scholarly journals 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

2021 ◽  
Author(s):  
Hongna Sun ◽  
Xiaofen Li ◽  
Shuang Dai ◽  
Xudong Shen ◽  
Meng Qiu
Keyword(s):  
Gallbladder Cancer ◽  
Acquired Resistance ◽  
Invasive Disease ◽  
Circulating Tumor Dna ◽  
Braf V600e ◽  
Tyrosine Kinase Receptor ◽  
Tract Cancer ◽  
First Case ◽  
Phase Ii Studies ◽  
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. MET encodes a tyrosine kinase receptor and its ligand hepatocyte growth factor (HGF), 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.

A large real-world study on the effectiveness of the combined inhibition of EGFR and MET in EGFR-mutant advanced non-small cell lung cancer (NSCLC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9043-9043
Author(s):  
Liu Li ◽  
Jingjing Qu ◽  
Jianfu Heng ◽  
Chunhua Zhou ◽  
Yi Xiong ◽  
...  
Keyword(s):  
Real World ◽  
Tp53 Mutation ◽  
Objective Response ◽  
Acquired Resistance ◽  
Braf V600e ◽  
Monotherapy Group ◽  
Chemotherapy Group ◽  
Met Amplification ◽  
Egfr Mutant ◽  
Egfr Tki

9043 Background: MET amplification is an important mechanism mediating acquired resistance to EGFR tyrosine kinase inhibitors (TKI). Until now, no consensus exists on the standard treatment strategy for this subset of patients due to the lack of clinical data from large cohort or controlled trials. In our clinical practice, three regimens were commonly administered to patients after MET amplification-mediated EGFR-TKI progression: EGFR-TKI and MET-TKI combination therapy, MET-TKI monotherapy, or chemotherapy. Our study aimed to compare the effectiveness of these three regimens. Methods: Seventy patients with EGFR-mutant advanced NSCLC who progressed from prior EGFR-TKI through the acquisition of MET amplification and received treatment between March 2015 and March 2020 were included in this study. Of them, 38 received EGFR-TKI plus crizotinib, 10 received crizotinib monotherapy, and 22 received platinum-based doublet chemotherapy. Somatic mutation profiling was performed on blood and tissue biopsy samples. Resistance mechanisms to the combination targeted therapy were also explored in 12 patients. Results: The objective response rate (ORR) and disease control rate (DCR) were 47.5% and 84.0% for EGFR-TKI+crizotinib group, 40.0% and 70.0% for crizotinib monotherapy group, and 18.2% and 50.0% for chemotherapy group, respectively. The EGFR-TKI+crizotinib group had significantly better ORR (P = 0.026) and DCR (P = 0.016) than the chemotherapy group but was not statistically different from the crizotinib monotherapy group (ORR, P = 0.73; DCR, P = 0.39). Progression-free survival (PFS) was significantly longer for the EGFR-TKI+crizotinib group than those who received crizotinib monotherapy (5.0 vs 2.3 months, P = 0.004) or chemotherapy (5.0 vs 2.9 months, P = 0.036), but overall survival was comparable (10.0 vs 4.1 vs 8.5 months, P = 0.088). TP53 mutation (58.5%) and EGFR amplifications (42.9%) were the two common concurrent mutations in the three cohorts. PFS was significantly longer for patients with either concurrent TP53 mutation (n = 17) (6.0 vs 2.3 vs 2.9 months, P = 0.009) or concurrent EGFR amplification (n = 13) (5.0 vs 1.2 vs 2.4 months, P = 0.016) who received EGFR-TKI+crizotinib. Potential molecular mechanisms of acquired resistance to EGFR-TKI+crizotinib therapy included EGFR T790M (n = 2), EGFR L718Q (n = 1), EGFR S645C (n = 1), MET D1228H (n = 1), BRAF V600E (n = 1), NRAS Q61H (n = 1), and amplifications in KRAS (n = 2), ERBB2 (n = 1), CDK4 (n = 1), and MYC (n = 2). Conclusions: Our study provides real-world clinical evidence, in the largest cohort to date, that simultaneous inhibition of EGFR and MET improves clinical outcomes of patients with EGFR-mutant NSCLC who acquired MET amplification from prior EGFR-TKI therapy, indicating that combinatorial regimen of EGFR-TKI and MET-TKI could be a more effective therapeutic strategy in this subset of patients.

