KRAS Exon 4 Mutation | ScienceGate

3631 Background: PEAK estimated the tx effect of FOLFOX6 with pmab or bev in 1st-line WT KRAS mCRC. The PRIME study showed significantly improved progression free survival (PFS) and overall survival (OS) with pmab + FOLFOX vs FOLFOX in pts with WT RAS (KRAS/NRAS exons 2, 3, 4) mCRC in a prospective-retrospective analysis (unpublished data). Methods: This prospective-retrospective analysis of PEAK was designed to assess the effect of pmab + FOLFOX6 or bev + FOLFOX6 on PFS (primary endpoint) and OS in WT RAS (KRAS/NRAS exons 2, 3, 4) mCRC. Pts were required to have WT KRAS exon 2 tumors. Bidirectional Sanger sequencing and Transgenomic SURVEYOR/WAVE analysis were independently conducted to detect mutations in KRAS exon 3 (codons 59/61), exon 4 (codons 117/146); NRAS exon 2 (codons 12/13), exon 3 (codons 59/61), exon 4 (codons 117/146); BRAF exon 15 (codon 600) in banked specimens. Results: 285 WT KRAS (exon 2) mCRC patients (pts) were randomized, 278 received tx. The current RAS ascertainment rate is 75%. Tx HRs (pmab:bev) for pts with WT RAS were 0.63 (95% CI, 0.43-0.94; p = 0.02) for PFS and 0.55 (95% CI, 0.30-1.01; p = 0.06) for OS (Table). The incidence of worst grade 3-5 adverse events was consistent with the primary analysis. Updated OS and BRAF results will be presented. Conclusions: In this 1st-line estimation study in WT RAS mCRC, PFS and OS HR favored pmab + FOLFOX6 relative to bev + FOLFOX6, suggesting that activating RAS mutations appear to be predictive for pmab tx effect. The safety profile for both arms was consistent with previously reported studies. Clinical trial information: NCT00819780. [Table: see text]

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RAS mutations in EXPERT-C, a randomized phase II trial of neoadjuvant capecitabine and oxaliplatin (CAPOX) and chemoradiotherapy (CRT) with or without cetuximab (C) in MRI-defined, high-risk rectal cancer (RC).

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.489 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 489-489 ◽

Cited By ~ 1

Author(s):

Francesco Sclafani ◽

David Gonzalez ◽

David Cunningham ◽

Sanna Hullki Wilson ◽

Clare Peckitt ◽

...

Keyword(s):

High Risk ◽

Phase Ii ◽

Phase Ii Trial ◽

Locally Advanced ◽

Progression Free Survival ◽

Ras Mutations ◽

Randomized Phase Ii ◽

Exon 4 ◽

The Impact ◽

Kras Exon

489 Background: Studies indicate that RAS mutations beyond KRAS exons 2-3 may predict anti-EGFRs benefit. EXPERT-C was a randomized phase II trial of neoadjuvant CAPOX and CRT ± C in MRI-defined, high-risk RC. We have previously shown that adding C in KRAS (exons 2-3)/BRAF wild type (WT) patients did not improve complete response (CR) and was associated with a non-significant improvement in progression-free survival (PFS) (HR 0.62, p=0.23) and overall survival (OS) (HR 0.56, p=0.20). The aim of this study was to analyse the impact of RAS mutations on the outcome of C-treated patients in this trial. Methods: Between October 2005 and July 2008, 164 eligible patients were randomly assigned to 4 cycles of CAPOX followed by CRT, surgery, and 4 cycles of adjuvant CAPOX (n=81) or the same regimen plus C (CAPOX-C, n=83). KRAS (exons 2-3) and NRAS (exon 3) mutations were prospectively analysed. Of 90 KRAS/NRAS WT patients, 84 were retrospectively analysed for additional KRAS (exon 4) and NRAS (exons 2/4) mutations by using bi-directional Sanger sequencing. The effect of C on CR, PFS, and OS in patients with RAS WT tumors was analyzed. PFS and OS were estimated with the Kaplan-Meier method and treatment arms compared using a log-rank analysis. Results: Eleven (13%) of 84 patients initially classified as KRAS/NRAS WT were found to have tumours harbouring a mutation in KRAS exon 4 (11%) or NRAS exons 2/4 (2%). Overall, after this retrospective mutation analysis, 78/149 (52%) assessable patients were RAS WT (CAPOX, n=40; CAPOX-C, n=38). After a median follow-up of 63.8 months, in line with the initial analysis, the addition of C in the group of RAS WT patients, was associated with numerically higher, but not statistically significant, rates of CR (15.8% vs. 7.5%, p=0.31), 5-year PFS (78.4% vs. 67.5%, p=0.17) and 5-year OS (83.8% vs. 70%, p=0.20). Conclusions: Although the results of our analysis are potentially affected by the small numbers, in our locally advanced RC population the status of RAS did not appear to significantly improve the selection of patients who may benefit from the use of an anti-EGFR therapy.

