NeoRAS wild-type in metastatic colorectal cancer: Myth or truth?—Case series and review of the literature

Osumi, Hiroki; Vecchione, Loredana; Keilholz, Ulrich; Vollbrecht, Claudia; Alig, Annabel Helga Sophie; Einem, Jobst C. von; Stahler, Arndt; Kurreck, Annika; Kind, Andreas; Modest, Dominik Paul; Stintzing, Sebastian; Jelas, Ivan

doi:10.1016/j.ejca.2021.05.010

Cited by 23 publications

(21 citation statements)

References 60 publications

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“… 8 In contrast, in 19%-46% of patients with RAS -mutant mCRC, RAS mutations in the blood disappeared after chemotherapy. 9 , 10 , 11 In our study, RAS mutations disappeared in 62% of the patients who progressed to intensive first-line chemotherapy with FOLFOXIRI plus bevacizumab. There are several possible explanations for the disappearance of the RAS gene in the blood.…”

Section: Discussionsupporting

confidence: 54%

“…The concept of NeoRAS wild type has been recently discussed, which pertains to the observation of vanishing RAS -mutant alleles in the blood during standard-of-care chemotherapy for RAS -mutant mCRC. 10 Analysis of tumour-related genes, such as APC and TP53 , would allow us to assess the clearance of RAS -mutant clones more accurately. In our study, it was difficult to evaluate if RAS -mutant tumours changed to ‘NeoRAS wild type’ because we did not measure other gene alterations than RAS mutations.…”

Section: Discussionmentioning

confidence: 99%

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Dynamic changes in RAS gene status in circulating tumour DNA: a phase II trial of first-line FOLFOXIRI plus bevacizumab for RAS-mutant metastatic colorectal cancer (JACCRO CC-11)

Sunakawa¹,

Satake²,

Usher³

et al. 2022

ESMO Open

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Dynamic changes in RAS gene status in circulating tumour DNA: a phase II trial of first-line FOLFOXIRI plus bevacizumab for RAS-mutant metastatic colorectal cancer (JACCRO CC-11)

Sunakawa¹,

Satake²,

Usher³

et al. 2022

ESMO Open

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“…In fact, the absence of any clinically relevant mutation of RAS genes in blood has been recently used as a therapeutically exploitable window to change the clinically-based selection of patients to be treated with EGFR inhibitors ( 7 – 11 ). The rate of RAS mutation clearance in plasma is highly variable, ranging from 8% to 70% of cases according to studies ( 15 ). The inconsistency of results among studies might be attributed to a misinterpretation of the term “ RAS mutation clearance”.…”

Section: Discussionmentioning

confidence: 99%

Genomic landscape and survival analysis of ctDNA “neo-RAS wild-type” patients with originally RAS mutant metastatic colorectal cancer

et al. 2023

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BackgroundThe term “neo-RAS wild-type” refers to the switch to RAS wild-type disease in plasma circulating tumor DNA (ctDNA) from originally RAS mutant colorectal cancers. Consistently, the hypothesis to re-determine RAS mutational status in ctDNA at disease progression in RAS mutant mCRC opened to a new perspective for clinically-based selection of patients to be treated with EGFR inhibitors. Currently, the genomic landscape of “neo-RAS wild-type” is unknown. This is a prospective study aimed to investigate clinical and genomic features associated with RAS mutation clearance in a large cohort of RAS mutant mCRC patients who converted to RAS wild- type in liquid biopsy at failure of first-line treatments. Secondary aim was to investigate the long term prognostic significance of “true neo-RAS wild- type”.Patients and methods70 patients with stage IV RAS mutant colorectal cancer were prospectively enrolled. Plasma samples were collected at progression from first-line treatment. RAS/BRAF mutations in plasma were assessed by RT-PCR. In RAS/BRAF wild-type samples, ctDNA was used to generate libraries using a 17 genes panel whose alteration has clinical relevance. To investigate the prognostic significance of RAS mutation clearance, test curves for PFS and OS were represented by Kaplan-Meier estimator plot and Log-rank test.ResultsThe most commonly detected actionable mutations in “neo-RAS wild-type” were: PIK3CA (35.7%); RET (11.9%); IDH1 (9.5%); KIT (7%); EGFR (7%); MET (4.7%); ERBB2 (4.7%); FGFR3 (4.7%). Both OS and post-progression survival were longer in patients with “neo-RAS wild-type” compared to those who remained RAS mutant (p<0.001 for both).ConclusionsDe-novo-targetable mutations occured in a large percentage of “neo-RAS wild-type”, being PIK3CA the most commonly detected. RAS mutation clearance in ctDNA is associated with long- term improvement of overall survival.

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“…Several previous studies suggested the effectiveness of anti-EGFR antibodies in NeoRAS WT mCRC. 23,[30][31][32][33][34] However, all of these findings were obtained in combination with cytotoxic chemotherapy, and the extent to which anti-EGFR antibodies contributed to these findings is unclear. In Case 2, remarkable tumor shrinkage was observed following the initiation of cetuximab monotherapy.…”

Section: Discussionmentioning

confidence: 99%

Anti-epidermal growth factor receptor treatment for patients with NeoRAS wild-type metastatic colorectal cancer: a case report of two cases

Harada,

Yuki,

Kawamoto

et al. 2023

Ther Adv Med Oncol

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The Neo RAS phenomenon is defined as the conversion of tumor RAS status from mutant-type (MT) to wild-type (WT) after systemic chemotherapy in metastatic colorectal cancer (mCRC). Cetuximab, an anti-epidermal growth factor receptor (EGFR) antibody, is effective in patients with RAS WT mCRC but ineffective in those with RAS MT mCRC; however, its outcome in patients with Neo RAS WT mCRC is unclear. Herein, we report two cases of Neo RAS WT mCRC that responded clinically to anti-EGFR treatment. The first was a 40-year-old man with synchronous peritoneal metastatic rectosigmoid cancer. The first RAS testing on tumor tissue revealed a KRAS G12C mutation, which was converted to RAS WT after two lines of chemotherapy, as assessed by liquid biopsy. After initiating irinotecan plus cetuximab treatment, a computed tomography (CT) scan revealed that malignant ascites had resolved. The treatment was discontinued after 4 months because of disease progression. The second was a 68-year-old male patient with synchronous liver metastasis from sigmoid colon cancer. The KRAS G12D mutation, initially detected in tumor tissue, was not detected by liquid biopsy after six lines of chemotherapy. Cetuximab monotherapy was initiated, and the liver metastases shrank significantly. The patient continued cetuximab monotherapy for 8 months without disease progression. Our cases demonstrate the efficacy of anti-EGFR therapy for Neo RAS WT mCRC and highlight the importance of capturing the gene mutation profile throughout the clinical course for optimal treatment selection.

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NeoRAS wild-type in metastatic colorectal cancer: Myth or truth?—Case series and review of the literature

Cited by 23 publications

References 60 publications

Dynamic changes in RAS gene status in circulating tumour DNA: a phase II trial of first-line FOLFOXIRI plus bevacizumab for RAS-mutant metastatic colorectal cancer (JACCRO CC-11)

Dynamic changes in RAS gene status in circulating tumour DNA: a phase II trial of first-line FOLFOXIRI plus bevacizumab for RAS-mutant metastatic colorectal cancer (JACCRO CC-11)

Genomic landscape and survival analysis of ctDNA “neo-RAS wild-type” patients with originally RAS mutant metastatic colorectal cancer

Anti-epidermal growth factor receptor treatment for patients with NeoRAS wild-type metastatic colorectal cancer: a case report of two cases

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