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A case report of response to crizotinib in chemotherapy-refractory metastatic gallbladder cancer with met amplification and acquired resistance resulting from the loss of MET amplification.

ABSTRACT: Gallbladder cancer (GBC) is a highly invasive disease and the most prevalent malignancy of the biliary system. Patients with GBC are commonly diagnosed at a late stage and have an unfavorable prognosis. Palliative chemotherapy has been the standard care for recurrent or metastatic disease in the past decades. Recently, several targeted therapies have been investigated in advanced biliary tract cancer (BTC) including inhibitors of genes or pathways such as FGFR2 fusions or rearrangements, IDH1 mutations, and NTRK gene fusions. Also, several clinical studies involving molecular stratification have been performed in defined patient groups, for example, BRAF V600E and HER2. Mesenchymal epithelial transition(MET)encodes a tyrosine kinase receptor and its ligand hepatocyte growth factor is a proto-oncogene. Targeting the MET signaling pathway is an effective strategy in numerous cancer types. However, the poor efficacy of MET inhibitors has been demonstrated in several phase II studies, but currently no reports have explained the potential mechanisms of resistance to MET inhibitors in BTC. In this article, we report a case of metastatic GBC with MET amplification that exhibited a rapid response to crizotinib after the failure of two lines of chemotherapy. After the patient had progressed and discontinued crizotinib, cabozantinib was introduced. Analysis of circulating tumor DNA (ctDNA) by next-generation sequencing (NGS) indicated a loss of MET amplification status. To our knowledge, this is the first case study demonstrating the use of NGS in ctDNA to monitor the development of acquired resistance during anti-MET treatment in GBC.

SUBMITTER: Sun H

PROVIDER: S-EPMC8982584 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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A case report of response to crizotinib in chemotherapy-refractory metastatic gallbladder cancer with met amplification and acquired resistance resulting from the loss of MET amplification.

Sun Hongna H Li Xiaofen X Dai Shuang S Shen Xudong X Qiu Meng M

Precision clinical medicine 20210730 3

Gallbladder cancer (GBC) is a highly invasive disease and the most prevalent malignancy of the biliary system. Patients with GBC are commonly diagnosed at a late stage and have an unfavorable prognosis. Palliative chemotherapy has been the standard care for recurrent or metastatic disease in the past decades. Recently, several targeted therapies have been investigated in advanced biliary tract cancer (BTC) including inhibitors of genes or pathways such as <i>FGFR2</i> fusions or rearrangements, ...[more]

PMID: 35693217

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Project description:Background: In non-small cell lung cancer (NSCLC) patients harboring MET mutations, MET-tyrosine kinase inhibitors (TKIs) have been proven to achieve a good response. However, the relative efficacy of different therapeutics in primary NSCLC patients with MET amplification and the treatment options for patients harboring acquired MET amplification after the failure of epidermal growth factor receptor (EGFR)-TKIs remain unclear. Methods: In total, 33 patients harboring primary MET amplification and 9 patients harboring acquired MET alterations identified by next-generation sequencing were enrolled. A retrospective analysis was conducted to compare the efficacy of different therapeutics. In addition, studies reporting various treatments for patients harboring MET alterations were included in the meta-analysis. Results: In our cohort of patients harboring primary MET amplification, crizotinib displayed better efficacy than immunotherapy and chemotherapy, as demonstrated both in first-line (P = .0378) and second-line treatment regimens (P = .0181). The disease control rates for crizotinib, immunotherapy, and chemotherapy were 81.8%, 72.7%, and 63.6%, respectively. In particular, the median progression-free survival (PFS) time after immunotherapy in patients harboring MET amplification and high programed death ligand 1 (PD-L1) expression (>50%) was only 77.5 days. The meta-analysis revealed that the median PFS times after crizotinib and immunotherapy were 4.57 and 2.94 months, respectively. In patients harboring acquired MET amplification, chemotherapy plus bevacizumab had superior efficacy (310.0 days vs 73.5 days, P = .0360) compared with MET-TKIs ± EGFR-TKIs. Conclusions: Immunotherapy showed a low response in patients harboring MET alterations, even those with concurrent high PD-L1 expression. MET-TKIs might be an optional treatment with worth-expecting efficacy. However, chemotherapy plus bevacizumab could benefit the subpopulation of patients harboring acquired MET amplification after the failure of EGFR-TKIs.

Project description:Backgroundc-mesenchymal epithelial transition factor receptor (c-MET) and fibroblast growth factor receptor 2 (FGFR2) amplification have been identified as factors associated with advanced stage and poor prognosis in gastric cancer (GC). While they are typically considered mutually exclusive, concurrent amplifications have been reported in a small subset of GC patients.Methodsin this retrospective study, we analyzed the clinical outcomes of GC patients with MET and FGFR2 amplification using the next-generation sequencing (NGS) database cohort at Samsung Medical Center, which included a total of 2119 patients between October 2019 and April 2021.ResultsOf 2119 cancer patients surveyed, the number of GC patients was 614 (29.0%). Out of 614 GC patients, 39 (6.4%) had FGFR2 amplification alone, 22 (3.6%) had MET amplification, and 2 GC patients (0.3%) had concurrent FGFR2 and MET amplification. Two patients with concurrent FGFR2 and MET amplification did not respond to first-line chemotherapy. These two patients had significantly shorter overall survival (3.6 months) compared to patients with FGFR2 or MET amplification alone (13.6 months and 8.4 months, respectively) (p = 0.004). Lastly, we tested the existence of FGFR2 and MET in tumor specimens from different organ sites. Initially, the NGS was tested in a primary tumor specimen from stomach cancer, where the MET copy number was 14.1 and the FGFR2 copy number was 5.3. We confirmed that both MET and FGFR2 were highly amplified in the primary tumor using FISH (MET-CEP7 ratio = 5 and FGFR2-CEP7 ratio = 3). However, although the MET copy number was normal in peritoneal seeding using FISH, FGFR2 remained amplified using FISH (FGFR2-CEP7 ratio = 7) with high FGFR2 protein overexpression. Hence, there was intra-patient molecular heterogeneity.Conclusionsour findings suggest that concurrent amplification of FGFR2 and MET in GC patients is associated with clinical aggressiveness and may contribute to non-responsiveness to chemotherapy or targeted therapy.

Dataset Information

A case report of response to crizotinib in chemotherapy-refractory metastatic gallbladder cancer with met amplification and acquired resistance resulting from the loss of MET amplification.

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A case report of response to crizotinib in chemotherapy-refractory metastatic gallbladder cancer with met amplification and acquired resistance resulting from the loss of MET amplification.

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