Abstract A032: Circulating tumor (ct)DNA mutations in EGFR pathway genes and clinical outcomes for patients with metastatic colorectal cancer (mCRC) treated with panitumumab from the ASPECCT study
Authors: Boedigheimer Michael , Ang Agnes Lee , Kim Tae Won , Thomas Anne , Gibbs Peter , Ruff Paul , Hool Kristina , Price Timothy 
Published: August 2018

Background: Mutations in RAS family genes are a negative predictor for response to anti-EGFR therapy. ASPECCT was the first prospective study to show that panitumumab was noninferior to cetuximab for overall survival (OS) in chemorefractory wild-type (WT) KRAS exon 2 mCRC. This analysis used next-generation sequencing of ctDNA before and after panitumumab therapy to explore mutations in EGFR pathway genes and their association with outcomes. Methods: Plasma samples collected at baseline (BL) and safety follow-up (SFU) were analyzed for ctDNA mutations using the PlasmaSelect-R™ 63-gene panel. Mutations for six major genes within the EGFR pathway (BRAF, KRAS, MAP2K1, NRAS, PIK3CA, and PTEN) were analyzed as categorical and continuous variables, and were evaluated for association with OS using univariate Cox proportional hazards (PH) model. Results: Of the 499 patients randomized to panitumumab, 208 had paired plasma samples at BL and SFU. Of the 113 (54.3%) patients who were WT for all genes at BL, 59 (52%) remained WT at SFU. At BL, 65 patients had single gene mutations in either BRAF (7.7%), KRAS (6.7%), PIK3CA (6.3%), NRAS (5.8%), PTEN (3.8%), or MAP2K1 (1.0%), and 30 patients had mutations in multiple genes (at &lt;2% prevalence). The majority of mutations at BL were in BRAF (16.3%), PIK3CA (14.4%), and KRAS (13.5%). At SFU, 62 patients gained single gene mutations in either KRAS (9.1%), BRAF (7.7%), PIK3CA (4.8%), MAP2K1 (3.8%), NRAS (3.4%), or PTEN (1.0%). The majority of mutations gained at SFU were in KRAS (22.6%) and BRAF (21.2%). Categorical analysis of mutations at BL found that patients with WT status for all six genes survived longer, and that KRAS and PTEN WT status had the most significant association to OS. Furthermore, continuous analysis indicated that patients with low mutation levels survived longer (table). Conclusions: Patients were more likely to have a mutation in a single gene at BL and in multiple genes at SFU. Based on the Cox PH model, KRAS had the smallest P value for correlation with OS at BL. Continuous analysis of ctDNA fraction suggests that patients with low-level KRAS mutations may still benefit from anti-EGFR therapy; however, a threshold for treatment benefit cannot be determined from a single-arm trial. These findings suggest that the tumor genetic landscape can become increasingly complex after treatment despite a single selection pressure. Categorical and Continuous Analysis for EGFR Pathway Genes and Median Overall Survival (mOS)*Categorical (Y/N)ContinuousGeneWild-typeMutantLow Risk†High Risk†Any/Sumn (%)113 (54.3)95 (45.7)153 (73.6)55 (26.4)mOS, months (95% CI)38.17 (31.58-48.08)21.92 (19.25-25.67)34.92 (29.25-38.67)18.42 (14.50-21.25)Cox PH P value2.803E-074.185E-09BRAFn (%)174 (83.7)34 (16.3)199 (95.7)9 (4.3)mOS, months (95% CI)31.58 (26.25-36.17)21.25 (15.67-28.67)29.25 (25.25-34.75)18.42 (6.08-21.92)Cox PH P value0.0030.014KRASn (%)180 (86.5)28 (13.5)192 (92.3)16 (7.7)mOS, months (95% CI)31.58 (27.33-36.17)19.92 (12.42-21.83)30.33 (26.67-35.33)15.67 (11.08-21.25)Cox PH P value1.597E-052.953E-06MAP2K1‡n (%)201 (96.6)7 (3.4)N/AN/AmOS, months (95% CI)29.17 (24.67-34.58)14.50 (0.00-43.42)Cox PH P value0.025NRASn (%)188 (90.4)20 (9.6)201 (96.6)7 (3.4)mOS, months (95% CI)29.17 (24.67-34.83)24.25 (16.33-33.67)29.17 (24.75-34.58)15.25 (0.00-45.58)Cox PH P value0.0450.002PIK3CAn (%)178 (85.6)30 (14.4)200 (96.2)8 (3.8)mOS, months (95% CI)29.50 (25.67-35.33)21.83 (15.67-29.42)29.17 (24.75-34.75)21.83 (6.08-33.17)Cox PH P value0.0090.021PTENn (%)190 (91.3)18 (8.7)197 (94.7)11 (5.3)mOS, months (95% CI)30.33 (26.25-35.50)19.75 (6.42-23.92)29.25 (25.25-34.83)15.25 (6.25-21.83)Cox PH P value6.907E-065.715E-05*A limitation of this analysis is the low number of mutants in some cases.†The cutoff was defined as the mutation level where the predicted hazard equals the baseline hazard.‡Insufficient numbers above cutoff to perform continuous analysis.CI, confidence interval; PH, proportional hazards; Y/N, yes/no

Citation Format: Michael Boedigheimer, Agnes Lee Ang, Tae Won Kim, Anne Thomas, Peter Gibbs, Paul Ruff, Kristina Hool, Timothy Price. Circulating tumor (ct)DNA mutations in EGFR pathway genes and clinical outcomes for patients with metastatic colorectal cancer (mCRC) treated with panitumumab from the ASPECCT study [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A032.