Perspectives in the Treatment of RAS or BRAF Mutated Metastatic Colorectal Cancer Patients

Rosati, Gerardo; Aprile, Giuseppe; Basile, Debora; Avallone, Antonio

doi:10.3389/fonc.2021.602596

Cited by 6 publications

(5 citation statements)

References 36 publications

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“…BRAF mutation is reported in approximately 5–10% of CRCs 23 . Patients with BRAF mutated CRC tend to respond poorly to chemotherapy and progress rapidly with a poorer prognosis compared to those with BRAF wild-type CRC 6 , 24 . Additionally, these patients develop resistance to anti-EGFR inhibitors due to activation of the MAPK pathway downstream of EGFR 25 .…”

Section: Discussionmentioning

confidence: 99%

RAS/RAF mutations and microsatellite instability status in primary colorectal cancers according to HER2 amplification

Lee,

2024

Sci Rep

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HER2 amplification-associated molecular alterations and clinicopathologic features in colorectal cancers (CRCs) have not been well established. In this study, we assessed the prevalence of HER2 amplification and microsatellite instability (MSI) status of 992 patients with primary CRC. In addition, molecular alterations of HER2 amplified and unamplified CRCs were examined and compared by next-generation sequencing. HER2 amplifications were found in 41 (4.1%) of 992 primary CRCs. HER2 amplification was identified in 1.0% of the right colonic tumors, 5.1% of the left colonic tumors, and 4.8% of the rectal tumors. Approximately 95% of HER2 amplification was observed in the left colon and rectum. Seven (87.5%) of eight metastatic tumors showed HER2 amplification. Most clinicopathologic features were unrelated to HER2 amplification except tumor size and MSI status. All 41 HER2 amplified CRCs were microsatellite stable. In a molecular analysis of frequently identified somatic mutations in CRCs, HER2 amplified CRCs showed a lower rate of KRAS mutations (24.4%) but a higher rate of TP53 mutations (83%) than unamplified CRCs. No BRAF and NRAS mutations were identified in HER2 amplified CRCs. Our study suggests that HER2 amplified CRCs are mutually exclusive of MSI and harbor less frequent KRAS/NRAS/BRAF mutations but frequent T53 mutations.

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Section: Discussionmentioning

confidence: 99%

RAS/RAF mutations and microsatellite instability status in primary colorectal cancers according to HER2 amplification

Lee,

2024

Sci Rep

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“… 10 It is known that mutations in the downstream KRAS , NRAS and BRAF part of the epidermal growth factor receptor (EGFR) of the RAS / RAF / MAPK pathway are important in the process of carcinogenesis. 11 However, these mutations are associated with anti-EGFR monoclonal antibodies therapy resistance in patients with CRC; 10 which, by binding to the extracellular domain of EGFR, inhibits and nullifies cell proliferation. 11 Recently, the National Comprehensive Cancer Network and the American Society for Clinical Oncology have posted guidance recommending testing of exon 2 (codons 12 and 13), 3 exon (codon 59 and 61) and 4 exon (codon 117 and 146) in both genes of KRAS and NRAS, and in BRAF gene of exon 15 (codon 600) prior to anti-EGFR therapy.…”

Section: Introductionmentioning

confidence: 99%

“… 11 However, these mutations are associated with anti-EGFR monoclonal antibodies therapy resistance in patients with CRC; 10 which, by binding to the extracellular domain of EGFR, inhibits and nullifies cell proliferation. 11 Recently, the National Comprehensive Cancer Network and the American Society for Clinical Oncology have posted guidance recommending testing of exon 2 (codons 12 and 13), 3 exon (codon 59 and 61) and 4 exon (codon 117 and 146) in both genes of KRAS and NRAS, and in BRAF gene of exon 15 (codon 600) prior to anti-EGFR therapy. 11 , 12 These alterations can behave as prognostic-predictive and driver mutations, which makes them a notable therapeutic target.…”

Section: Introductionmentioning

confidence: 99%

“… 11 Recently, the National Comprehensive Cancer Network and the American Society for Clinical Oncology have posted guidance recommending testing of exon 2 (codons 12 and 13), 3 exon (codon 59 and 61) and 4 exon (codon 117 and 146) in both genes of KRAS and NRAS, and in BRAF gene of exon 15 (codon 600) prior to anti-EGFR therapy. 11 , 12 These alterations can behave as prognostic-predictive and driver mutations, which makes them a notable therapeutic target. In particular, the KRAS and BRAF V600 E mutations appear to be the lack of benefit of anti-EGFR mAbs, and they are biomarkers of poor prognosis and resistance to standard therapies.…”

Section: Introductionmentioning

confidence: 99%

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KRAS, NRAS and BRAF Mutational Profile of Colorectal Cancer in a Series of Moroccan Patients

