A multi-institutional observational study evaluating the incidence and the clinicopathological characteristics of NeoRAS wild-type metastatic colorectal cancer
Open accessAbstract
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.
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NeoRAS WT occurred in 21.5% of 107 patients in a multi-institutional study, particularly among those with non-KRAS exon 2 mutations.
“A multi-institutional study highlighted the occurrence of NeoRAS WT in 21.5% of 107 patients, particularly among those with non-KRAS exon 2 mutations.”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [52]
The NeoRAS phenomenon is a shift from RAS-mutant to wild-type status in metastatic colorectal cancer following treatment.
“The NeoRAS phenomenon, a notable shift from RAS-mutant to wild-type (WT) status in mCRC following treatment, introduces an intriguing therapeutic avenue.”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [52]
Smaller tumor burden and absence of liver metastases were significantly linked to NeoRAS WT shift.
“Clinical factors such as a smaller tumor burden and the absence of liver metastases were significantly linked to this shift, suggesting specific patient profiles may predispose individuals to NeoRAS WT emergence [52].”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [52]
Direct inhibition of SOS1 effectively inhibits guanine exchange factor (GEF) activity.
“The direct inhibition of SOS1 effectively inhibits guanine exchange factor (GEF) activity [52].”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [52]
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- Authors
- Osumi, H., Takashima, A., Ooki, A., Yoshinari, Y., Wakatsuki, T., Hirano, H., Nakayama, I., Okita, N., Sawada, R., Ouchi, K., Fukuda, K., Fukuoka, S., Ogura, M., Takahari, D., Chin, K., Shoji, H., Kato, K., Ishizuka, N., Boku, N., Yamaguchi, K., & Shinozaki, E.
- Affiliations
- The Cancer Institute Hospital (JP)
- National Cancer Center Hospital (JP)
- Jikei University School of Medicine (JP)
- Tohoku University Hospital (JP)
- IMSUT Hospital (JP)
- Corresponding author
- Shinozaki, Eiji
- ORCID
- Venue
- Translational Oncology
- Publisher
- Elsevier BV
- Published
- 2023-09
- Volume
- 35
- Pages
- 101718
- ISSN
- 1936-5233 (ISSN-L)
- PMC
- PMC10319337
- OpenAlex
- W4381848366
- Cited by
- 16
- References
- 38
- Citations by year
- 2026: 7 · 2025: 3 · 2024: 6
- FWCI
- 1.95
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Translational Oncology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- metastatic colorectal cancer, circulating tumor DNA, KRAS mutation, NRAS mutation, EGFR inhibitors, treatment response, liver metastasis, carcinoembryonic antigen, carbohydrate antigen 19-9, tumor size, sex differences, clinicopathological features, incidence, liquid biopsy
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