Abstract 5245: Characterization of sub-clonal RAS/BRAF alterations in an anti-EGFR treated advanced CRC cohort using a liquid biopsy-based real world clinical genomics database
Authors: Abubaker Khalid , Wang Danyi , Feng Zheng , Stroh Christopher , Liao Jiemin , Otto Gordon , Scheuenpflug Juergen 
Published: June 2022

Background: Anti-EGFR monoclonal antibodies are treatment options for RAS and BRAF V600 mutation-negative CRC patients. However, the literature suggests that CRC patients with sub-clonal RAS and BRAF mutations may still benefit from anti-EGFR therapies. The Guardant INFORM™ real-world clinical-genomic database was utilized to assess the impact of sub-clonal RAS and BRAF alterations detected in circulating tumor DNA (ctDNA) by the Guardant360® test on the clinical outcome of CRC patients treated with anti-EGFR therapy.

Methods: Patients were selected from the Guardant INFORM™ database using the following inclusion criteria: diagnosed with advanced CRC in the US; treated with anti-EGFR therapies starting within 90 days after a Guardant360 test result; and the presence of BRAF V600E and/or canonical KRAS/NRAS mutations (codons 12, 13, 59, 61, 117, 146). Time to next treatment (TTNT) and overall survival (OS) were compared for various RAS/BRAF mutation clonality cutoffs using the Cox proportional hazards model.

Results: Of the 13,798 CRC patients in the Guardant INFORM database, 91% had detectable ctDNA, 913 received a Guardant360® test before anti-EGFR therapy, and 446 (48.8%) initiated anti-EGFR therapy within 90 days after the test. Among this cohort, 11% (n = 50) had a BRAF V600E mutation and 9% (n = 40) had a RAS mutation. The median RAS/BRAF clonality was 0.84 (IQR = 0.57, 1.00). The associated clinical outcomes for patients with sub-clonal and clonal RAS/BRAF mutations using clonality cutoffs from 0.3 to 0.8 are reported (Table).

Conclusion: Using a liquid biopsy-based clinical-genomic dataset, we demonstrate that patients harboring sub-clonal RAS or BRAF mutations benefit from anti-EGFR therapy to a degree similar to wild-type patients. Given the limited patient numbers, this finding warrants additional investigation into the utility of ant-EGFR therapies as a treatment option for this subgroup of CRC patients.

RAS/BRAF Mutation Clonality* Cutoff Sub-clonal** Clonal** HR (95% CI) P value HR (95% CI) P value TTNT 0.3 0.96 (0.42, 2.18) 0.913 1.72 (1.15, 2.59) 0.009 0.4 1.03 (0.48, 2.21) 0.946 1.72 (1.14, 2.60) 0.010 0.5 0.97 (0.45, 2.08) 0.931 1.77 (1.17, 2.66) 0.007 0.6 1.04 (0.51, 2.13) 0.922 1.76 (1.16, 2.66) 0.008 0.7 1.03 (0.55, 1.94) 0.919 1.90 (1.23, 2.93) 0.004 0.8 1.30 (0.75, 2.24) 0.350 1.72 (1.08, 2.74) 0.022 OS 0.3 1.72 (0.84, 3.54) 0.142 2.47 (1.61, 3.79) &lt;0.001 0.4 1.85 (0.93, 3.66) 0.079 2.42 (1.57, 3.74) &lt;0.001 0.5 1.79 (0.90, 3.54) 0.097 2.46 (1.59, 3.80) &lt;0.001 0.6 1.92 (1.00, 3.69) 0.050 2.40 (1.55, 3.73) &lt;0.001 0.7 1.83 (1.03, 3.26) 0.041 2.60 (1.63, 4.14) &lt;0.001 0.8 2.16 (1.29, 3.61) 0.003 2.33 (1.40, 3.86) 0.001 *Clonality = (RAS or BRAF MAF)/(maximum MAF). **Reference group is patients without RAS/BRAF mutations.

Citation Format: Khalid Abubaker, Danyi Wang, Zheng Feng, Christopher Stroh, Jiemin Liao, Gordon Otto, Juergen Scheuenpflug. Characterization of sub-clonal RAS/BRAF alterations in an anti-EGFR treated advanced CRC cohort using a liquid biopsy-based real world clinical genomics database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5245.