Influence of KRAS exon 2 mutation variants as well as NRAS- and BRAF-mutations on outcome of patients with metastatic colorectal cancer (mCRC) receiving combination chemotherapy with or without bevacizumab.

624 Background: A randomized phase II WJOG6510G study demonstrated non-inferiority of panitumumab (Pmab) plus irinotecan (IRI) to cetuximab (Cmab) plus IRI in terms of progression-free survival (PFS) in wild-type (WT) KRAS exon 2 metastatic colorectal cancer (mCRC). Here, we performed exploratory analyses of updated survival data using KRAS exon 2 and RAS/BRAF statuses. Methods: In this trial, patients with WT KRAS exon 2 mCRC who progressed after failure of fluoropyrimidine, IRI, and oxaliplatin were randomized to receive Pmab or Cmab in combination with IRI. An independent central laboratory performed RAS/BRAF testing using a PCR-reverse sequence specific oligonucleotide method which can detect 48 types of KRAS/NRAS and 34 types of BRAF mutations. Results: In the ITT population, patient characteristics included the following (Pmab/Cmab): number 61/59; male 69%/63%; median age 64 y/64 y; ECOG PS 0 62%/54%; left-sided primary tumor 85%/88%; multiple sites of metastases 51%/66%. At the time of updated analysis, 113 (94%) and 117 (98%) out of 120 patients had OS and PFS events, respectively. Median PFS was 5.42 months in the Pmab arm and 4.27 months in the Cmab arm (HR 0.674, unstratified log-rank p = 0.035). Median overall survival (OS) was 14.85 months in the Pmab arm and 11.53 months in the Cmab arm (HR 0.675, p = 0.037). In 83 patients, RAS/BRAF tests revealed 19 patients (23%) with RAS and 4 patients (5%) with BRAF mutations (two with V600E, two with non-V600E). Patients with RAS and BRAF mutations did not respond to the treatments. In the RAS WT population, a better PFS trend was observed for Pmab treatment (median 6.06 months vs. 5.26 months, HR 0.629, p = 0.08); however, OS was similar in both arms (median 14.85 months vs. 11.26 months, HR 0.818, p = 0.449). Conclusions: In this analysis, a modest survival benefit was found to be associated with Pmab plus IRI compared to Cmab plus IRI in WT KRAS exon2 mCRC, which warrants further evaluation in the WT RAS population. The number of analytic cases of RAS/BRAF status will be updated in the presentation. Clinical trial information: UMIN000006643.

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FOLFOX4 plus cetuximab administered weekly or every two weeks in first-line treatment of patients with KRAS and NRAS wild-type (wt) metastatic colorectal cancer (mCRC).

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.lba391 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. LBA391-LBA391 ◽

Cited By ~ 4

Author(s):

Thomas Brodowicz ◽

Damir Vrbanec ◽

Klaus Kaczirek ◽

Tudor-Eliade Ciuleanu ◽

Regina Knittelfelder ◽

...

Keyword(s):

