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Small-Cell Lung Cancer Transformation as a Mechanism of Resistance to Pralsetinib in RET-Rearranged Lung Adenocarcinoma: A Case Report

  • Author Footnotes
    # Dr Gazeu A and Dr Aubert M contributed equally to this work. Dr Franceschi T and Dr Swalduz A contributed equally to this work.
    Alexia Gazeu
    Footnotes
    # Dr Gazeu A and Dr Aubert M contributed equally to this work. Dr Franceschi T and Dr Swalduz A contributed equally to this work.
    Affiliations
    Department of Biopathology, Centre Léon Bérard, Lyon, France
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  • Author Footnotes
    # Dr Gazeu A and Dr Aubert M contributed equally to this work. Dr Franceschi T and Dr Swalduz A contributed equally to this work.
    Mylena Aubert
    Footnotes
    # Dr Gazeu A and Dr Aubert M contributed equally to this work. Dr Franceschi T and Dr Swalduz A contributed equally to this work.
    Affiliations
    Department of Medical Oncology, Centre Léon Bérard, Lyon, France
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  • Daniel Pissaloux
    Affiliations
    Department of Biopathology, Centre Léon Bérard, Lyon, France

    Université de Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS UMR5286, Centre Léon Bérard, Cancer Research Center of Lyon, Lyon, France
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  • Sylvie Lantuejoul
    Affiliations
    Department of Biopathology, Centre Léon Bérard, Lyon, France

    Université de Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS UMR5286, Centre Léon Bérard, Cancer Research Center of Lyon, Lyon, France

    Grenoble Alpes University, Grenoble, France
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  • Maurice Pérol
    Affiliations
    Department of Medical Oncology, Centre Léon Bérard, Lyon, France
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  • Nadia Ikhlef
    Affiliations
    Department of Biopathology, Centre Léon Bérard, Lyon, France
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  • Amine Bouhamama
    Affiliations
    Department of radiology, Centre Léon Bérard, Lyon, France
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  • Author Footnotes
    # Dr Gazeu A and Dr Aubert M contributed equally to this work. Dr Franceschi T and Dr Swalduz A contributed equally to this work.
    Tatiana Franceschi
    Footnotes
    # Dr Gazeu A and Dr Aubert M contributed equally to this work. Dr Franceschi T and Dr Swalduz A contributed equally to this work.
    Affiliations
    Department of Biopathology, Centre Léon Bérard, Lyon, France
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  • Author Footnotes
    # Dr Gazeu A and Dr Aubert M contributed equally to this work. Dr Franceschi T and Dr Swalduz A contributed equally to this work.
    Aurélie Swalduz
    Correspondence
    Address for correspondence: Aurélie Swalduz, MD, Department of Medical Oncology, Centre Léon Bérard, 28 rue Laënnec, 69008 Lyon, France.
    Footnotes
    # Dr Gazeu A and Dr Aubert M contributed equally to this work. Dr Franceschi T and Dr Swalduz A contributed equally to this work.
    Affiliations
    Department of Medical Oncology, Centre Léon Bérard, Lyon, France

    Université de Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS UMR5286, Centre Léon Bérard, Cancer Research Center of Lyon, Lyon, France
    Search for articles by this author
  • Author Footnotes
    # Dr Gazeu A and Dr Aubert M contributed equally to this work. Dr Franceschi T and Dr Swalduz A contributed equally to this work.
Published:November 01, 2022DOI:https://doi.org/10.1016/j.cllc.2022.10.005

      Abstract

      The majority of resistance to Rearranged during transfection (RET)-specific tyrosine kinase inhibitors (TKI) described in RET-rearranged non-small cell lung cancer (NSCLC) patients are driven by RET-independent mechanisms. We provide the first case report of a RET-rearranged lung adenocarcinoma (LUAD) transformation into small-cell lung cancer (SCLC) as a mechanism of acquired resistance to pralsetinib. A 43-year-old patient presented with a RET-rearranged LUAD revealed by pleural effusion. After 14 months of response to pralsetinib, biopsy of a progressive pleural lesion found a phenotypic transformation into SCLC. Molecular analysis identified the same RET fusion and TP53 mutation in both primary adenocarcinoma and recurrence as SCLC. The patient achieved partial response after switch to carboplatin and etoposide chemotherapy and presented with progression disease after 6 months. Histological transformation could be a mechanism of resistance to RET-TKIs and rebiopsy should be considered to adapt subsequent treatment.