El Zaitouni,

Laraqui,

Ghaouti

et al. 2024

Cancer Control

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Objectives The present study aimed to evaluate the frequencies of KRAS, NRAS, and BRAF mutations and their possible associations with clinicopathological features in 249 Moroccan patients with colorectal cancer (CRC). Methods A retrospective investigation of a cohort of formalin-fixed paraffin-embedded tissues of 249 patients with CRC was screened for KRAS/ NRAS/ BRAF mutations using Idylla™ technology and pyrosequencing. Results KRAS, NRAS, and BRAF mutations were revealed in 46.6% (116/249), 5.6% (14/249), and 2.4% (6/249) of patients. KRAS exon 2 mutations were identified in 87.9% of patients (102/116). KRAS G12D and G12 C were the most frequent, at 32.8% and 12.93%, respectively. Among the patients with KRAS exon 2 wild-type (wt), 27.6% (32/116) harbored additional KRAS mutations. Concurrent KRAS mutations were identified in 9.5% (11/116); including six in codon 146 (A146P/T/V), three in codon 61 (Q61H/L/R), one in codon 12 (G12 A and Q61H), and one in codon 13 (G13D and Q61 L). Among the NRAS exon 2 wt patients, 64.3% (9/14) harbored additional NRAS mutations. Concurrent NRAS mutations were identified in 28.6% (4/14) of NRAS-mutant patients. Since 3.2% wt KRAS were identified with NRAS mutations, concomitant KRAS and NRAS mutations were identified in 2.4% (6/249) of patients. KRAS mutations were higher in the >50-year-old age-group ( P = .031), and the tumor location was revealed to be significantly associated with KRAS mutations ( P = .028) predominantly in left colon (27.5%) and colon (42.2%) locations. NRAS mutations were most prevalent in the left colon (42.8%) and in well-differentiated tumors (64.2%). Conclusion Detection of KRAS mutations, particularly the G12 C subtype, may be significant for patients with CRC and has possible therapeutic implications. However, rare KRAS concomitant mutations in CRC patients suggest that each individual may present distinct therapeutic responses. KRAS testing alongside the identification of other affected genes in the same patient will make the treatments even more personalized by contributing more accurately to the clinical decision process. Overall, early diagnosis using novel molecular techniques may improve the management of CRC by providing the most efficient therapies for Moroccan patients.

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“…These mutations cause resistance to EGFR therapeutic antibodies and RAS and BRAF testing is now recommended for all patients with mCRC [2,[5][6][7]. BRAF-V600E is the dominant BRAF mutation in CRC, found in more than 90% of patients with a BRAF mutated type (BRAFmt) gene [8]. BRAFmt is associated with higher tumour grade, right-sided primary tumours, female gender, older age, deficient mismatch repair (dMMR) status and higher prevalence of peritoneal and lymph node metastases [4].…”

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confidence: 99%

Resectability, conversion, metastasectomy and outcome according to RAS and BRAF status for metastatic colorectal cancer in the prospective RAXO study

et al. 2022

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Background Outcomes after metastasectomy for metastatic colorectal cancer (mCRC) vary with RAS and BRAF mutational status, but their effects on resectability and conversion rates have not been extensively studied. Methods This substudy of the prospective RAXO trial included 906 patients recruited between 2011 and 2018. We evaluated repeated centralised resectability assessment, conversion/resection rates and overall survival (OS), according to RAS and BRAF status. Results Patients included 289 with RAS and BRAF wild-type (RAS and BRAFwt), 529 with RAS mutated (RASmt) and 88 with BRAF mutated (BRAFmt) mCRC. Metastatic prevalence varied between the RAS and BRAFwt/RASmt/BRAFmt groups, for liver (78%/74%/61%), lung (24%/35%/28%) and peritoneal (15%/15%/32%) metastases, respectively. Upfront resectability (32%/29%/15%), conversion (16%/13%/7%) and resection/local ablative therapy (LAT) rates (45%/37%/17%) varied for RASa and BRAFwt/RASmt/BRAFmt, respectively. Median OS for patients treated with resection/LAT (n = 342) was 83/69/30 months, with 5-year OS-rates of 67%/60%/24%, while systemic therapy-only patients (n = 564) had OS of 29/21/15 months with 5-year OS-rates of 11%/6%/2% in RAS and BRAFwt/RASmt/BRAFmt, respectively. Resection/LAT was associated with improved OS in all subgroups. Conclusions There were significant differences in resectability, conversion and resection/LAT rates according to RAS and BRAF status. OS was also significantly longer for RAS and BRAFwt versus either mutant. Patients only receiving systemic therapy had poorer long-term survival, with variation according to molecular status. Clinical trial registration NCT01531621/EudraCT2011-003158-24

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Perspectives in the Treatment of RAS or BRAF Mutated Metastatic Colorectal Cancer Patients

Cited by 6 publications

References 36 publications

RAS/RAF mutations and microsatellite instability status in primary colorectal cancers according to HER2 amplification

RAS/RAF mutations and microsatellite instability status in primary colorectal cancers according to HER2 amplification

KRAS, NRAS and BRAF Mutational Profile of Colorectal Cancer in a Series of Moroccan Patients

Resectability, conversion, metastasectomy and outcome according to RAS and BRAF status for metastatic colorectal cancer in the prospective RAXO study

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