NeoRAS wild-type metastatic colorectal cancer in the SCRUM-Japan GOZILA study.
Authors: Osumi Hiroki , Shinozaki Eiji , Nakamura Yoshiaki , Esaki Taito , Yasui Hisateru , Taniguchi Hiroya , Satake Hironaga , Sunakawa Yu , Komatsu Yoshito , Kagawa Yoshinori , Denda Tadamichi , Shiozawa Manabu , Satoh Taroh , Nishina Tomohiro , Goto Masahiro , Takahashi Naoki , Kato Takeshi , Bando Hideaki , Yamaguchi Kensei , Yoshino Takayuki 
Published: June 2023

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Background: The ’’Neo RAS’’ phenomenon refers to RAS mutant (MT) metastatic colorectal cancer (mCRC) that becomes RAS wild-type (WT) following treatment. This Neo RAS WT population might represent a novel indication for EGFR inhibitors, which are less effective in RAS MT mCRC. The incidence and clinicopathological characteristics of Neo RAS WT mCRC using plasma cell-free DNA (cfDNA) next generation sequencing has not been defined. Methods: As part of a large-scale nationwide screening platform (SCRUM-Japan GOZILA), 478 patients with an initial diagnosis of RAS MT mCRC by tissue analysis (MEBGEN RASKET-B) who received systemic therapy underwent cfDNA testing (Guardant 360) prior to later lines of treatment. Based on the cfDNA results, we evaluated the clinicopathological characteristics of those with Neo RAS WT and RAS MT. Neo RAS WT was defined as no RAS MT ( KRAS or NRAS) detected in plasma and was assessed in the overall cohort (Cohort A) and in the subgroup with at least one somatic alteration detected in plasma (Cohort B) to exclude those with insufficient tumor DNA shedding. Results: Median age at the time of blood sampling was 62.0 years old, and 257 (51.9%) were men. 160 (32.3%) and 319 (64.4%) had right-sided tumors and multi-organ metastases. The lungs were the most frequent site of metastasis (60.2%), followed by liver (57.4%), lymph nodes (28.9%), and peritoneum (28.5%). The prevalence of Neo RAS WT was 19.0% (91/478) in Cohort A and 9.8% (41/429) in Cohort B. The frequency of Neo RAS WT in tumors originally with KRAS exon 2 MT tended to be lower than in those with other RAS MT (18.1% vs 25.4%, P = 0.21 in Cohort A, 9.0% vs 15.4%, P = 0.14 in Cohort B). There were significant differences in the prevalence of Neo RAS WT between patients with single organ vs multi-organ metastases (P < 0.001 in Cohort A, P = 0.004 in Cohort B), absence vs presence of liver metastasis (P < 0.001 in both Cohort A and B), lymph node metastasis (P = 0.006 in Cohort A), peritoneal metastasis (P = 0.002 in group A), and bone metastasis (P = 0.029 in Cohort A), testing immediately prior to 2nd through to 4th line treatment vs later lines (P = 0.007 in Cohort A), immediate prior use of regorafenib (P = 0.027 in Cohort A) and any history of vascular endothelial growth factor inhibitors (P = 0.003 in Cohort A, P = 0.035 in Cohort B). In the logistic regression multivariate analysis, absence of liver metastasis (odds ratio [OR], 5.83; P < 0.001 in Cohort A, OR, 2.84; P = 0.005 in Cohort B), absence of lymph node metastasis (OR, 2.18; P = 0.034 in Cohort A) and tissue RAS MT other than KRAS exon 2 (OR, 2.35; P = 0.049 in Cohort B) were significantly related to the emergence of Neo RAS WT. Among 6 Neo RAS WT patients tretd with EGFR inhibitors, one had partial response and another one had stable disease for at least 6 months. Conclusions: Liver and lymph node metastasis and RAS MT other than those in KRAS exon 2 are factors associated with the development of Neo RAS WT mCRC. EGFR inhibitors might be effective treatment.