Details

Autor(en) / Beteiligte

• 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.

Titel

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

Ist Teil von

• Annals of oncology, 2019-02, Vol.30 (2), p.243-249

Ort / Verlag

England: Elsevier Ltd

Erscheinungsjahr

2019

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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. 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. 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. These results provide scientific support for anti-EGFR re-challenge and guide the optimal timing of re-challenge initiation.