Incidence and heterogeneity of C797S and other EGFR resistance mutations on routine comprehensive genomic profiling (CGP).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9101-9101
Author(s):  
Pasi A. Janne ◽  
Jessica Kim Lee ◽  
Russell Madison ◽  
Jeffrey Michael Venstrom ◽  
Alexa Betzig Schrock ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Acquired Resistance ◽  
Standard Of Care ◽  
Circulating Tumor Dna ◽  
Resistance Mechanisms ◽  
Braf V600e ◽  
Resistance Mutations ◽  
Line Of Therapy ◽  
Egfr Mutant ◽  
Platinum Doublet

9101 Background: The emergence of osimertinib (osi) as standard of care therapy for EGFR-mutant NSCLC has led to investigations into understanding and overcoming drug resistance. There are now a number of therapeutic approaches aimed at overcoming EGFR resistance mutations (muts). We sought to understand the biology of EGFR C797S and other EGFR resistance muts through querying our clinico-genomic database (CGDB). Methods: CGP results from tissue (n = 60,889) or circulating tumor DNA (ctDNA; [n = 9,922]) samples from 70,811 NSCLC patients (pts) were queried for known osi resistance muts in EGFR (C797, L792, G796, L718, G724). Clinical outcomes were evaluated for a cohort of NSCLC pts with osi resistance from the Flatiron Health-Foundation Medicine CGDB, a nationwide de-identified EHR-derived database linked to CGP data. Results: Between 12/2014 and 11/2020, 261 osi resistance mutations in EGFR were detected in 228 samples. The most common were C797S (66%), L718X (14%), G724S (11%), and others (9%). 173 C797S muts were detected in 155 samples (123 ex19del, 30 L858R, 2 other EGFR muts); 100 tissue, 55 ctDNA (median VAF = 7.6%). EGFR T790M co-occurred with C797S muts (96% cis, 3.7% trans) in 118 (76%) samples and decreased over time, occurring in 92% (24/26) of C797S samples tested in 2017 vs 56% (20/36) of samples tested in 2020 (p = 0.002). In 19/155 (12%) samples with C797S (14 ctDNA), multiple changes resulting in EGFR resistance muts were present: 16 samples had > 1 nucleotide changes resulting in C797S (100% trans), 3 samples had other resistance muts (L718Q/V, L792H, L792F) and 3 samples had multiple C797S changes with other resistance muts (C797G, L792H/F + G796S, L718Q + G796S+C797G). 29 pts (14 ctDNA) had C797S with potential off-target resistance (17 PIK3CA muts, 4 BRAF muts, 3 CCDC6- RET fusions, 3 KRAS muts, 2 ERBB2 amplifications (amps), 1 ERBB2 ex16 del, 1 STRN- ALK fusion, 1 FGFR3- TACC3 fusion). In the CGDB, 527 EGFR-mut NSCLC pts had documented receipt of osi. Pre and post osi-treated specimens were available for 19 of these pts (12 ex19del, 6 L858R, 1 G719A/S768I). Heterogeneous acquired resistance mechanisms were observed in the post-osi specimen, including 2 CCDC6- RET fusions, 2 MET amps, 2 BRAF fusions, BRAF V600E, and secondary EGFR muts (C797S, L704F, L718V). 161/527 pts had a documented line of therapy after osi discontinuation and most frequently received platinum doublet + immunotherapy (27%) or platinum doublet alone (23%); 17 (11%) pts received another EGFR tyrosine kinase inhibitor. 214/527 had documented osi progression and median post-progression survival was 11.8 months. Conclusions: Osi resistance in EGFR-mutant NSCLC is a poor prognosis condition. EGFR C797S is a recurring resistance mut which, in a minority of cases, can co-occur with alternate on and off target resistance muts detected with tissue and liquid biopsy.

