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

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

doi:10.1016/j.tranon.2023.101718

Cited by 6 publications

(6 citation statements)

References 39 publications

(59 reference statements)

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“…In this study, the frequency of ctDNA RAS MT was 40.5% which was associated with high tumor burden, such as liver metastasis and high tumor marker levels. On the contrary, neoRAS, which is de ned as conversion from initially diagnosed RAS MT to WT following treatment, was reportedly associated with the absence of liver metastasis, small tumor diameter, and low tumor markers (Osumi et al 2023). ctDNA RAS MT detectability may depend on tumor volumes, although the reason for association of primary tumor resection with ctDNA RAS MT is not clear.…”

Section: Discussionmentioning

confidence: 99%

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Multi-institutional observational study evaluating the efficacy of anti-epidermal growth factor antibody re- challenge in RAS/BRAF wild-type metastatic colorectal cancer

Fukuda,

Osumi,

Yoshinami

et al. 2024

Preprint

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Purpose: We aimed to investigate the incidence of circulating tumor DNA (ctDNA) RAS mutant (MT) before salvage-line treatment and explore the clinicopathological features and molecular biological factors associated with the efficacy of anti-epithelial growth factor receptor (EGFR) monoclonal antibody (mAb) re-challenge for tissue RAS/BRAF wild type (WT) metastatic colorectal cancer (mCRC). Methods: This multi-institutional retrospective observational study included 74 mCRC patients with tissue RAS/BRAF WT refractory to first-line chemotherapy containing anti-EGFR mAb, whose RAS status in ctDNA was assessed using the OncoBEAMTM RAS CRC Kit. We explored the clinicopathological features associated with RAS status in ctDNA and the factors related to the efficacy of re-challenge of anti-EGFR mAb in multivariate Cox proportional hazard regression. Results: The incidence of RAS MT in ctDNA was 40.5% (30/74), which was associated with primary tumor resection (P=0.016), liver metastasis (P<0.001), and high tumor marker levels (P<0.001). Among the 39 patients treated with anti-EGFR mAb re-challenge, those with ctDNA RAS WT showed significantly longer progression-free survival (PFS) than those with ctDNA RAS MT (median 4.1 vs. 2.7 months, hazard ratio [HR]=0.39, P=0.045). Similarly, patients who responded to first-line anti-EGFR mAb showed significantly longer PFS than those with stable disease. In multivariate analysis, response to first-line anti-EGFR mAb was significantly associated with longer PFS (HR=0.21, P=0.0026) and overall survival (HR=0.23, P=0.026). Conclusions: The incidence of ctDNA RAS MT mCRC was 40.5%, which was associated with liver metastases and high tumor volumes. Anti-EGFR mAb re-challenge may be effective for mCRC patients who responded to first-line chemotherapy containing anti-EGFR mAb. No patients with RAS MT in ctDNA responded to Anti-EGFR mAb re-challenge.

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Section: Discussionmentioning

confidence: 99%

“…15.6%, compared to 0% in those with ctDNA RAS MT, and patients with ctDNA RAS WT had a signi cantly better prognosis than those with ctDNA RAS MT. According to the results of the CRICKET trial, patients with ctDNA RAS WT had ctDNA prior to anti-EGFR mAb as these gene alterations may be associated with acquired resistance to anti-EGFR mAb.…”

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confidence: 87%

Multi-institutional observational study evaluating the efficacy of anti-epidermal growth factor antibody re- challenge in RAS/BRAF wild-type metastatic colorectal cancer

Fukuda,

Osumi,

Yoshinami

et al. 2024

Preprint

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“…Thus, although some studies have reported EGFR antibody rechallenge using ctDNA assays in recent years, the clinical significance of a RAS -ML in mCRC is not well established. Mutation loss after induction chemotherapy in patients with RAS -MT was between 21.5 and 90% (Klein-Scory et al 2020 ; Sunakawa et al 2022 ; Wang et al 2022 ; Osumi et al 2023 ).…”