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Comprehensive analysis of KRAS and NRAS mutations as predictive biomarkers for single agent panitumumab (pmab) response in a randomized, phase III metastatic colorectal cancer (mCRC) study (20020408).

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.3617 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 3617-3617 ◽

Cited By ~ 24

Author(s):

Scott D. Patterson ◽

Marc Peeters ◽

Salvatore Siena ◽

Eric Van Cutsem ◽

Yves Humblet ◽

...

Keyword(s):

Single Agent ◽

Objective Response ◽

Predictive Biomarkers ◽

Progression Free Survival ◽

Best Supportive Care ◽

Phase Iii ◽

Exon 2 ◽

Biomarker Analysis ◽

Exon 4 ◽

Kras Exon

3617 Background: An exploratory biomarker analysis of the randomized, phase 3 monotherapy 20020408 study of pmab vs best supportive care (BSC) demonstrated that mutations in KRAS exon 3 and NRAS exons 2 and 3 appeared to be predictive of pmab response (Peeters et al, 2013). We expanded these results to determine whether mutations in exon 4 of the KRAS and NRAS genes are predictive for pmab treatment and to determine the treatment effect in the overall wild-type (WT) KRAS and NRAS population. Methods: Using a combination of Next Generation Sequencing, Sanger Sequencing, and WAVE-based SURVEYOR Scan Kits from Transgenomic, archival patient tumors were examined for mutations in KRAS and NRAS exon 4. These data were combined with previously presented data from KRAS and NRAS exon 2 and 3 analyses for evaluation of the comprehensive WT KRAS and NRAS subgroup. Results: 9/243 (3.7%) and 2/243 (0.8%) patient tumors with WT KRAS exon 2 status harbored a mutation in KRAS or NRAS exon 4, respectively. One tumor had mutations in both KRAS and NRAS exon 4. In the pmab arm, patients with WT KRAS and WT NRAS tumor status had an objective response rate (ORR) of 15% (11/72) whereas patients with mutant (MT) KRAS or MT NRAS tumor status had an ORR of 1% (1/95; 1 patient with MT KRAS exon 4 had a partial response). There were no responses in the BSC arm regardless of the tumor status. In this analysis set, the treatment hazard ratio (HR; pmab:BSC) for progression-free survival (PFS) in the WT KRAS and WT NRAS subgroup was 0.38 (95% CI: 0.27 - 0.56), and in the MT KRAS or MT NRAS subgroup was 0.98 (95% CI: 0.73 - 1.31). The original WT KRAS exon 2 subgroup PFS HR was 0.45 (95% CI: 0.34 - 0.59) (Amado et al, 2007). Conclusions: This exploratory analysis suggests that mutations in KRAS and NRAS exon 4 occur in a small, but meaningful percentage of patients with mCRC. Extending previous findings from this study in patients with MT KRAS and/or MT NRAS exon 2 and/or 3 tumors, patients with MT KRAS and/or MT NRAS exon 4 tumors do not appear to benefit from pmab therapy. Clinical trial information: NCT00113763.

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Exploratory RAS analysis of the phase Ib/II 20060447 trial of rilotumumab (R) or ganitumab (G) plus panitumumab (pmab) versus pmab alone in patients (pts) with previously treated metastatic colorectal cancer (mCRC).

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.3_suppl.694 ◽

2015 ◽

Vol 33 (3_suppl) ◽

pp. 694-694

Author(s):

Cathy Eng ◽

Eric Van Cutsem ◽

Elzbieta Nowara ◽

Anna Swieboda-Sadlej ◽

Niall C. Tebbutt ◽

...

