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  • The mechanism of transformation into SCLC is unclear but

    2024-02-22

    The mechanism of transformation into SCLC is unclear but the loss of retinoblastoma gene (RB) seems important and constitutes an initial event in the tumorigenic process. Some reports revealed the role of the RB gene loss in EGFR mutated NSCLC who transformed into SCLC [15]. In NGS we retrieved mutations in P53 and PTEN kinase inhibitors which are consistent with precedent reports of genomic profiling [16], [17] in SCLC. The exact role of PTEN and TP53 mutations remain unclear in this case. PTEN mutation in adenocarcinoma is a rare event. However, loss of PTEN was reported as contributing to EGFR inhibitors resistance by activation of AKT [18]. While other authors published a case of PTEN mutation in a patient with EGFR mutation transforming into SCLC [19], it seems unlikely that this mechanism has contributed in our case as the PTEN mutation was present initially in the primary adenocarcinoma. Also, despite P53 mutations are frequently found in lung cancers, we cannot retrieve publications describing the mutation p.V203M in small cell lung cancer [16], [17], [20]. We also reported a complete loss of the 5′ region of the ALK gene on the second FISH analysis. This atypical pattern was already described. Dai et al. [21] found an atypical pattern in 15 cases among 49 ALK gene rearrangement with the loss of the 5′ region of the ALK gene while complete loss of the two copies was not yet described in the literature. The clinical implication of this observation is unclear yet if one report suggested that the loss of the 5′ region can be associated with a reduced sensitivity to crizotinib [22]. No biopsy was obtained after progression under crizotinib, so that we cannot determine if the 5′ region loss could be incriminated in the SCLC transformation.
    Conflict of interest
    Introduction Crizotinib is now the established standard of care of for advanced treatment-naïve anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) [1]. There are many second generation ALK inhibitors in clinical development including three that have achieved US Food and Drug Administration (FDA) breakthrough designation: ceritinib (approved in the US), alectinib (approved in Japan), and brigatinib [2]. However, it remains challenging to decide the optimal sequence to deploy these ALK inhibitors when they are all approved in the future. One of the deciding factors will be the acquired resistance mutations that developed during treatment of crizotinib.
    Case presentation Patient is a 61-year-old Asian never-smoker male with stage IV ALK-rearranged NSCLC achieved partial response with crizotinib with a 70% decrease in the primary tumor. Two subsequent separate progressing pulmonary nodules developed after 34 months of crizotinib treatment satisfying RECIST-defined progression (>1cm) (Fig. 1A and B). The larger of the two pulmonary nodules was biopsied and subjected to comprehnsive genomic profiling (CGP) which identified an acquired ALK F1174V mutation which we have previously reported [3]. The patient was then enrolled onto a phase 2 alectinib trial (ClinicalTrials.gov Identifier: NCT01871805). The larger of the two pulmonary nodule that harbored ALK F1174V mutation achieved a complete response (Fig. 1C and D). The other nodule achieved only a 44% decrease in the longest diameter (Fig. 1C). However, during the course of alectinib treatment, the same pulmonary nodule in the right lower lobe grew and eventually achieved progressive disease (PD) as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (40% increase over the smallest diameter achieved although still smaller than prior to starting alectinib) at 18 months (Fig. 1D). The decision was to resect that pulmonary nodule as this was the only site of disease after repeat staging workup including MRI of the brain revealed no other site of metastasis. The resected pulmonary nodule was subjected to CGP and revealed an acquired ALK I1171S mutation in 31% of the sequencing runs. Interestingly comparison of the CGP of the two pulmonary nodules revealed the same EML4-ALK variant 3a/b and deletion of beta-catenin at exon 3 (CTNBB1 S45del) and shared eight out of the eleven variance of unknown significance (data not shown) indicating the two pulmonary nodules are from synchronous primary. Patient continues on alectinib after resection of the right lower lobe metastatic pulmonary nodule as the primary tumor and the ALK F1174V metastatic pulmonary nodule continues to achieve complete remission with alectinib.