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

Hiroki Osumi; Atsuo Takashima; Akira Ooki; Yuri Yoshinari; Takeru Wakatsuki; Hidekazu Hirano; Izuma Nakayama; Natsuko Okita; Ryoichi Sawada; Kota Ouchi; Koshiro Fukuda; Shota Fukuoka; Mariko Ogura; Daisuke Takahari; Keisho Chin; Hirokazu Shoji; Ken Kato; Naoki Ishizuka; Narikazu Boku; Kensei Yamaguchi; Eiji Shinozaki

doi:10.1016/j.tranon.2023.101718

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

Transl Oncol. 2023 Sep:35:101718. doi: 10.1016/j.tranon.2023.101718. Epub 2023 Jun 24.

Authors

Hiroki Osumi¹, Atsuo Takashima², Akira Ooki¹, Yuri Yoshinari², Takeru Wakatsuki¹, Hidekazu Hirano², Izuma Nakayama¹, Natsuko Okita², Ryoichi Sawada³, Kota Ouchi⁴, Koshiro Fukuda¹, Shota Fukuoka¹, Mariko Ogura¹, Daisuke Takahari¹, Keisho Chin¹, Hirokazu Shoji², Ken Kato², Naoki Ishizuka⁵, Narikazu Boku⁶, Kensei Yamaguchi¹, Eiji Shinozaki⁷

Affiliations

¹ Department of Gastroenterological Chemotherapy, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan.
² Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan.
³ Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
⁴ Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan.
⁵ Department of Clinical Trial Planning and Management, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan.
⁶ Department of Oncology and General Medicine, IMSUT Hospital, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
⁷ Department of Gastroenterological Chemotherapy, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan. Electronic address: eiji.shinozaki@jfcr.or.jp.

Abstract

Purpose: As circulating tumor DNA (ctDNA) measurement becomes more widespread, the "NeoRAS" phenomenon, where 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 ineffective epidermal growth factor receptor (EGFR) inhibitors may made effective. This study investigated its incidence and clinicopathological characteristics.

Patients and methods: In total, 107 mCRC patients (refractory or intolerant to previous chemotherapies) with tissue RAS MT were enrolled in four institutions from June 2021 to August 2022. The RAS status in ctDNA was assessed using OncoBEAM™ RAS CRC assay. Clinicopathologic features were compared between patients according to their RAS status in ctDNA, whether WT conversion was noted or not.

Results: The incidence rate of NeoRAS WT mCRC was 21.5% (23/107). According to tissue RAS mutation sites, NeoRAS WT frequency in patients with KRAS mutation in exon 2 was significantly lower than those in exon 3 and 4 or NRAS (18.2% [18/99] vs 62.5% [5/8], P = 0.011). Regarding clinical background, there were significant differences in NeoRAS WT frequency between male vs female patients (30.6% [19/62] vs 8.9% [4/45], P = 0.008), and absence vs presence of liver metastasis (38.6% [17/44] vs 9.5% [6/63], P < 0.001). Comparing the two groups divided by the median value, NeoRAS WT was associated with smaller tumor diameter (>60.9 mm vs ≤, 3.8% [2/53] vs 38.9% [21/54], P < 0.001), lower carcinoembryonic antigen level (>38.2 ng/ml vs ≤, 11.3% [6/53] vs 31.5% [17/54], P = 0.018), and lower carbohydrate antigen 19-9 level (>158.0 U/ml vs ≤, 9.4% [5/53] vs 33.3% [18/54], P = 0.004). In the logistic regression multivariate analysis, liver metastasis absence (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 conversion to NeoRAS WT in ctDNA.

Conclusions: Original RAS variants in tissue, tumor diameter, and liver metastasis are related to conversion to NeoRAS WT mCRC in ctDNA.

Keywords: Circulating tumor DNA (ctDNA); Liquid biopsy; Metastatic colorectal cancer; NeoRAS.