Keyword(s):

Objective Response ◽

Progression Free Survival ◽

Braf V600e ◽

Exon 2 ◽

Ras Mutations ◽

Secondary Endpoints ◽

Previously Treated ◽

Exon 4 ◽

Double Blinded ◽

Kras Exon

694 Background: Pmab, R, and G are fully human monoclonal antibodies that target EGFR, HGF, and IGF-1R, respectively. In part 2 of this 3-part study in previously treated pts with wild-type (WT) KRAS mCRC, pmab+R met the pre-specified criterion for improvement in objective response rate (ORR) whereas pmab+G did not. We report an exploratory analysis of the treatment effect of pmab, R, and G in pts with activating RAS mutations beyond KRAS exon 2. Methods: Part 2 was a phase II, randomized, double-blinded trial of pmab+R or pmab+G vs. pmab+placebo, administered Q2W until disease progression or intolerance. The primary endpoint was ORR. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. Mutations in KRAS exon 3 (codons 59/61) and exon 4 (codons 117/146); NRAS exon 2 (codons 12/13), exon 3 (codons 59/61), and exon 4 (codons 117/146); and BRAF exon 15 (codon 600) were detected by bidirectional Sanger sequencing. Results: Of 142 pts randomized, 92 (65%) were evaluable for RAS. Of 92 evaluable pts, 79 (86%) were WT RAS (WT in KRAS and NRAS exons 2, 3, and 4) and 13 (14%) had RAS mutations beyond KRAS exon 2 (mutant in any KRAS exon 3 or 4 or NRAS exon 2, 3, or 4). None of the pts with RAS mutations had an objective response (Table). Of 93 pts evaluable for BRAF, 7 (8%) had V600E mutations (all 7 were WT RAS). Two pts with BRAF V600E tumors had a partial response and were in the pmab+R arm (n=3). No new safety signals were identified. Conclusions: In this small, retrospective study, ORR, PFS and OS were similar between the arms of R or G plus pmab vs pmab alone in pts with WT RAS mCRC tumors. Our findings indicate that RAS mutations beyond KRAS exon 2 impact ORR, PFS, and OS. Clinical trial information: NCT00788957. [Table: see text]

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Concomitant Rare KRAS and BRAF Mutations in Lung Adenocarcinoma: A Case Report

Journal of Molecular Pathology ◽

10.3390/jmp1010006 ◽

2020 ◽

Vol 1 (1) ◽

pp. 36-42

Author(s):

Antonino Iaccarino ◽

Pasquale Pisapia ◽

Marco De Felice ◽

Francesco Pepe ◽

Gianluca Gragnano ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Ct Scanning ◽

Limited Data ◽

Braf Mutations ◽

Right Lobe ◽

Exon 4 ◽

Total Body ◽

Exon 11 ◽

Oncology Unit ◽

Kras Exon

In July 2020, an active smoker, 63-year old man was admitted to the oncology unit of A.O.R.N. Sant’Anna e San Sebastiano (Caserta, Italy). Chest radiology highlighted right pleural effusion. Total-body CT scanning revealed a solid lesion with lobulated contours in the apical segment of the upper right lobe. The patient’s oncologist requested a molecular assessment of EGFR, ALK, ROS1, BRAF, and KRAS, as well as an evaluation of PD-L1 expression level. To this end, we carried out NGS analysis, on DNA extracted from cytospins, by adopting a custom-designed NGS panel (SiRe®). Overall, no actionable mutations in the tested genes were identified. Conversely, concomitant BRAF exon 11 p.G469A and a KRAS exon 4 p.A146T mutations were detected. Owing to the limited data on the presence of KRAS exon 4 p.A146T point mutation in lung adenocarcinoma patients, a further molecular confirmatory analysis was carried out with a dedicated KRAS cartridge on a fully automated real time polymerase chain reaction. When DNA was extracted from the TTF-1 positive tumor cell slide, the same KRAS alteration was observed. Unfortunately, the patient died in August 2020 before having the chance to start any type of treatment.

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Analysis of KRAS/NRAS and BRAF mutations in the phase III PRIME study of panitumumab (pmab) plus FOLFOX versus FOLFOX as first-line treatment (tx) for metastatic colorectal cancer (mCRC).

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.3511 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 3511-3511 ◽

Cited By ~ 31

Author(s):

Kelly S. Oliner ◽

Jean-Yves Douillard ◽

Salvatore Siena ◽

Josep Tabernero ◽

Ronald L. Burkes ◽

...

