor (red arrow) and of the lingular nodule (green arrow). (G) CT after 15 months on alectinib: tumor progression with increased size of the primary tumor (red arrow) and appearance of a left pleural effusion (area under red dots). (H) Radiography after two months on BRAF/MEK inhibitors in fourth-line: left pleural effusion (area under red dots).
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TKIs were not reimbursed in first-line and so, the patient initially received cisplatin-pemetrexed chemotherapy, with partial tumor response observed after three ( Figures 2A, B ) and five cycles. Then, pemetrexed maintenance was initiated but stopped after seven cycles despite stable disease because of a grade 2 asthenia and a grade 1 renal failure. He experienced tumor progression 2.5 months after stopping pemetrexed ( Figure 2C ). Crizotinib was initiated in second-line, with partial response achieved after two months ( Figure 2D ) and disease progression observed in the left lung after 5.5 months ( Figure 2E ). Partial response was observed after two months ( Figure 2F ), followed by stabilization until tumor progression after 15 months (increase of the lesions in the left lower lobe and occurrence of a left pleural carcinomatosis) ( Figure 2G ). Unfortunately, the patient died two months later in a context of tumor progression ( Figure 2H ) and toxicity (grade 3 skin rash and amylase elevation).
Timeline graph of patient clinical history, with tumor evolution and treatments. P, tumor progression; PR, tumor partial response; SD, tumor stable disease; TKI, tyrosine kinase inhibitor.
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The timeline of patient clinical history, with tumor evolution and treatments, is represented in  Figure 3 .