Prognostic value of BRAF V600E and KRAS exon 2 mutations in microsatellite stable (MSS), stage III colon cancers (CC) from patients (pts) treated with adjuvant FOLFOX+/- cetuximab: A pooled analysis of 3934 pts from the PETACC8 and N0147 trials.

318 Background: We have previously reported a rate of 23% RAS/RAF mutations in plasma from patients with KRAS exon 2 and 3 wild-type, non-resectable biliary tract tumors. We wanted to explore the changes in circulating tumor specific DNA (ctDNA) during systemic chemotherapy in these patients. Methods: Patients with non-resectable biliary tract cancer treated within a phase II trial were included if they had KRAS exon 2 and 3 wild-type tumor tissue, had quantifiable levels of tumor specific DNA in plasma and progressive disease on imaging. They received gemcitabine, oxaliplatin and capecitabine with either bevacizumab or panitumumab. Treatment continued for up to six months until progression. Blood sampling and evaluation according to RECIST 1.1 were done every 12 weeks. Droplet Digital PCR was performed on DNA isolated from 4 ml plasma. A pre-amplification step was done and adequate positive and negative controls were included. The extended RAS and BRAF mutation analysis covered 20 mutations in KRAS exons 3/4, NRAS exon 2/3, PIK3CA and BRAF V600E. The percentage of tumor specific DNA relative to total DNA was reported. Results: The inclusion criteria were met by 13 patients, 10 women and three men. The typical pattern was seen in eight cases, where the percentage of tumor specific DNA dropped at least half during therapy and rose at least two-fold at progression. In three patients, a baseline sample was not available or there was not an initial drop, but the ctDNA rose at progression. One patient had an initial drop, but not a rise a progression based on imaging. The last patient progressed rapidly. Conclusions: This exploratory analysis pointed toward changes in percentage of tumor specific mutations in plasma as a marker of effect and progression. Dynamics of liquid biopsies is a promising tool in monitoring biliary tract cancer patients during systemic therapy. Clinical trial information: NCT01206049.

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Mutations within the EGFR signaling pathway: Influence on efficacy in FIRE-3—A randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.445 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 445-445 ◽

Cited By ~ 43

Author(s):

Sebastian Stintzing ◽

Andreas Jung ◽

Lisa Rossius ◽

Dominik Paul Modest ◽

Ludwig Fischer von Weikersthal ◽

...

Keyword(s):

Pik3ca Mutation ◽

Braf V600e ◽

Phase Iii ◽

Line Treatment ◽

First Line ◽

Exon 2 ◽

Ras Mutations ◽

Egfr Signaling Pathway ◽

Kras Exon ◽

First Line Treatment

445 Background: The FIRE-3 study (AIO KRK-0306) was designed as a randomized multicenter trial to compare the efficacy of FOLFIRI plus cetuximab (cet) to FOLFIRI plus bevacizumab (bev) as first-line treatment in KRAS WT mCRC patients. FOLFIRI plus cet as first-line treatment of KRAS WT mCRC patients resulted in comparable overall response rates (ORR) and progression free survival (PFS) when compared to FOLFIRI plus bev. Overall survival (OS) was significantly longer in the FOLFIRI plus cet arm. Methods: In a preplanned analysis, the effect of mutations within the EGFR dependent pathway were investigated. Next to mutations within KRAS (exon 2, 3, 4), NRAS (exon 2, 3, 4) and BRAF (V600E), mutations within PIK3CA (exon 9 and 20) and Akt were investigated and their impact on ORR, PFS and OS within the FIRE-3 population was evaluated. The analysis of all mutations was carried out employing pyrosequencing. Results: The ITT population consisted of 592 KRAS WT (exon 2) patients. The current analysis includes 488 cases (82.4%) with tumor tissue available. In 407 pts sequencing of all RAS mutations was possible. The ORR within the WT RAS patient group was higher in the FOLFIRI plus cet arm (65.5% vs 59.6%; Fisher´s p: 0.157). HRs (cet; bev) for pts with WT RASwere 0.93 (95% CI, 0.74-1.17; p = 0.54) for PFS and 0.70 (95% CI, 0.53-0.92; p = 0.01) for OS. PIK3CA mutation did not influence PFS nor OS when compared to the RAS wt population. Conclusions: ORR and OS were increased in patients with cet plus FOLFIRI as compared to bev plus FOLFIRI in patients without RAS mutations. Exclusion of patients with RAS mutations identifies a population which is more likely to benefit from cetuximab. Clinical trial information: NCT00433927.