      Keywords

      Abbreviations:

      LUAD (lung adenocarcinoma), SCLC (small cell lung carcinoma), CT (computed tomography), MRI (magnetic resonance imaging), ALK (anaplasic lymphoma kinase), PFS (progression free survival), Rearranged during transfection (RET)

      Introduction

      RET-fusion genes have been reported in 1% to 2% of lung cancer. Chemotherapy and or immunotherapy, as well as multiple kinase inhibitors, exhibit modest efficacy. Selpercatinib and pralsetinib are 2 new selective RET TKIs, which demonstrated a favorable tolerability profile and a robust efficacy including on central nervous system metastases, with objective response rates ranging from 55% to 85% in pretreated and treatment-naive patients, respectively.
      • Gainor JF
      • Curigliano G
      • Kim DW
      • et al.
      Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study.
      Mechanisms of resistance to these selective RET-TKI are currently being studied and remain largely unknown. Lin et al. showed that most of the identified resistance mechanisms were driven by RET-independent mechanisms, such as MET- or KRAS-amplification. However, no histologic transformation to squamous cell or SCLC were reported as in the case of EGFR- and ALK-driven lung adenocarcinoma.
      • Lin JJ
      • Liu SV
      • McCoach CE
      • et al.
      Mechanisms of resistance to selective RET tyrosine kinase inhibitors in RET fusion-positive non-small-cell lung cancer.
      Herein, we describe to the best of our knowledge the first case of transformation of a RET-rearranged lung adenocarcinoma to SCLC after pralsetinib.

      Case Presentation

      A 43-year-old woman with a light smoking history presented with parietal thoracic pain, dyspnea asthenia, and weight loss. Computed tomography (CT) demonstrated isolated left pleural effusion with no other lesions on PET scanner and brain magnetic resonance imaging (cTxN0M1a). Cytologic examination of pleural fluid revealed an adenocarcinoma of pulmonary origin (TTF1 +) with no PD-L1 expression. Because of the detection of anaplastic lymphoma kinase (ALK) expression by immunochemistry, a treatment with alectinib was promptly initiated. However, Nanostring DNA analysis did not identify any ALK-rearrangement, leading to pleural biopsies in order to solve this discrepancy. Upon microscopic examination, the parietal pleura was infiltrated by an adenocarcinoma with acinar or papillary patterns (Figure 1A-1E). Immunohistochemistry showed a strong nuclear expression of TTF1 and TP53 by tumor cells, consistent with a TP53 mutation and no staining with synaptophysin, RB1, CD56 and chromogranin antibodies (Figure 1B-1E) (Supplementary Data). The immunoreactivity for ALK was weak. A fusion between the 5’ end of CCDC6 and the 3’region of RET (coiled-coil domain containing 6 gene) was identified by targeted RNA sequencing (FusionPlex RNA CTL_V6 ArcherDx, Supplementary Data) without ALK-rearrangement, MET-amplification or KRAS-mutation. In the meantime, a worsening of respiratory symptoms and chest pain, as well as an increase of the pleural effusion and occurrence of lymphangitis were observed under alectinib (Figure 2A). Because of this newly detected CCDC6::RET rearrangement, treatment was switched to pralsetinib, which resulted in a rapid and almost complete response for 14 months, with excellent clinical tolerance and grade I neutropenia (Figure 2B).
      Figure 1
