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As an aggressive tumor, intrahepatic cholangiocarcinoma (ICC) originates in the epithelium of the bile duct and has a poor prognosis. The therapeutic options for ICC are challenging and limited because of poor response to chemotherapy and the lack of targeted therapy. Here we report on a 41‐year‐old female patient with ICC with EHBP1MET fusion and multiple intrahepatic metastases responding to crizotinib. Next‐generation sequencing–based tumor mutation profiling was performed on the tumor biopsy and circulating tumor DNA from plasma. A novel EHBP1MET fusion was identified and confirmed by Sanger sequencing. Immunohistochemistry of biopsy sample also revealed c‐MET positivity. Subsequently, the patient started treatment with MET inhibitor crizotinib. Magnetic resonance imaging scan demonstrated a partial response for 8 months. To the best of our knowledge, this is the first clinical case report of a patient with MET‐rearranged ICC successfully treated with crizotinib. This case suggests that crizotinib may be a promising treatment option for patients with ICC with MET fusion, warranting further clinical investigation.Key Points
  • To the authors'' knowledge, this is the first reported case of EHBP1MET fusion.
  • This is also the first clinical case report of clinical benefit from crizotinib treatment in an intrahepatic cholangiocarcinoma (ICC) with MET fusion.
  • MET fusion is rare in ICC, and inhibition of MET could be a viable option for ICC that warrants further clinical investigation.
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Patients with non‐small cell lung cancer (NSCLC) containing ROS1 fusions can have a marked response to the ROS1‐targeted tyrosine kinase inhibitors (TKIs), such as crizotinib. Common resistance mechanisms of ROS1‐fusion targeted therapy are acquired mutations in ROS1. Along with the use of next‐generation sequencing in the clinical management of patients with NSCLC during sequential targeted therapy, many mechanisms of acquired resistance have been discovered in patients with activated tyrosine kinase receptors. Besides acquired resistance mutations, bypass mechanisms of resistance to epidermal growth factor receptor (EGFR)‐TKI treatment are common in patients with EGFR mutations. Here we describe a patient with metastatic lung adenocarcinoma with CD74‐ROS1 fusion who initially responded to crizotinib and then developed resistance by the acquired mutation of D1228N in the MET kinase domain, which showed short‐term disease control for cabozantinib.Key Points
  • The D1228N point mutation of MET is an acquired mutation for crizotinib resistance.
  • The patient obtained short‐term clinical benefit from cabozantinib therapy after resistance to crizotinib.
  • The clinical use of next‐generation sequencing could maximize the benefits of precision medicine in patients with cancer.
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IntroductionROS1 rearrangements are found in 1% of lung cancer patients. Therapeutic efficacy of crizotinib in this subset has been shown in early phase trials in the United States and East Asia. Here we present data on efficacy and safety of a prospective phase II trial evaluating crizotinib in European ROS1-positive patients (EUCROSS).Patients and MethodsThe trial was a multicenter, single-arm phase II trial (Clinicaltrial.gov identifier: NCT02183870). Key eligibility criteria included patients who were 18 years of age or older with advanced/metastatic lung cancer and centrally confirmed ROS1-rearranged lung cancer (fluorescence-in situ hybridization). Treatment included 250 mg crizotinib twice daily. The primary endpoint was investigator-assessed objective response rate (ORR) (Response Evaluation Criteria in Solid Tumors, version 1.1). Key secondary endpoints were progression-free survival (PFS), overall survival, efficacy by independent radiologic review, safety, health-related quality of life, and molecular characterization of tumor tissue.ResultsThirty-four patients received treatment. Four patients were excluded from efficacy analysis. Investigator ORR was 70% (95% confidence interval [CI]: 51–85; 21 of 30 patients) and median PFS was 20.0 months (95% CI: 10.1–not reached). Two patients with ROS1 wild-type sequences assessed by DNA sequencing had progression as best response. CD74-ROS1-positive patients had a trend towards a higher ORR and longer median PFS. TP53-co-mutant patients had a significantly shorter median PFS than wild-type patients (7.0 months, 95% CI: 1.7–20.0 versus 24.1 months, 95% CI: 10.1–not reached; p = 0.022). Treatment-related adverse events were documented in 33 of 34 patients (97%).ConclusionsCrizotinib is highly effective and safe in patients with ROS1-rearranged lung cancer. ROS1-/TP53-co-aberrant patients had a significantly worse outcome compared to TP53 wild-type patients.  相似文献   

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Background: ERCC1 is considered as a promising molecular marker that may predict platinum basedchemotherapy response in non small cell lung cancer patients. We therefore investigated whether its expression isindeed associated with clinical outcomes in advanced stage NSCLC patients. Materials and Methods: Pretreatmenttumor biopsy samples of 83 stage 3B and 4 non-small cell lung cancer patients treated with platinum basedchemotherapy were retrospectively analyzed for immunohistochemical ERCC1 expression. None of the patientsreceived curative surgery or radiotherapy. Results: By calculating H- scores regarding the extent and intensityof immunohistochemical staining of tumor biopsy samples, ERCC1 expression was found to be positive in 50patients (60.2%). ERCC1 positive and negative groups had no statistically significant differences regardingtreatment response, progression free survival and overall survival (respectively p=0.161; p=0.412; p=0.823).Conclusions: In our study we found no association between ERCC1 expression and survival or treatmentresponse. The study has some limitations, such as small sample size and retrospective analysis method. There isneed of more knowledge for use of ERCC1 guided chemotherapy regimens in advanced stage NSCLC.  相似文献   