Genomic analysis of circulating tumor DNA in 3,334 patients with advanced prostate cancer to identify targetable BRCA alterations and AR resistance mechanisms.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 25-25
Author(s):  
Hanna Tukachinsky ◽  
Russell Madison ◽  
Jon Chung ◽  
Lucas Dennis ◽  
Bernard Fendler ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Advanced Prostate Cancer ◽  
Acquired Resistance ◽  
Genomic Analysis ◽  
Circulating Tumor Dna ◽  
Resistance Mechanisms ◽  
Cancer Tissue ◽  
Castration Resistant Prostate Cancer ◽  
High Level ◽  
Tumor Dna

25 Background: Comprehensive genomic profiling (CGP) by next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) from plasma provides a minimally invasive method to identify targetable genomic alterations (GAs) and resistance mechanisms in patients with metastatic castration-resistant prostate cancer (mCRPC). The circulating tumor fraction in patients with mCRPC and the clinical validity of GAs detected in plasma remain unknown. We evaluated the landscape of GAs using ctDNA-based CGP and assessed concordance with tissue-based CGP. Methods: Plasma from 3,334 patients with advanced prostate cancer (including 1,674 mCRPC screening samples from the TRITON2/3 trials and 1,660 samples from routine clinical CGP) was analyzed using hybrid-capture-based gene panel NGS assays. Results were compared with CGP of 2,006 metastatic prostate cancer tissue biopsies. Concordance was evaluated in 837 patients with both tissue (archival or contemporaneous) and plasma NGS results. Results: 3,127 patients [94%] had detectable ctDNA. BRCA1/2 were mutated in 295 patients [8.8%]. In concordance analysis, 72/837 [8.6%] patients had BRCA1/2 mutations detected in tissue, 67 [93%] of whom were also identified by ctDNA, and 20 patients were identified using ctDNA but not tissue [23% of all patients identified using ctDNA]. ctDNA detected subclonal BRCA1/2 reversions in 10 of 1,660 [0.6%] routine clinical CGP samples. AR alterations, including amplifications and hotspot mutations, which were detected in 940/2,213 patients [42%]. Rare AR compound mutations, rearrangements, and novel in-frame deletions were identified. Altered pathways included PI3K/AKT/mTOR [14%], WNT/β-catenin [17%], and RAS/RAF/MEK [5%]. Microsatellite instability was detected in 31/2,213 patients [1.4%]. Conclusions: In the largest study of mCRPC plasma samples conducted to date, CGP of ctDNA recapitulated the genomic landscape detected in tissue biopsies, with a high level of agreement in detection of BRCA1/2 alterations. It also identified patients who may have gained somatic BRCA1/2 alterations since archival tissue was collected. ctDNA detected more acquired resistance GAs than tissue, including novel AR-activating variants. The large percentage of patients with rich genomic signal from ctDNA, and the sensitive, specific detection of BRCA1/2 alterations position liquid biopsy as a compelling clinical complement to tissue CGP for patients with mCRPC.

BRCA Reversion Mutations in Circulating Tumor DNA Predict Primary and Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma

2018 ◽  
Vol 9 (2) ◽  
pp. 210-219 ◽  
Author(s):  
Kevin K. Lin ◽  
Maria I. Harrell ◽  
Amit M. Oza ◽  
Ana Oaknin ◽  
Isabelle Ray-Coquard ◽  
...  
Keyword(s):  
Ovarian Carcinoma ◽  
Parp Inhibitor ◽  
Acquired Resistance ◽  
Circulating Tumor Dna ◽  
High Grade ◽  
Tumor Dna

scholarly journals Dual HER2 Blockade: An Emerging Option in Metastatic Biliary Tract Cancer?

