Anti-EGFR-resistant clones decay exponentially after progression: Implications for anti-EGFR re-challenge
| Autor: | A.A. Talasaz, Benny Johnson, Xian De Liu, Jason Henry, Naveen Garg, Bryan K. Kee, Michael J. Overman, Ryan B. Corcoran, David S. Hong, Arvind Dasari, Katherine Clifton, Kanwal Pratap Singh Raghav, Kimberly C. Banks, Stefania Napolitano, R.B. Lanman, John H. Strickler, Scott Kopetz, Christine Megerdichian Parseghian, Van K. Morris, V.M. Raymond, Ji Yuan Wu, Allan Andresson Lima Pereira, Jonathan M. Loree, Eduardo Vilar |
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| Přispěvatelé: | Parseghian, C. M., Loree, J. M., Morris, V. K., Liu, X., Clifton, K. K., Napolitano, S., Henry, J. T., Pereira, A. A., Vilar, E., Johnson, B., Kee, B., Raghav, K., Dasari, A., Wu, J., Garg, N., Raymond, V. M., Banks, K. C., Talasaz, A. A., Lanman, R. B., Strickler, J. H., Hong, D. S., Corcoran, R. B., Overman, M. J., Kopetz, S. |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Oncology Colorectal cancer Mutant Colorectal Neoplasm 0302 clinical medicine Retrospective Studie Anti-EGFR therapy Epidermal growth factor receptor Neoplasm Metastasis biology Hematology Prognosis Neoplastic Cells Circulating ErbB Receptors Neoplasm Metastasi Survival Rate Ectodomain 030220 oncology & carcinogenesis Disease Progression Colorectal Neoplasms Human medicine.medical_specialty Prognosi Protein Kinase Inhibitor Follow-Up Studie 03 medical and health sciences Exponential growth Internal medicine medicine Humans Progression-free survival ErbB Receptor Protein Kinase Inhibitors Retrospective Studies Circulating tumor DNA business.industry Retrospective cohort study Original Articles medicine.disease ras Protein Discontinuation 030104 developmental biology Drug Resistance Neoplasm Mutation biology.protein ras Proteins business Clonal decay Follow-Up Studies |
| Popis: | Background Colorectal cancer (CRC) has been shown to acquire RAS and EGFR ectodomain mutations as mechanisms of resistance to epidermal growth factor receptor (EGFR) inhibition (anti-EGFR). After anti-EGFR withdrawal, RAS and EGFR mutant clones lack a growth advantage relative to other clones and decay; however, the kinetics of decay remain unclear. We sought to determine the kinetics of acquired RAS/EGFR mutations after discontinuation of anti-EGFR therapy. Patients and methods We present the post-progression circulating tumor DNA (ctDNA) profiles of 135 patients with RAS/BRAF wild-type metastatic CRC treated with anti-EGFR who acquired RAS and/or EGFR mutations during therapy. Our validation cohort consisted of an external dataset of 73 patients with a ctDNA profile suggestive of prior anti-EGFR exposure and serial sampling. A separate retrospective cohort of 80 patients was used to evaluate overall response rate and progression free survival during re-challenge therapies. Results Our analysis showed that RAS and EGFR relative mutant allele frequency decays exponentially (r2=0.93 for RAS; r2=0.94 for EGFR) with a cumulative half-life of 4.4 months. We validated our findings using an external dataset of 73 patients with a ctDNA profile suggestive of prior anti-EGFR exposure and serial sampling, confirming exponential decay with an estimated half-life of 4.3 months. A separate retrospective cohort of 80 patients showed that patients had a higher overall response rate during re-challenge therapies after increasing time intervals, as predicted by our model. Conclusion These results provide scientific support for anti-EGFR re-challenge and guide the optimal timing of re-challenge initiation. |
| Databáze: | OpenAIRE |
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