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

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 ¼0.93 for RAS; r 2 ¼0.94 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.

A Retrospective Exploration of Targeted Maintenance Therapy in Advanced Colorectal Cancer: Based on the Background of Chinese Patient Assistance Program

“…Siena et al also found that the analysis of plasma samples showed that the first detected emergence of RAS mutations occurred a median of 3.6 months (range, 0.3-7.5 months) earlier than imaging progression. In addition, those who had emerging RAS mutations at progression had a similar median PFS to those patients who remained wildtype (29). These results suggested that except RAS mutations led to resistance to anti-EGFR antibodies, other mechanisms led to disease progression.…”

“…Diaz et al (27) and Siravegna et al (28) found that in KRAS wild-type mCRC patients, KRAS mutation gradually increased during treatment with anti-EGFR antibody and gradually decreased after stopping treatment with anti-EGFR antibody or switching to other targeted drugs. The half-life of RAS mutations was 3.4 months (29). Siena et al also found that the analysis of plasma samples showed that the first detected emergence of RAS mutations occurred a median of 3.6 months (range, 0.3-7.5 months) earlier than imaging progression.…”

Clinical utility of circulating tumor DNA for colorectal cancer

“…Serial liquid biopsies may have particular utility in which resistant mutations could be prospectively identified and treatment could be changed in real time. For example, liquid biopsies have been successfully applied to identify mechanisms of resistance for epidermal growth factor (EGFR) inhibitor in mCRC patients . Significant proportions of CRC harbor mutations in KRAS , BRAF , or NRAS that could cause resistance to an EGFR inhibitor, and these hotspot mutations are candidates for mutations detectable in plasma .…”

“…For example, liquid biopsies have been successfully applied to identify mechanisms of resistance for epidermal growth factor (EGFR) inhibitor in mCRC patients. 63 Significant proportions of CRC harbor mutations in KRAS, BRAF, or NRAS that could cause resistance to an EGFR inhibitor, and these hotspot mutations are candidates for mutations detectable in plasma. 55,58 Previous reports showed that patients with RAS wild-type CRC in tissue, and plasma that is positive for KRAS and BRAF mutations can be resistant to the EGFR inhibitor.…”

“…• Absence of ctDNA after surgery is associated with a better prognosis and smaller chance of relapse, irrespective of the use of adjuvant chemotherapy [60][61][62][63] Treatment response, clonal evolution, and resistance…”