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Mutation status and prognostic value of KRAS and NRAS mutations in Moroccan colon cancer patients: A first report

PLoS ONE ◽

10.1371/journal.pone.0248522 ◽

2021 ◽

Vol 16 (3) ◽

pp. e0248522

Author(s):

Fatima El agy ◽

Sanae el Bardai ◽

Ihsane El Otmani ◽

Zineb Benbrahim ◽

Ibn Majdoub Hassani Karim ◽

...

Keyword(s):

Lymph Node ◽

Lymph Nodes ◽

Clinicopathological Features ◽

Wild Type ◽

Braf Mutations ◽

Poor Overall Survival ◽

Exon 2 ◽

Colon Cancers ◽

Kras Codon ◽

Kras Exon

This study aimed to estimate the incidence of KRAS, NRAS, and BRAF mutations in the Moroccan population, and investigate the associations of KRAS and NRAS gene mutations with clinicopathological characteristics and their prognosis value. To achieve these objectives, we reviewed medical and pathology reports for 210 patients. RAS testing was investigated by Sanger sequencing and Pyrosequencing technology. BRAF (exon 15) status was analyzed by the Sanger method. The expression of MMR proteins was evaluated by Immunohistochemistry. KRAS and NRAS mutations were found in 36.7% and 2.9% of 210 patients, respectively. KRAS exon 2 mutations were identified in 76.5% of the cases. RAS-mutated colon cancers were significantly associated with female gender, presence of vascular invasion, classical adenocarcinoma, moderately differentiated tumors, advanced TNM stage III-IV, left colon site, higher incidence of distant metastases at the time of diagnostic, microsatellite stable phenotype, lower number of total lymph nodes, and higher means of positive lymph nodes and lymph node ratio. KRAS exon 2-mutated colon cancers, compared with KRAS wild-type colon cancers were associated with the same clinicopathological features of RAS-mutated colon cancers. NRAS-mutated patients were associated with lower total lymph node rate and the presence of positive lymph node. Rare RAS-mutated tumors, compared with wild-type tumors were more frequently moderately differentiated and associated with lower lymph node rate. We found that KRAS codon 13-mutated, tumors compared to codon 12-mutated tumors were significantly correlated with a higher death cases number, a lower rate of positive lymph, lower follow-up time, and poor overall survival. Our findings show that KRAS and NRAS mutations have distinct clinicopathological features. KRAS codon 13-mutated status was the worst predictor of prognosis at all stages in our population.

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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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A phase Ib/II study of second-line therapy with panitumumab, irinotecan and everolimus (PIE) in metastatic colorectal cancer (mCRC) with KRAS wild type (WT): Biomarker substudy.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.643 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 643-643

Author(s):

Amanda Rose Townsend ◽

Jennifer Hardingham ◽

Niall C. Tebbutt ◽

Christos Stelios Karapetis ◽

Nimit Singhal ◽

...

Keyword(s):

