Translational Oncology (Sep 2023)

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

Journal volume & issue
Vol. 35
p. 101718

Abstract

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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 60.9 mm vs ≤, 3.8% [2/53] vs 38.9% [21/54], P 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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