Keyword(s):

Braf Mutation ◽

Predictive Biomarker ◽

Primary Objective ◽

Phase Iii ◽

Braf Mutations ◽

Exon 2 ◽

Mutation Status ◽

Exon 4 ◽

Kras Exon ◽

Clinical Trial Information

3511 Background: Analysis of a phase III pmab monotherapy study indicated that KRAS and NRAS mutations beyond KRAS exon 2 may be predictive of pmab efficacy (Peeters et al, 2013). Methods: The primary objective of this prospectively defined retrospective analysis of PRIME was to assess the effect of pmab + FOLFOX vs FOLFOX on overall survival (OS) in pts with mCRC based on RAS (KRAS or NRAS) or BRAF mutation status. "Gold standard" bidirectional Sanger sequencing and WAVE-based SURVEYOR Scan Kits from Transgenomic (conducted independently) were used to detect mutations in KRAS exon 3, exon 4; NRAS exon 2, exon 3, exon 4; and BRAF exon 15. Results: RAS ascertainment rate was 90%. Tx HRs for pts with WT RAS were 0.78 (95% CI, 0.62 - 0.99; p = 0.04) for OS (median gain of 5.8 months in the pmab arm) and 0.72 (95% CI, 0.58 - 0.90; p = < 0.01) for PFS. Tx HRs for WT KRAS exon 2/mutant (MT) other RAS were 1.29 (95% CI, 0.79 - 2.10; p = 0.31) for OS and 1.28 (95% CI, 0.79 - 2.07; p = 0.32) for PFS. Tx HRs for pts with WT or MT BRAF were inconsistent with a predictive biomarker (Table). Prognostic effects of the tested biomarkers will be presented. Conclusions: A statistically significant OS benefit was observed in pts with WT RAS mCRC treated with pmab + FOLFOX vs FOLFOX. Pmab is unlikely to benefit pts with any RAS mutations. In this analysis, BRAF mutation had no predictive value. Clinical trial information: NCT00364013. [Table: see text]

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Relationship of RAS and TP53 predictive value for cetuximab (C) benefit: Results of the EXPERT-C trial.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.447 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 447-447

Author(s):

Francesco Sclafani ◽

David Gonzalez ◽

David Cunningham ◽

Sanna Hullki Wilson ◽

Clare Peckitt ◽

...

Keyword(s):

Predictive Value ◽

Locally Advanced ◽

Progression Free Survival ◽

Predictive Biomarker ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Kras Mutations ◽

Exon 4 ◽

Tp53 Status ◽

Kras Exon

447 Background: We previously reported that TP53 status may predict C benefit in patients with locally advanced rectal cancer treated with neoadjuvant chemotherapy and chemoradiotherapy (CRT) and this effect appeared to be independent of KRAS. Recent studies indicate that NRAS mutations and KRAS mutations beyond exons 2-3 may also preclude benefit from anti-EGFRs. We analyzed whether the predictive value of TP53 in EXPERT-C was independent of RAS. Methods: 164 patients received 4 cycles of CAPOX followed by CRT, surgery, and 4 cycles of adjuvant CAPOX (n=81) or the same regimen plus C (CAPOX-C, n=83) and were analyzed for KRAS (exons 2-3) and NRAS (exon 3). TP53 mutations (exons 4-9) were screened for by CE-SSCA. KRAS (exon 4) and NRAS (exons 2 and 4) mutations were screened for by bi-directional Sanger sequencing. Progression-free survival (PFS) and overall survival (OS) were estimated with Kaplan-Meier methods and log-rank analysis was used to compare the treatment arms. The interaction between treatment and TP53 was adjusted for prognostic variables and RAS in a multivariate model. Results: 75/144 (52%) eligible patients had a TP53 mutation. 81/86 patients with known KRAS (exons 2-3) and NRAS (exon 3) wild-type (WT) status were analyzed for the remaining RAS mutations. Of these, 11 (13%) had tumours with mutation in KRAS exon 4 (11%) or NRAS exons 2/4 (2%). Overall, 75/144 (52%) patients were RAS WT (CAPOX, n=39; CAPOX-C, n=36). After a median follow-up of 65 months, no difference in PFS (HR 1.21, p=0.59) and OS (HR 0.97, p=0.94) was observed between TP53 mutant patients treated with CAPOX or CAPOX-C. In TP53 WT patients, the addition of C was associated with a statistically significant improvement in PFS (HR 0.23, p=0.02) and OS (HR 0.16, p=0.02). A significant interaction between TP53 status and C effect was found (PFS, p=0.029; OS, p=0.036). In multivariate analyses, this interaction remained significant even after adjusting for RAS status (PFS, p=0.026; OS, p=0.033). Conclusions: In EXPERT-C, the value of TP53 as predictive biomarker for C benefit was independent of RAS. The value of monoallelic vs. biallelic TP53 inactivation will be presented at the meeting.

