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

C. M. Parseghian, J. M. Loree, V. K. Morris, X. Liu, K. K. Clifton, S. Napolitano, J. T. Henry, A. A. Pereira, E. Vilar, B. Johnson, B. Kee, K. Raghav, A. Dasari, J. Wu, N. Garg, V. M. Raymond, K. C. Banks, A. A. Talasaz, R. B. Lanman, J. H. StricklerD. S. Hong, R. B. Corcoran, M. J. Overman, S. Kopetz

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

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 (r 2 =0.93 for RAS; r 2 =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.

Original languageEnglish
Pages (from-to)243-249
Number of pages7
JournalAnnals of Oncology
Volume30
Issue number2
DOIs
StatePublished - Feb 1 2019
Externally publishedYes

Keywords

  • Anti-EGFR therapy
  • Circulating tumor DNA
  • Clonal decay
  • Colorectal cancer

Fingerprint Dive into the research topics of 'Anti-EGFR-resistant clones decay exponentially after progression: Implications for anti-EGFR re-challenge'. Together they form a unique fingerprint.

  • Cite this

    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., ... Kopetz, S. (2019). Anti-EGFR-resistant clones decay exponentially after progression: Implications for anti-EGFR re-challenge. Annals of Oncology, 30(2), 243-249. https://doi.org/10.1093/annonc/mdy509