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目的分析ROS1(c-ros oncogene 1,receptor tyrosine kinase)融合基因在晚期非小细胞肺癌原发灶和转移灶中的差异表达。方法选取非小细胞肺癌原发灶162例,其中配对转移灶139例。采用实时荧光定量PCR检测ROS1融合基因的表达,并分析其在晚期非小细胞肺癌原发灶和转移灶中的表达差异。结果晚期非小细胞肺癌原发灶ROS1融合基因表达阳性率4.3%(7/162),配对原发灶ROS1融合基因表达阳性率2.6%(5/139),配对转移灶融合基因表达阳性率2.2%(3/139);原发灶较转移灶ROS1融合基因检出阳性率显著增高,差异具统计学意义(χ~2=13.517,P=0.000);ROS1融合基因阳性表达在原发灶和转移灶一致性好(κ=0.479,P=0.000)。非小细胞肺癌原发灶中ROS1融合基因表达与病理类型存在密切关系(χ~2=5.195,P=0.031),与患者性别、年龄等不存在明显相关性(P>0.05)。非小细胞肺癌配对原发灶以及转移灶中ROS1融合基因表达与患者性别、年龄、吸烟以及病理类型不存在明显相关性(P>0.05)。结论晚期非小细胞肺癌ROS1融合基因的阳性表达在原发灶中与病理类型有关,其在配对原发灶和转移灶中阳性表达一致性较好,可作为检测ROS1融合基因的备选手段。  相似文献   

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Background: Despite the dramatic efficacy of ABT-737, a large percentage of cancer cells ultimately become resistance to this drug. Evidences show that over-expression of Mcl-1 is linked to ABT-737 resistance in NSCLC cells. The aim of this study was to investigate the effect of miRNA-101 on Mcl-1 expression and sensitivity of the A549 NSCLC cells to ABT-737. Methods: After miRNA-101 transfection, the Mcl-1 mRNA expression levels were quantified by RT-qPCR. Trypan blue staining was used to explore the effect of miRNA-101 on cell growth. The cytotoxic effects of miRNA-101 and ABT-737, alone and in combination, were measured using MTT assay. The effect of drugs combination was determined using the method of Chou-Talalay. Cell death was assessed using cell death detection ELISA assay kit. Results: Results showed that miRNA-101 markedly suppressed the expression of Mcl-1 mRNA in a time dependent manner, which led to A549 cell proliferation inhibition and enhancement of apoptosis (p < 0.05, relative to blank control). Pretreatment with miRNA-101 synergistically decreased the cell survival rate and lowered the IC50 value of ABT-737. Furthermore, miRNA-101 dramatically enhanced the apoptotic effect of ABT-737. Negative control miRNA had no remarkable effect on cellular parameters. Conclusions: Our findings propose that suppression of Mcl-1 by miRNA-101 can effectively inhibit the cell growth and sensitize A549 cells to ABT-737. Therefore, miRNA-101 can be considered as a potential therapeutic target in patients with non-small cell lung cancer.  相似文献   

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目的探讨CYP1A1和GSTM1基因多态性与个体肺癌易感性的关系。方法全面检索相关文献,应用Meta分析方法对各研究进行数据的合并与分析。结果共8篇文献入选,累计肺癌病例1067人,对照1416人,分别对CYP1A1*A和GSTM1-、CYP1A1*B/C和GSTM1+、CYP1A1*B/C和GSTM1-联合基因型进行统计分析。异质性检验χ2值分别为6.43、8.83与9.63,P>0.05,文献有同质性,各合并OR及95%CI分别为1.36(1.09~2.77)、1.65(1.26~2.15)和2.01(1.57~2.59)。结论CYP1A1和GSTM1突变基因型为罹患肺癌的易感基因型,且两者存在协同作用,在肿瘤防治方案中应加以重视从而采取相应措施达到有效预防肿瘤的目的。  相似文献   

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Crizotinib, an ALK/MET/ROS1 inhibitor, was approved by the U.S. Food and Drug Administration for the treatment of anaplastic lymphoma kinase (ALK)‐rearranged non‐small cell lung cancer (NSCLC) in August 2011, merely 4 years after the first publication of ALK‐rearranged NSCLC. The crizotinib approval was accompanied by the simultaneous approval of an ALK companion diagnostic fluorescent in situ hybridization assay for the detection of ALK‐rearranged NSCLC. Crizotinib continued to be developed as an ALK and MET inhibitor in other tumor types driven by alteration in ALK and MET. Crizotinib has recently been shown to be an effective ROS1 inhibitor in ROS1‐rearranged NSCLC, with potential future clinical applications in ROS1‐rearranged tumors. Here we summarize the heterogeneity within the ALK‐ and ROS1‐rearranged molecular subtypes of NSCLC. We review the past and future clinical development of crizotinib for ALK‐rearranged NSCLC and the diagnostic assays to detect ALK‐rearranged NSCLC. We highlight how the success of crizotinib has changed the paradigm of future drug development for targeted therapies by targeting a molecular‐defined subtype of NSCLC despite its rarity and affected the practice of personalized medicine in oncology, emphasizing close collaboration between clinical oncologists, pathologists, and translational scientists.  相似文献   

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