Anti-EGFR-resistant clones decay exponentially after progression: implications for anti-EGFR re-challenge.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Parseghian, CM; Loree, JM; Morris, VK; Liu, X; Clifton, KK; Napolitano, S; Henry, JT; Pereira, AA; Vilar, E; Johnson, B; Kee, B; Raghav, K; Dasari, A; Wu, J; Garg, N; Raymond, VM; Banks, KC; Talasaz, AA; Lanman, RB; Strickler, JH; Hong, DS; Corcoran, RB; Overman, MJ; Kopetz, S

Published Date

  • February 2019

Published In

Volume / Issue

  • 30 / 2

Start / End Page

  • 243 - 249

PubMed ID

  • 31987421

Electronic International Standard Serial Number (EISSN)

  • 1569-8041

Digital Object Identifier (DOI)

  • 10.1093/annonc/mdy509

Language

  • eng

Conference Location

  • England