A multi-institutional observational study evaluating the incidence and the clinicopathological characteristics of NeoRAS wild-type metastatic colorectal cancer.

Abstract

206 Background: The ’’Neo RAS’’ phenomenon, in which tissue rat sarcoma viral oncogene homolog ( RAS) status converts from mutant (MT) to wild-type (WT) after treatment in metastatic colorectal cancer (mCRC), is gaining attention because epidermal growth factor receptor (EGFR) inhibitors, which were originally considered to be ineffective, may converted to be effective. This multi-center study investigated its incidence and clinicopathological characteristics that are still unclear. Methods: 107 mCRC patients with tissue RAS MT, confirmed using MEBGEN RASKET-B, who were refractory or intolerant to previous chemotherapies, including fluoropyrimidines, oxaliplatin, or irinotecan were enrolled in 4 institutions from June 2021 to August 2022. The RAS status in ctDNA was investigated after prior chemotherapy using ONCOBEAMTM RAC CRC. Clinicopathological characteristics were compared between patients with RAS MT and RAS WT (Neo RAS) in ctDNA. Results: The incidence of Neo RAS WT mCRC was 21.5% (23/107). The frequency of Neo RAS in KRAS exon 2 was significantly lower than that in other alleles such as exon 3 and 4 or NRAS (18.2% [18/99] vs 62.5% [5/8], P = 0.011). There were significant differences in frequency of Neo RAS between male vs female (30.6% [19/62] vs 8.9% [4/45], P = 0.008), absence vs presence of liver metastasis (38.6% [17/44] vs 9.5% [6/63], P < 0.001), and between two groups divided at the median: tumor diameter (> 60.9 mm vs ≤, 3.8% [2/53] vs 38.9% [21/54], P < 0.001), carcinoembryonic antigen level (> 38.2 ng/ml vs ≤, 11.3% [6/53] vs 31.5% [17/54], P = 0.018), carbohydrate antigen 19-9 level (> 158.0 U/ml vs ≤, 9.4% [5/53] vs 33.3% [18/54], P = 0.004). Logistic regression multivariate analysis, absence of liver metastasis (Odds ratio [OR], 4.62; P = 0.019), smaller tumor diameter (OR, 7.92; P = 0.012) and tissue RAS MT in other than KRAS exon 2 (OR, 9.04; P = 0.026) were significantly related to the appearance of Neo RAS WT mCRC. Conclusions: Original RAS status in tissue, tumor diameter and liver metastasis are related to conversion to Neo RAS WT mCRC.

Clinical features associated with NeoRAS wild-type metastatic colorectal cancer A SCRUM-Japan GOZILA substudy

“…Sato et al reported that all patients ( N = 4) with tissue RAS Q61H mutations had Neo RAS WT 30 . Yoshinami et al also showed a high incidence of Neo RAS among patients with tissue RAS MTs in exons other than the KRAS exon 2 (5/8, 62.5%), and this finding was related to the emergence of Neo RAS WT in their multivariate analysis 33 , 34 . Loree et al 35 similarly described that the allelic fractions of MTs in KRAS exons 3 and 4 and NRAS were lower than those of KRAS exon 2 MTs.…”