Medicina ◽  
2021 ◽  
Vol 57 (12) ◽  
pp. 1301
Author(s):  
Angela Dalia Ricci ◽  
Alessandro Rizzo
Keyword(s):  
Gallbladder Cancer ◽  
Biliary Tract ◽  
Intrahepatic Cholangiocarcinoma ◽  
Biliary Tract Cancer ◽  
Heterogeneous Group ◽  
Perihilar Cholangiocarcinoma ◽  
Extrahepatic Cholangiocarcinoma ◽  
Tract Cancer ◽  
Hepatobiliary Malignancies

Biliary tract cancer (BTC) includes a heterogeneous group of aggressive and rare hepatobiliary malignancies, including gallbladder cancer, ampullary carcinomas, intrahepatic cholangiocarcinoma (iCCA), and extrahepatic cholangiocarcinoma, further subclassified into distal (dCCA) and perihilar cholangiocarcinoma (pCCA) [...]

scholarly journals Efficacy of Sym004 in Patients With Metastatic Colorectal Cancer With Acquired Resistance to Anti-EGFR Therapy and Molecularly Selected by Circulating Tumor DNA Analyses

JAMA Oncology ◽  
2018 ◽  
Vol 4 (4) ◽  
pp. e175245 ◽  
Author(s):  
Clara Montagut ◽  
Guillem Argilés ◽  
Fortunato Ciardiello ◽  
Thomas T. Poulsen ◽  
Rodrigo Dienstmann ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Acquired Resistance ◽  
Circulating Tumor Dna ◽  
Dna Analyses ◽  
Tumor Dna

A Review of Recent Data in the Treatment of Gallbladder Cancer: What We Know, What We Do, and What Should Be Done

2014 ◽  
pp. e165-e170 ◽  
Author(s):  
Bettina G. Müller ◽  
Xabier De Aretxabala ◽  
Manuel González Domingo
Keyword(s):  
Gallbladder Cancer ◽  
Abdominal Mass ◽  
Multidisciplinary Treatment ◽  
Single Agent ◽  
Biliary Tree ◽  
Clinical Entity ◽  
Phase Iii ◽  
Separate Analysis ◽  
Two Phase ◽  
Phase Ii Studies

Gallbladder cancer is now considered a distinct clinical entity, allowing for a separate analysis from that of other malignancies of the biliary tree. Symptoms related to a malignant tumor of the gallbladder include jaundice and abdominal pain, or a palpable abdominal mass that occurs in a late stage of the disease. The majority of patients with operable gallbladder cancer are diagnosed by cholecystectomy performed for presumed benign disease, mostly cholelithiasis, a clinical entity known as incidental gallbladder cancer. Given the poor prognosis if tumor invasion beyond the muscular layer and/or nodal metastasis is found, adjuvant treatments have been implemented, but few data are available to guide treatment decisions in this setting. For advanced disease, a multidisciplinary treatment approach including biliary drainage procedures and palliative support is needed in the management of this aggressive disease. Palliative chemotherapy with a combination of gemcitabine and cisplatin or oxaliplatin is the standard treatment based on the findings of two phase III trials that showed improved overall survival compared to single-agent chemotherapy and best supportive care. Several phase II studies have been reported investigating the role of targeted agents against EGFR, VEGF, HER2, and MEK. International collaboration to enhance our knowledge of gallbladder cancer should be encouraged.

scholarly journals Resistance mechanism for ibrutinib in marginal zone lymphoma

2019 ◽  
Vol 3 (4) ◽  
pp. 500-502 ◽  
Author(s):  
Narendranath Epperla ◽  
Arwa Y. Shana’ah ◽  
Dan Jones ◽  
Beth A. Christian ◽  
Sabarish Ayyappan ◽  
...  
Keyword(s):  
Marginal Zone ◽  
Acquired Resistance ◽  
Resistance Mechanism ◽  
Marginal Zone Lymphoma ◽  
First Case ◽  
Molecular Events ◽  
Key Points

Key Points The molecular events leading to primary and acquired resistance to ibrutinib in marginal zone lymphoma have not been studied. We describe the first case of MZL with acquired resistance to ibrutinib in which mutations in both BTK (C481S) and PLCG2 are documented.

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