Colorectal Cancer ◽

Monoclonal Antibody ◽

Metastatic Colorectal Cancer ◽

Objective Response ◽

Wild Type ◽

First Line ◽

Braf Mutations ◽

Exon 2 ◽

The Impact ◽

Kras Exon

LBA391^ Background: Efficacy and safety of first-line FOLFOX4 plus either cetuximab (weekly or every two weeks) have been reported to be similar in 152 patients with KRAS exon 2 wt mCRC within the randomized phase II CECOG/CORE2 study. Recent analyses have shown that also mutations in KRAS exons 3/4 and NRAS (exons 2, 3, and 4) are associated with an inferior PFS and OS with EGFR-targeted monoclonal antibody containing therapy. The impact of these additional mutations on the reported findings in the CECOG/CORE2 study were investigated. Methods: Tumor samples of 148 randomized KRAS exon 2 wild-type metastatic colorectal cancer patients were available for testing of additional mutations by conventional Sanger sequencing. Objective response rate (ORR), PFS and OS were compared in patients with KRAS (exons 2, 3, and 4) and NRAS (exons 2, 3, and 4) wild-type tumors [RAS wt] versus patients with mutations in KRAS (exons 3 and 4) or NRAS (exons 2, 3 and 4) [RAS mt]. Patients with BRAF mutations were excluded from this comparison. The Cochran-Mantel-Haenszel procedure was used to compare the ORR. Kaplan-Meier methods, log-rank test and Cox proportional hazard methods were used to analyze PFS and OS. Results: Of the 148 KRAS exon 2 wt patients 124 patients had RAS and BRAF wt tumors, 10 patients had RAS mutations only and 14 had only BRAF mutations. In the RAS wt and the RAS mt groups ORR was 61.3% (95% CI 52.1-69.9) and 40% (95%CI 12.2-73.8), (Odds ratio 0.43, p=0.1966). Median PFS was 9.7 months (95% CI 8.9-11.2) versus 7.2 months (95% CI 6.7-10.8) (hazard ratio HR=0.56, p=0.1135). Median OS was 28.5 months (95% CI 24.0-31.3) versus 16.3 months (95% CI 15.9-20.7), (HR=0.43, p=0.0199). The difference in OS remained statistically significant in the Cox model, if adjusted for significant confounding factors. ORR, PFS, and OS in BRAF mt and RAS mt patients were similar. Conclusions: RAS wt patients treated with cetuximab and FOLFOX4 experience a significant prolongation of OS as compared to RAS mt patients. This analysis supports the findings of other trials that RAS mutational analyses in metastatic CRC disease is recommended prior to initiation of an EGFR-targeted monoclonal antibody therapy. Clinical trial information: NCT00479752.

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KRAS and NRAS mutational gene profile of metastatic colorectal cancer patients in Jordan: Molecular spectrum, frequency and distribution pattern

10.21203/rs.2.11767/v1 ◽

2019 ◽

Author(s):

Muhammad Awidi ◽

Nidaa Ababneh ◽

Maha Shomaf ◽

Feras Al Fararjeh ◽

Laila Owaidi ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Distribution Pattern ◽

Cancer Patients ◽

Molecular Spectrum ◽

Kras Mutations ◽

Exon 2 ◽

Ras Mutations ◽

Colorectal Cancer Patients ◽

Kras Exon

Abstract Background A constitutively active RAS protein in the absence of stimulation of the epidermal growth factor receptor (EGFR) is the result of mutations in KRAS and NRAS genes. Mutations in the KRAS exon 2 and outside exon 2 have been found to predict the resistance to anti-EGFR monoclonal therapy. A substantial proportion of metastatic colorectal cancer cases (mCRC) exhibit RAS mutations outside KRAS exon 2, particularly in KRAS exon 3 and 4 and NRAS exons 2, 3. No data about RAS mutations outside KRAS exon 2 are available for Jordanian patients with mCRC. We aim to study the molecular spectrum, frequency, and distribution pattern of KRAS and NRAS mutations in Jordanian patients with mCRC. Methods A cohort of 190 Jordanian metastatic colorectal cancer patients were enrolled in the trial. We detected mutations in exon 2 of the KRAS and NRAS gene as well as mutations outside of exon 2 using the StripAssay technique. The KRAS StripAssay covered 29 mutations and 22 NRAS mutations. Results Mutations were observed in 92 (48.42%) cases, and KRAS exon 2 accounted for 76 cases (83.69%). KRAS G12D was the most common mutation, occurring in 18 cases, followed by KRAS G12A in 16 cases, and G12T in 13 cases. Mutations outside of KRAS exon 2 represented 16.3% of the mutated cases. Among those, 6 cases (6.48%) carried mutations in NRAS exon 2, 3 and 10 cases (10.87%) in KRAS exon 3 and 4. Conclusion The frequency of NRAS and KRAS mutations outside of exon 2 appears to be higher in Jordanian patients in comparison with patients from western countries. KRAS mutations outside of exon 2 should be tested routinely to identify patients who should not be treated with anti-EGFR antibodies.

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