NGS-based liquid biopsy profiling identifies mechanisms of resistance to ALK inhibitors: a step toward personalized NSCLC treatment
Por:
Sanchez-Herrero, E, Serna-Blasco, R, Ivanchuk, V, Garcia-Campelo, R, Gomez, M, Sanchez, J, Massuti, B, Reguart, N, Camps, C, Sanz-Moreno, S, Calabuig-Farinas, S, Jantus-Lewintre, E, Arnal, M, Fernandez-Orth, D, Calvo, V, Gonzalez-Rumayor, V, Provencio, M and Romero, A
Publicada:
1 sep 2021
Ahead of Print:
1 jun 2021
Resumen:
Despite impressive and durable responses, nonsmall cell lung cancer (NSCLC) patients treated with anaplastic lymphoma kinase (ALK) inhibitors (ALK-Is) ultimately progress due to development of resistance. Here, we have evaluated the clinical utility of circulating tumor DNA (ctDNA) profiling by next-generation sequencing (NGS) upon disease progression. We collected 26 plasma and two cerebrospinal fluid samples from 24 advanced ALK-positive NSCLC patients at disease progression to an ALK-I. These samples were analyzed by NGS and digital PCR. A tool to retrieve variants at the ALK locus was developed (VALK tool). We identified at least one resistance mutation in the ALK locus in ten (38.5%) plasma samples; the G1269A and G1202R mutations were the most prevalent among patients progressing to first- and second-generation ALK-Is, respectively. Overall, 61 somatic mutations were detected in 14 genes: TP53, ALK, PIK3CA, SMAD4, MAP2K1 (MEK1), FGFR2, FGFR3, BRAF, EGFR, IDH2, MYC, MET, CCND3, and CCND1. Specifically, a deletion in exon 19 in EGFR, a non-V600 BRAF mutation (G466V), and the F129L mutation in MAP2K1 were identified in four patients who showed no objective survival benefit from ALK-Is. Potential ALK-I-resistance mutations were also found in PIK3CA and IDH2. Finally, a c-MYC gain, along with a loss of CCND1 and FGFR3, was detected in a patient progressing on a first-line treatment with crizotinib. We conclude that NGS analysis of liquid biopsies upon disease progression identified different putative ALK-I-resistance mutations in most cases and could be a valuable approach for therapy decision making.
Filiaciones:
Sanchez-Herrero, E:
Biomed Sci Res Inst Puerta de Hierro Majadahonda, Liquid Biopsy Lab, Madrid, Spain
Atrys Hlth, Barcelona, Spain
Serna-Blasco, R:
Biomed Sci Res Inst Puerta de Hierro Majadahonda, Liquid Biopsy Lab, Madrid, Spain
Ivanchuk, V:
Biomed Sci Res Inst Puerta de Hierro Majadahonda, Liquid Biopsy Lab, Madrid, Spain
Garcia-Campelo, R:
Complejo Hosp Univ A Coruna, Med Oncol Dept, La Coruna, Spain
Gomez, M:
Univ Autonoma Madrid, Hosp Univ Fdn Jimenez Diaz, Oncohlth Inst, Med Oncol Dept, Madrid, Spain
Sanchez, J:
Hosp La Princesa, Med Oncol Dept, Madrid, Spain
:
Hosp Univ Alicante, Med Oncol Dept, ISABIAL, Alicante, Spain
Reguart, N:
Hosp Clin Barcelona, Med Oncol Dept, Barcelona, Spain
Camps, C:
Fdn Hosp Gen Univ Valencia, Mol Oncol Lab, Valencia, Spain
CIBERONC, Valencia, Spain
Hosp Gen Univ Valencia, Dept Med Oncol, Valencia, Spain
Univ Valencia, Dept Med, Valencia, Spain
Sanz-Moreno, S:
Biomed Sci Res Inst Puerta de Hierro Majadahonda, Liquid Biopsy Lab, Madrid, Spain
Calabuig-Farinas, S:
Fdn Hosp Gen Univ Valencia, Mol Oncol Lab, Valencia, Spain
CIBERONC, Valencia, Spain
Univ Valencia, Dept Pathol, Valencia, Spain
Jantus-Lewintre, E:
Fdn Hosp Gen Univ Valencia, Mol Oncol Lab, Valencia, Spain
CIBERONC, Valencia, Spain
Univ Valencia, Dept Biotechnol, Valencia, Spain
Arnal, M:
IMIM Hosp del Mar Med Res Inst, MARGen, Barcelona, Spain
Fernandez-Orth, D:
Ctr Genom Regulat CRG, European Genome Phenome Arch, Barcelona, Spain
Calvo, V:
Hosp Univ Puerta de Hierro Majadahonda, Med Oncol Dept, Madrid, Spain
Gonzalez-Rumayor, V:
Atrys Hlth, Barcelona, Spain
Provencio, M:
Biomed Sci Res Inst Puerta de Hierro Majadahonda, Liquid Biopsy Lab, Madrid, Spain
Hosp Univ Puerta de Hierro Majadahonda, Med Oncol Dept, Madrid, Spain
Romero, A:
Biomed Sci Res Inst Puerta de Hierro Majadahonda, Liquid Biopsy Lab, Madrid, Spain
Hosp Univ Puerta de Hierro Majadahonda, Med Oncol Dept, Madrid, Spain
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