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  • br Conflict of interest statement br Introduction Currently

    2023-11-29


    Conflict of interest statement
    Introduction Currently, adenocarcinoma is the most common histological subtype of lung cancer. Activating mutations and translocations with a potential for targeted therapy are reported predominantly in non-smokers. ALK rearrangement is found in less than 5% of unselected adenocarcinoma. This alteration is resulting in a constitutive activity of the fusion EML4–ALK kinase which contribute to different parts of the carcinogenetic process [1]. Two large phase III trials demonstrated the high efficacy of crizotinib, a first generation tyrosine kinase inhibitor, front-line or for salvage therapy [2], [3] while second-generation agents as ceritinib or alectinib showed very promising activity whatever in crizotinib-naïve and crizotinib-pretreated patients. However, the majority of the patients experience disease progression within one or two years of treatment initiation. Different resistance mechanisms to these tyrosine kinase inhibitors have been described [4], [5]: secondary mutations in the tyrosine kinase domain, ALK amplification, bypass signaling (EGFR or KRAS mutation)… Histology transformation into SCLC has been well reported in EGFR mutant tumors but this mechanism is not well known in ALK rearranged adenocarcinomas.
    Case report A 53-years old Caucasian woman with no smoking history and no relevant medical history presented with cough and anorexia. A chest computed tomography (CT) revealed a nodular mass of 35mm in the paracardiac right lung with an enlarged right hilar lymph node of 25mm. Positron Emission Tomography scan with computed tomography (PET-CT Scan) demonstrated bone, hepatic and adrenal metastases and enlarged mediastinal lymph nodes (stage IV). Brain magnetic resonance imaging (MRI) was normal. Transbronchial biopsy revealed adenocarcinoma. The research for the epidermal growth factor receptor (EGFR) mutation was negative (kit CE-IVD Therascreen EGFR performed on Qiagen Rotor Gene). The patient underwent chemotherapy with cisplatin and pemetrexed. After two cycles, PET Scan and Eltrombopag MRI revealed brain and nodal progression. A whole brain irradiation was performed (5×4Gy). A new transbronchial biopsy was therefore performed. The biopsy material consisted in small fragments of bronchial mucosa invaded by a tumor consisting in small tumor cells, densely packed, with scant cytoplasm and a finely granular nuclear chromatin (Fig. 1A–C). Tumor cells showed immunoreactivity for synaptophysin and chromogranin (Fig. 1D–E). Ki67 immunostaining revealed a very high growth fraction (Fig. 1F). A strong and diffuse immunoreactivity was observed for ALK antibody (Fig. 1H). The final diagnosis was small cell lung carcinoma. DNA and RNA were extracted from the formalin-fixed paraffin-embedded biopsy and subjected to gene panel analysis using next generation sequencing (NGS). Gene mutations were analyzed using the Colon and Lung Cancer panel (Ampliseq™, Life Technologies) for sequencing 1825 hotspot mutations in 22 genes including AKT1, ALK, BRAF, CTNNB1, DDR2, EGFR, ERBB2, ERBB4, FBXW7, FGFR1, FGFR2, FGFR3, KRAS, MAP2K1, MET, NOTCH1, NRAS, PIK3CA, PTEN, SMAD4, STK11, TP53, as already described [6], [7]. No EGFR or ALK mutations were detected. On the other hand, two mutations were found: p.T319del of the PTEN gene and p.V203M of the TP53 gene. Retrospectively, we applied the NGS (48 genes, Truseq Amplicon cancer panel, Illumina) to the initial biopsy of the primary tumor. This demonstrated the presence of the same PTEN mutation while no other mutation was found.
    Discussion This case report is illustrating a new, rare, mechanism of resistance to ALK inhibitors in ALK rearranged adenocarcinoma with histological transformation in SCLC. Up to now, only 5 other cases have been reported [8], [9], [10], [11], [12] (Table 1). Different mechanisms of resistance to ALK inhibitors have nowadays been described but, at the difference of EGFR mutated adenocarcinoma, SCLC transformation was not recognized until now. Five cases have been reported in 2016. In those five reports and the present case was the ALK translocation conserved in the SCLC, confirming that both adenocarcinoma and SCLC originated from the same cell. A supplemental argument is the extremely rare presence of ALK translocation in primitive SCLC with only two published cases of whom one with a mixed histology [13], [14]. While we cannot formally exclude that the primary tumor was a mixed tumor due to the small sample size of the histological specimen, this appear unlikely when considering response to crizotinib and ceritinib and the clinical presentation.