Dose Level ◽

Cox Regression ◽

Outcome Data ◽

Braf V600e ◽

Mtor Inhibition ◽

Exon 2 ◽

Phase Ib ◽

Level 1 ◽

Level 2 ◽

Kras Exon

643 Background: Inhibition of mTOR in addition to EGFR may overcome upstream resistance to EGFR inhibitors in CRC. This phase Ib/II study evaluated the efficacy and safety of irinotecan, panitumumab and everolimus (Townsend et al. ESMO 2016).These are the results of the biomarker substudy. Methods: Patients with KRAS exon 2 WT mCRC after failure of fluoropyrimidine based therapy received IV irinotecan (200mg/m2) and panitumumab (6mg/kg) 2 weekly. Everolimus dose was 5mg orally alternate days for dose level 1/expansion, and 5mg daily for level 2. Survival outcomes were calculated using Kaplan-Meier method. DNA was isolated from FFPE tumour sections for whole exome sequencing. Reads were mapped to hg19 reference genome and variants called using GATK tool. RAS/RAF mutations (MT) identified were correlated with response (Fishers exact test), progression free survival (PFS) and overall survival (OS). Filtering for variants in genes associated with progressive disease (PD) was performed. Results: 48 patients were enrolled. 33 had adequate tissue and outcome data for analysis (29 dose level 1, 4 level 2). Median age 63 yrs (41-82), M/F 23/10, ECOG 0/1 17/16. 14 (42%) had partial response (PR), 15 (45%) stable disease (SD) as best response. Median PFS was 5.3 ms and OS 11.1 ms. Three patients had RAS MTs (KRAS exon 2 G12V, KRAS exon 3 Q61H, NRAS exon 2 G12D) and 5 BRAF V600E MT. 2/3 RAS MT had SD and 1/3 PR. 3/5 BRAF MT had SD and 2/5 PD. 13/25 all WT had PR (52%) and 10/25 (40%) SD. BRAF V600E was associated with poorer PFS v WT (median 2.7 v 6.1 ms; P < 0.0001). In all WT patients median PFS was 5.8 ms and OS 12.2 ms. In exploratory analysis 4 patients were heterozygous for PPP1R17 L12V variant (rs3735422) which correlated with PD in 3/4 (P = 0.003) and worse PFS (P = 0.0001). On multivariate analysis (COX regression) BRAF V600E MT and PPP1R17 L12V remained associated with worse PFS (p = 0.005 & p = 0.001 respectively). Conclusions: No responses were seen in patients with BRAF MT. One of 3 with RAS MT had a PR suggesting mTOR inhibition may overcome resistance in this group however this may represent purely a chemotherapy effect. PPP1R17 L12V variant should be validated in larger cohorts. Clinical trial information: NCT01139138.

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Microsatellite Instability in Patients With Stage III Colon Cancer Receiving Fluoropyrimidine With or Without Oxaliplatin: An ACCENT Pooled Analysis of 12 Adjuvant Trials

Journal of Clinical Oncology ◽

10.1200/jco.20.01600 ◽

2020 ◽

pp. JCO.20.01600

Author(s):

Romain Cohen ◽

Julien Taieb ◽

Jack Fiskum ◽

Greg Yothers ◽

Richard Goldberg ◽

...

Keyword(s):

Colon Cancer ◽

Microsatellite Instability ◽

Prognostic Value ◽

Randomized Clinical Trials ◽

Disease Free Survival ◽

Pooled Analysis ◽

Stage Iii ◽

Cox Models ◽

Stage Iii Colon Cancer ◽

Similar Survival

PURPOSE: In patients with stage III colon cancer (CC) whose tumors demonstrate microsatellite instability (MSI), the efficacy of adjuvant fluoropyrimidine (FP) with or without oxaliplatin has not been clearly demonstrated and the prognostic value of MSI remains uncertain. MATERIALS AND METHODS: Individual patient data from the ACCENT database were used to evaluate the effect of FP with or without oxaliplatin on disease-free survival (DFS) and overall survival (OS) among patients with MSI stage III CC and the prognostic value of MSI in patients treated with FP plus oxaliplatin, by stratified Cox models adjusted for demographic and clinicopathological factors. RESULTS: MSI status was available for 5,457 patients (609 MSI, 11.2%; 4848 microsatellite stable [MSS], 88.8%) from 12 randomized clinical trials (RCTs). Oxaliplatin significantly improved OS of MSI patients from the two RCTs testing FP with or without oxaliplatin (n = 185; adjusted hazard ratio [aHR] = 0.52, 95% CI, 0.28 to 0.93). Among the 4,250 patients treated with FP plus oxaliplatin (461 MSI and 3789 MSS), MSI was associated with better OS in the N1 group compared with MSS (aHR = 0.66; 95% CI, 0.46 to 0.95) but similar survival in the N2 population (aHR = 1.13; 95% CI, 0.86 to 1.48; P interaction = .029). The main independent prognosticators of MSI patients treated with FP plus oxaliplatin were T stage (aHR = 2.09; 95% CI, 1.29 to 3.38) and N stage (aHR = 3.57; 95% CI, 2.32 to 5.48). Similar results were observed for DFS in all analyses. CONCLUSION: Adding oxaliplatin to FP improves OS and DFS in patients with MSI stage III CC. Compared with MSS, MSI patients experienced better outcomes in the N1 group but similar survival in the N2 group.

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