Paola Bordi1, Marcello Tiseo2, Eleonora Rofi3, Iacopo Petrini4, Giuliana Restante3, Romano Danesi3, Marzia Del Re3. 1. Medical Oncology Unit, University Hospital of Parma, Parma, Italy. 2. Medical Oncology Unit, University Hospital of Parma, Parma, Italy. Electronic address: mtiseo@ao.pr.it. 3. Clinical Pharmacology and Pharmacogenetic Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. 4. Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
Abstract
BACKGROUND: In patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC), disease progression occurs after a median of 9 to 10 months of crizotinib treatment. Several mechanisms of resistance have been identified and include ALK mutations and amplification or the activation of bypassing signaling pathways. Rebiopsy in NSCLC patients represents a critical issue and the analysis of circulating cell-free DNA (cfDNA) has a promising role for the identification of resistance mechanisms. PATIENTS AND METHODS: Twenty patients with advanced ALK-positive NSCLC were enrolled after disease progression during crizotinib treatment; cfDNA was analyzed using digital droplet polymerase chain reaction (BioRad, Hercules, CA) for ALK (p.L1196M, p.G1269A, and p.F1174L) and Kirsten rat sarcoma (KRAS) (codons 12 and 13) mutations. RESULTS: ALK secondary mutations (p.L1196M, p.G1269A, and p.F1174L) were identified in 5 patients; 1 patient had 2 ALK mutations (p.L1196M and p.G1269A). Overall, 10 patients presented KRAS mutations (7 p.G12D, 2 p.G12V, and 1 p.G12C mutations, respectively). In 3 patients KRAS mutations were associated with ALK mutations. cfDNA was monitored during the treatment with second-generation ALK inhibitors and the amount of ALK as well as KRAS mutations decreased along with tumor regression. CONCLUSION: ALK and KRAS mutations are associated with acquired resistance to crizotinib in ALK-positive NSCLC. In particular, ALK acquired mutations can be detected in plasma and could represent a promising tumor marker for response monitoring.
BACKGROUND: In patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC), disease progression occurs after a median of 9 to 10 months of crizotinib treatment. Several mechanisms of resistance have been identified and include ALK mutations and amplification or the activation of bypassing signaling pathways. Rebiopsy in NSCLCpatients represents a critical issue and the analysis of circulating cell-free DNA (cfDNA) has a promising role for the identification of resistance mechanisms. PATIENTS AND METHODS: Twenty patients with advanced ALK-positive NSCLC were enrolled after disease progression during crizotinib treatment; cfDNA was analyzed using digital droplet polymerase chain reaction (BioRad, Hercules, CA) for ALK (p.L1196M, p.G1269A, and p.F1174L) and Kirsten ratsarcoma (KRAS) (codons 12 and 13) mutations. RESULTS:ALK secondary mutations (p.L1196M, p.G1269A, and p.F1174L) were identified in 5 patients; 1 patient had 2 ALK mutations (p.L1196M and p.G1269A). Overall, 10 patients presented KRAS mutations (7 p.G12D, 2 p.G12V, and 1 p.G12C mutations, respectively). In 3 patientsKRAS mutations were associated with ALK mutations. cfDNA was monitored during the treatment with second-generation ALK inhibitors and the amount of ALK as well as KRAS mutations decreased along with tumor regression. CONCLUSION:ALK and KRAS mutations are associated with acquired resistance to crizotinib in ALK-positive NSCLC. In particular, ALK acquired mutations can be detected in plasma and could represent a promising tumor marker for response monitoring.
Authors: Matteo Canale; Luigi Pasini; Giuseppe Bronte; Angelo Delmonte; Paola Cravero; Lucio Crinò; Paola Ulivi Journal: Transl Lung Cancer Res Date: 2019-11
Authors: Caroline E McCoach; Collin M Blakely; Kimberly C Banks; Benjamin Levy; Ben M Chue; Victoria M Raymond; Anh T Le; Christine E Lee; Joseph Diaz; Saiama N Waqar; William T Purcell; Dara L Aisner; Kurtis D Davies; Richard B Lanman; Alice T Shaw; Robert C Doebele Journal: Clin Cancer Res Date: 2018-03-29 Impact factor: 12.531