      Figure 1Histological features of the 2 tumors (magnification x200 1.A-1.H and 1.J / magnification x400 1.I). 1A-1E - The initial tumor displayed morphologic features of adenocarcinoma, with atypical cells in a glandular pattern, along with stroma reaction. (1A- HES (Hematoxylin Eosin Saffron)). Tumor cells displayed immunoreactivity for TTF1 (1B); no immunoreactivity with synaptophysin (1C); strong nuclear staining for TP53 (mutated pattern) (1D), and complete loss of RB (1E). 1F-1J - The second tumor showed features of small cell lung carcinoma, with densely packed small cells with scant cytoplasm, nuclear molding and a finely granular nuclear chromatin (1F- HES). The cells stained with TTF1 (1G); granular cytoplasmic immunoreactivity for synaptophysin (1H); nuclear staining for TP53 (mutated pattern) (1I) and displayed complete loss of RB (1J).
      Figure 2
      Figure 2Radiological images, treatment history and genomic results during timeline of the patient's clinical course. (A) baseline before pralsetinib initiation ; (B) best response to pralsetinib obtained after 2 scannographic evaluations ; (C) disease progression after 14 months of pralsetinib ; (D) best response after 4 cycles of carboplatin plus etoposide
      Unfortunately, the follow-up CT scan showed disease progression with appearance of nodular pleural lesions and an enlarged left-hilar lymph node (Figure 2C). A new pleural biopsy was performed to identify mechanisms of resistance to pralsetinib (Figure 1F-1J). Microscopic examination revealed densely packed small cells with scant cytoplasm, nuclear molding and a finely granular nuclear chromatin. The mitotic rate was high with a Ki-67 proliferation index of 90%. The cells diffusely expressed TTF1 and neuroendocrine markers (chromogranin, synaptophysin and CD56). Cytokeratin AE1/A3 showed a dot-like paranuclear staining, and RB1 expression was lost, leading to the diagnosis of SCLC. Molecular testing using full transcriptome RNA sequencing identified a TP53 mutation and the same CCDC6::RET fusion that was present in the first biopsy. Unsupervised hierarchical clustering analyses (Figure 3) were performed to compare the expression profile and the oncogenic alterations of the two tumors. These analyses showed that the initial LUAD clustered with other LUAD of our database, and the SCLC at progression clustered with SCLC of NeuroD1 subtype.
      Figure 3
      Figure 3. Unsupervised hierarchical clustering analysis, using Pearson correlation Adenocarcinomas are represented in orange, SCLC in blue, green or pink according to the molecular subtype (PMID 30926931). The cases hereby reported are highlighted by a red box. The initial adenocarcinoma grouped with other adenocarcinomas, and the SCLC grouped with SCLC, more precisely within the NeuroD1 subtype. The database included another case of exADK-SCLC (blue and pink), which grouped with ASCL1 subtype of SCLC.
      WT: Wild Type (tumors with no oncogenic driver or pathogenic mutations); LUAD: lung adenocarcinoma; SCLC: small cell lung carcinoma
      The patient was subsequently treated with etoposide-carboplatin chemotherapy. She achieved partial response after 6 cycles (Figure 2D) and a mediastinal radiotherapy was performed on residual hilar node. Unfortunately, the onset of abdominal pain led to the identification of a rapid diffuse progression with brain, liver, pleural and bone metastases. The biopsy confirmed liver invasion by the same SCLC. A second-line chemotherapy associating carboplatin plus paclitaxel is ongoing.

