C M Parseghian1, J M Loree2, V K Morris3, X Liu4, K K Clifton3, S Napolitano3, J T Henry3, A A Pereira3, E Vilar5, B Johnson3, B Kee3, K Raghav3, A Dasari3, J Wu3, N Garg6, V M Raymond7, K C Banks7, A A Talasaz7, R B Lanman7, J H Strickler8, D S Hong4, R B Corcoran9, M J Overman3, S Kopetz3. 1. Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA. Electronic address: cparseghian@mdanderson.org. 2. BC Cancer, Vancouver, Canada. 3. Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA. 4. Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, USA. 5. Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA; Division of Cancer Prevention and Population Sciences, Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, USA. 6. Division of Diagnostic Imaging, Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, USA. 7. Guardant Health Inc, Redwood City, USA. 8. Duke University Medical Center, Durham, USA. 9. Massachusetts General Hospital Cancer Center, Boston, USA; Department of Medicine, Harvard Medical School, Boston, USA.
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 (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.
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.
Authors: Marcelo V Negrao; Victoria M Raymond; Richard B Lanman; Jacqulyne P Robichaux; Junqin He; Monique B Nilsson; Patrick K S Ng; Bianca E Amador; Emily B Roarty; Rebecca J Nagy; Kimberly C Banks; Viola W Zhu; Chun Ng; Young Kwang Chae; Jeffrey M Clarke; Jeffrey A Crawford; Funda Meric-Bernstam; Sai-Hong Ignatius Ou; David R Gandara; John V Heymach; Trever G Bivona; Caroline E McCoach Journal: J Thorac Oncol Date: 2020-06-13 Impact factor: 15.609