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The prevalence RAS and BRAF mutations among patients in the Middle East and Northern Africa with metastatic colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.4_suppl.598 ◽

2016 ◽

Vol 34 (4_suppl) ◽

pp. 598-598

Author(s):

Tamer Garawin ◽

Kimberly Lowe ◽

George Kafatos ◽

Samuel Murray

Keyword(s):

Colorectal Cancer ◽

Saudi Arabia ◽

Middle East ◽

Wild Type ◽

Braf Mutations ◽

Real World Data ◽

Exon 2 ◽

Ras Mutation ◽

Exon 4 ◽

Kras Exon

598 Background: Anti-EGFR therapies are recommended for metastatic colorectal cancer (mCRC) patients with confirmed wild-type RAS (exons 2, 3, 4 of KRAS and NRAS) status. There is limited published information on the prevalence of RAS mutations using real world data. The objective of this study was estimate the prevalence of RAS and BRAF mutations among patients with mCRC in the Middle East and Northern Africa (MENA) in an effort to inform the rationale for biomarker testing and treatment choice. Methods: The study included 1,669 patients from August 2013 to July 2015 with mCRC from Algeria, Bahrain, Egypt, Jordan, Kuwait, Lebanon, Libya, Morocco, Oman, Qatar, Saudi Arabia, and the United Arab Emeritus. Information on RAS mutation status was obtained from one pathology lab using High Resolution Melting Analysis. Extended RAS analysis was conducted in a subset of patients, including: overall RAS (exon 2, 3, 4 of KRAS and NRAS; n = 750), KRAS exon 2 (n = 750), KRAS exon 3 and 4 (n = 507), NRAS exon 2, 3, and 4 (n = 507), and BRAF exon 15 (n = 78). The proportion of patients with each mutation was summarized. Results: The overall RAS mutation in the full sample was 35.3% (n = 589/1669). The observed mutation for KRAS exon 2 in a subset of patients with extended RAS analysis (n = 750) was 32.4% (243/750). Out of the subjects with wild-type exon 2 (n = 507), the observed mutations rates were as follows: KRAS exon 4 (20/507 = 3.9%), KRAS exon 3 (13/507 = 2.6%), NRAS exon 2 (7/507 = 1.4%), NRAS exon 3 (6/507 = 1.2%), and NRAS exon 4 (0%). The prevalence of BRAF exon 15 was 3.8% (3/78). The most robust data on specific RAS mutations was obtained from Algeria, Egypt, and Saudi Arabia. The prevalence of KRAS exon 2 mutations in these countries was as follows: Algeria (n = 33/86 = 38.4%), Egypt (n = 83/303 = 27.4%), Saudi Arabia (n = 85/245 = 34.7%). Conclusions: To our knowledge, this is the first study to evaluate the prevalence of RAS and BRAF mutations in the Middle East using real world data. The results of this descriptive study illustrate that there is variation in the prevalence of RAS and BRAF mutations in MENA.

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A Novel Missense Mutation in the Endoglin Gene in Hereditary Hemorrhagic Telangiectasia

Thrombosis and Haemostasis ◽

10.1055/s-0038-1655946 ◽

1997 ◽

Vol 77 (02) ◽

pp. 243-247 ◽

Cited By ~ 15

Author(s):

Hiroshi Yamaguchi ◽

Hiroyuki Azuma ◽

Toshio Shigekiyo ◽

Hideo Inoue ◽

Shiro Saito

Keyword(s):

Missense Mutation ◽

Hereditary Hemorrhagic Telangiectasia ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Autosomal Dominant Disorder ◽

Her Family ◽

Normal Individuals ◽

Oligonucleotide Hybridization ◽

Vascular Dysplasia ◽

Exon 4

SummaryHereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by multisystem vascular dysplasia and recurrent hemorrhage. Recent investigation has mapped one of the responsible genes for HHT to chromosome 9q33-q34; subsequently, nine different mutations have been identified in the endoglin gene, which encodes a transforming growth factor β(TGF-β) binding protein, in nine unrelated families with HHT. We examined the endoglin gene in a Japanese patient with HHT and her family members. Using PCR-SSCP. analysis followed by sequencing, we identified a C to A missense mutation in exon 4 which changed an Ala160 codon(GCT) to an Asp160 codon (GAT). Since this mutation destroys one of three Fnu4H I sites in exon 4, the Fnu4H I digestion patterns of the PCR-amplified exon 4 fragments from each family member were analyzed. In affected members, the restriction patterns were all consistent with a phenotype of HHT. PCR-amplified exon 4 fragments from 150 normal individuals were also analyzed by allele-specific oligonucleotide hybridization analysis. As a result, the mutation was not found in any of them. We conclude that the C to A mutation in exon 4 of the endoglin gene in this proband is responsible for the occurrence of HHT in this family.

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