      Discussion

      A SCLC transformation has already been described in EGFR-mutated and ALK-rearranged NSCLC patients under targeted therapy.
      • Jin CB
      • Yang L.
      Histological transformation of non-small cell lung cancer: clinical analysis of nine cases.
      • Lee JK
      • Lee J
      • Kim S
      • et al.
      Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas.
      Transformation to SCLC of EGFR-mutated LUAD TKI naive was also reported,
      • Hayashi T
      • Takamochi K
      • Kohsaka S
      • et al.
      Transformation from EGFR/PTEN co-mutated lung adenocarcinoma to small cell carcinoma in lymph node metastasis.
      suggesting that neither the initial genomic drivers nor the types of TKI are sufficient or even necessary for the SCLC transformation. Hereby, we report a phenotypic transformation of RET-rearranged lung adenocarcinoma to SCLC as a mechanism of acquired resistance to pralsetinib.
      In our case, the hypothesis of SCLC transformation as opposed to a secondary primary tumor is supported by the clinical presentation, with the initial occurrence of RET-rearranged LUAD in a young light smoking woman, which responded to pralsetinib. It is also supported by the molecular and clustering analyses, showing the same CCDC6::RET fusion in both tumors, the expression profile of each one clustering with tumors of the same histology from our database. In addition, the prolonged progression-free survival (PFS) of 14 months, longer than usually reported in first-line treatment (9.1 months), under pralsetinib is not consistent with a minor SCLC clone already present,
      • Jin CB
      • Yang L.
      Histological transformation of non-small cell lung cancer: clinical analysis of nine cases.
      ,
      • Marcoux N
      • Gettinger SN
      • O'Kane G
      • et al.
      EGFR-mutant adenocarcinomas that transform to small-cell lung cancer and other neuroendocrine carcinomas: clinical outcomes.
      which would have progressed rapidly without adapted therapy.
      • Ferrer L
      • Giaj Levra M
      • Brevet M
      • et al.
      A brief report of transformation from NSCLC to SCLC: molecular and therapeutic characteristics.
      We also observed the same TP53 mutation and RB1 inactivation by immunohistochemistry in the LUAD and in the SCLC. These two tumor suppressor genes play major roles in the tumorigenesis of SCLC, and probably contribute to tumor progression from adenocarcinoma to SCLC,
      • Rudin CM
      • Poirier JT
      • Byers LA
      • et al.
      Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data.
      • Offin M
      • Chan JM
      • Tenet M
      • et al.
      Concurrent RB1 and TP53 alterations define a subset of EGFR-mutant lung cancers at risk for histologic transformation and inferior clinical outcomes.
      • Lin MW
      • Su KY
      • Su TJ
      • et al.
      Clinicopathological and genomic comparisons between different histologic components in combined small cell lung cancer and non-small cell lung cancer.
      • Wang W
      • Xu C
      • Chen H
      • et al.
      Genomic alterations and clinical outcomes in patients with lung adenocarcinoma with transformation to small cell lung cancer after treatment with EGFR tyrosine kinase inhibitors: a multicenter retrospective study.
      in agreement with the potential shared cell of origin theory (alveolar type II cells) of lung adenocarcinoma and SCLC.
      • Lee JK
      • Lee J
      • Kim S
      • et al.
      Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas.
      Importantly, they could be predictive of LUAD transformation.
      • Offin M
      • Chan JM
      • Tenet M
      • et al.
      Concurrent RB1 and TP53 alterations define a subset of EGFR-mutant lung cancers at risk for histologic transformation and inferior clinical outcomes.
      ,
      • Lin MW
      • Su KY
      • Su TJ
      • et al.
      Clinicopathological and genomic comparisons between different histologic components in combined small cell lung cancer and non-small cell lung cancer.
      In the literature, the subtypes of SCLC according to Rudin et al.
      • Ferrer L
      • Giaj Levra M
      • Brevet M
      • et al.
      A brief report of transformation from NSCLC to SCLC: molecular and therapeutic characteristics.
      have not been described in LUAD transformed into SCLC. In our case, the SCLC at progression clustered with NeuroD1 subtype whereas another case of EGFR-LUAD transformed into SCLC from our database clustered with ASCL1 subtype. NEUROD1 and ASCL1 mRNA were respectively overexpressed in these 2 transformed cases, as suggested by clustering analyses. Further investigations are required to determine if these subtypes of SCLC are part of the transformed LUAD.
      The fact that the SCLC transformation led us to give carboplatin plus etoposide chemotherapy, with initial good response as reported in the literature
      • Marcoux N
      • Gettinger SN
      • O'Kane G
      • et al.
      EGFR-mutant adenocarcinomas that transform to small-cell lung cancer and other neuroendocrine carcinomas: clinical outcomes.
      ,
      • Ferrer L
      • Giaj Levra M
      • Brevet M
      • et al.
      A brief report of transformation from NSCLC to SCLC: molecular and therapeutic characteristics.
      for 45% of patients, strongly supports the need to rebiopsy patients with progression under targeted therapies. Moreover, the systematic screening of TP53 and RB1 genes in addicted-NSCLC could help to detect patients at risk of histological transformation and to adjust their treatment accordingly.

      Clinical Practice Points

      • The majority of resistance to RET-TKI described in RET-rearranged NSCLC patients are driven by RET-independent mechanisms.
      • RET-rearranged lung adenocarcinoma treated by selective RET-TKI can transform into small-cell lung cancer.
      • Histological transformation into small-cell lung cancer is a new mechanism of acquired resistance to pralsetinib.
      • Rebiopsy of RET-rearranged lung adenocarcinoma should be considered to identify these histological transformations and adapt subsequent treatment.
      • Identification of TP53 and RB1 genes alterations in addicted-NSCLC could help to identify patients at risk of histological transformation.
      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Acknowledgments

      The authors thank the patient and her family. The patient involved in this case report gave her informed consent authorizing the use and disclosure of her health information.

      Disclosure

      Maurice Perol and Aurélie Swalduz declare to have conflict of interest with Roche and Lilly.

      Appendix. Supplementary materials

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