Section: Discussionmentioning

confidence: 99%

“…As a result, ascertaining whether ctDNA could not be detected owing to a diminutive tumor volume and inability to determine metastatic involvement in specific organs remains a significant hurdle. Osumi et al pointed out that conversion to Neo RAS -WT may be more common in patients without liver metastases (Osumi et al 2023 ). Neo RAS -WT is defined as the absence of RAS mutation coupled with trunk mutations of genes such as TP53, APC, or methylated genes (Moati et al 2020 ; Nicolazzo et al 2020 , 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Temporal dynamics of RAS mutations in circulating tumor DNA in metastatic colorectal cancer: clinical significance of mutation loss during treatment

Iguchi,

Shiozawa,

Uchiyama

et al. 2024

J Cancer Res Clin Oncol

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Purpose In metastatic colorectal cancer (mCRC), RAS mutation loss may occur during the standard-of-care regimen. In this study, we aimed to investigate the temporal dynamics of the RAS gene and its clinical significance. Methods This was a retrospective, single-center study that included 82 patients with tissue RAS-mutant (RAS-MT) mCRC who underwent circulating tumor DNA (ctDNA) RAS monitoring between January, 2013–April, 2023. Patients were analyzed for the rate of change over time to acquired RAS mutation loss (aRAS-ML) and clinicopathological factors. The prognostic relevance of mutation loss was assessed. Results aRAS-ML was detected in 33 (40.2%) patients, 32 of whom had a mutation loss in the first ctDNA RAS assay. Patients with a RAS mutation detected in the first assay had a median time of 8 months until the second ctDNA RAS assay, with 4.5% cases newly converted to aRAS-ML; no new conversions were detected at the third assay. The aRAS-ML group exhibited more single-organ metastases in the target organ during ctDNA measurement (aRAS-ML: 84.8% vs. RAS-MT: 59.2%, p = 0.02). Of the 33 patients with aRAS-ML, seven (21.2%) received anti-epidermal growth factor receptor (EGFR) therapy, with a median progression-free survival of 8 months. Multivariate analysis revealed that persistent ctDNA RAS mutation was an independent prognostic factor for overall survival (hazard ratio: 2.7, 95% confidence interval: 1.1–6.3, p = 0.02). Conclusion The rate of ctDNA mutation loss in patients with RAS-MT mCRC decreases over time. Therefore, using a ctDNA RAS assay early in treatment will assist in challenging the use of EGFR regimens.

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“…Osumi et al [ 39 ] reported a multi-institutional observational study assessing the clinicopathologic features and incidence of NeoRAS WT mCRC. A total of 107 patients with tissue RAS mutation (refractory or intolerant to prior chemotherapy) were enrolled at four institutions.…”

Section: Treatments Targeting Ras Statusmentioning

confidence: 99%

Therapeutic strategies targeting the epidermal growth factor receptor signaling pathway in metastatic colorectal cancer

Zhou,

Wu,

2024

World J Gastrointest Oncol

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More than 1.9 million new colorectal cancer (CRC) cases and 935000 deaths were estimated to occur worldwide in 2020, representing about one in ten cancer cases and deaths. Overall, colorectal ranks third in incidence, but second in mortality. More than half of the patients are in advanced stages at diagnosis. Treatment options are complex because of the heterogeneity of the patient population, including different molecular subtypes. Treatments have included conventional fluorouracil-based chemotherapy, targeted therapy, immunotherapy, etc. In recent years, with the development of genetic testing technology, more and more targeted drugs have been applied to the treatment of CRC, which has further prolonged the survival of metastatic CRC patients.

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

Cited by 6 publications

References 39 publications

Multi-institutional observational study evaluating the efficacy of anti-epidermal growth factor antibody re- challenge in RAS/BRAF wild-type metastatic colorectal cancer

Multi-institutional observational study evaluating the efficacy of anti-epidermal growth factor antibody re- challenge in RAS/BRAF wild-type metastatic colorectal cancer

Temporal dynamics of RAS mutations in circulating tumor DNA in metastatic colorectal cancer: clinical significance of mutation loss during treatment

Therapeutic strategies targeting the epidermal growth factor receptor signaling pathway in metastatic colorectal cancer

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