Overall survival based on MSI and BRAF mutation status for stage II/III colorectal cancer.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 132-132
Author(s):  
Sophiya Karki ◽  
Rashna Madan ◽  
Sarah Schmitt ◽  
Ziyan Y. Pessetto ◽  
Andrew K. Godwin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Microsatellite Instability ◽  
Median Survival ◽  
Braf Mutation ◽  
Prognostic Value ◽  
Stage Ii ◽  
Age At Diagnosis ◽  
Mutation Status ◽  
Braf Mutant

132 Background: Colorectal cancer (CRC) is the second leading cause of cancer-associated deaths in the United States. Some of the poor prognostic factors for metastatic CRC (mCRC) include BRAF V600E mutation and microsatellite instability (MSI) that result from mutation or loss of mismatch-repair genes. While the prognostic value of MSI-high CRC for early-stage patients treated with resection and adjuvant chemotherapy is favorable, the prognostic value of BRAF mutation is still unclear. Furthermore, the impact of BRAF mutation with concurrent microsatellite instability on overall survival has not been well investigated. Methods: Here, we collected BRAF mutation status and MSI status of stage II/III CRC patients (n=106) treated at the University of Kansas Cancer Center between September 2009 and July 2020 and compared overall survival between 4 subtypes:MSI-H/BRAF mutant (n=16), MSS/BRAF mutant (n=4), MSI-H/BRAF WT (n=17) and MSS/BRAF WT (n=69), further stratifying patients by age at diagnosis and tumor location. Molecular data were obtained from molecular oncology laboratory as PCR or IHC-based or acquired from outside records. Subgroup analyses were done for stage II and stage III cancers. Results: Table shows the patient characteristics. From our preliminary analysis, MSI-H CRC was found to be primarily a right-sided tumor (MSI-H/BRAF mutant: 94% and MSI-H/BRAF WT 76%). On the contrary, MSS CRC had a more heterogenous localization, spanning left colon, right colon and rectum. In our patient cohort, median survival was not reached for stage II patients whereas for stage III patients, BRAF mutation was associated with poor median survival irrespective of MSI status (MSS/BRAF mutant: 27 months and MSI-H/BRAF mutant 29 months). Median overall survival was found to be 87 months, not reached, 27 months and 29 months for MSS/BRAF WT, MSI-H/BRAF WT, MSS/BRAF mutant and MSI-H/BRAF mutant, respectively. Although associated with poor survival, MSI-H/BRAF mutant displayed later age at diagnosis (mean age 73) compared to MSS/BRAF mutant (mean age 60, p-value<0.029). Conclusions: Our finding suggests that BRAF mutation has poor prognosis even at earlier stages of the disease and that MSS/BRAF mutation, in particular, has the worst prognostic features. These findings highlight the need for BRAF-targeted therapy for CRC at any stage. Due to small sample size, however, our results warrant validation in a larger cohort. [Table: see text]

BRAF and KRAS mutations as additional risk factors in the context of clinical parameters of patients with colorectal cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3522-3522
Author(s):  
Vlad Calin Popovici ◽  
Eva Budinska ◽  
Arnaud Roth ◽  
Fred Bosman ◽  
Sabine Tejpar ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Braf Mutation ◽  
Kras Mutation ◽  
Prognostic Value ◽  
Tumor Site ◽  
Kras Mutations ◽  
P Values ◽  
Significance Level ◽  
Survival After Relapse

3522 Background: The BRAF and KRAS mutations have been proposed as prognostic markers in colorectal cancer (CRC). Of them, only the BRAF V600E mutation has been validated as prognostic for overall survival and survival after relapse, while the value of KRAS mutation is still unclear. Methods: In a cohort of 1423 stage II-III patients from the PETACC-3 clinical trial, the prognostic value of the BRAF and KRAS mutations was retrospectively assessed in all possible stratifications defined by the 5 factors (T and N stage, tumor site and grade, and microsatellite instability status), by log rank test for overall survival (OS), relapse-free survival (RFS), and survival after relapse (SAR). The presence of interactions was tested by Wald test. The significance level was set to 0.01 for Bonferroni-adjusted p-values (P*), and a second level for a trend towards statistical significance was set at 0.05 for unadjusted p-values (P). Results: BRAF mutation was a marker of poor OS only in microsatellite stable (MSS) and left-sided tumors, with no prognostic value in microsatellite instable (MSI-H) or right-sided tumors. In MSS/left-sided tumors, BRAF mutation represents a marker of higher risk than previously reported: OS HR=6.4 [95% CI: 3.6-11.5], P* < 0.0001. For SAR, BRAF was prognostic in more stratifications, with higher risk in MSS/left-sided tumors (HR=3.9 [95% CI: 2.1-7.2], P* = 0.0002) than in MSS/right-sided (HR=2.3 [95% CI: 1.2-4.4], P=0.01). A novel observation was that BRAF mutation was prognostic also for RFS, but only in MSS/left-sided tumors (HR=3.6 [95% CI:2-6.3], P*=0.0005]). Additionally, heterogeneity in OS and RFS among BRAF mutants was observed. In general, KRAS mutation did not reach the significance level required, but showed a trend to become a prognostic marker for RFS in MSS tumors with early lymph node involvement (N1) (HR=1.6 [95% CI:1.1-2.2], P=0.01). Conclusions: The prognostic utility of the BRAF and KRAS mutations has to be interpreted in the context of other factors. For the BRAF mutation, a clear interaction with MSI status and tumor site was observed, with BRAF mutation indicating a much higher risk in MSS/left-sided tumors than previously considered.

Prognostic significance of KRAS and BRAF mutations in Japanese patients with colorectal cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14033-e14033
Author(s):  
Eiji Oki ◽  
Ryota Nakanishi ◽  
Koji Ando ◽  
Hiroshi Saeki ◽  
Takefumi Ohga ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Braf Mutation ◽  
Kras Mutation ◽  
Molecular Mechanisms ◽  
Prognostic Significance ◽  
Japanese Patients ◽  
Genetic Alterations ◽  
Stage Ii ◽  
Anatomical Site

e14033 Background: Recent evidence highlights the potential prognostic and predictive value of BRAF and K-RAS gene alterations in patients with colorectal cancer. To determine whether differences exist in the molecular mechanisms driving colorectal cancer between Japanese and Western, we characterized Japanese patients with colorectal cancer by assessing genetic alterations involved in cancer progression and response to treatment. Methods: We retrospectively evaluated 254 Japanese diagnosed with colorectal cancer at our institution between 1994 and 2009. Mutations in KRAS codons 12 and 13 and BRAF codon 600 were identified by direct sequencing. Microsatellite instability (MSI) status was determined by genotyping in the 5 loci. Associations between KRAS or BRAF mutation and clinicopathological characteristics and prognosis were evaluated. Results: KRAS and BRAF mutation were detected in 33.5% and 6.7% of all patients, respectively. KRAS mutation was correlated with poor recurrence free survival (RFS) (p = 0.03), especially in stage II patients (p = 0.007). BRAF mutation was significantly correlated with the anatomical site of tumor (p < 0.001), tumor grade (p = 0.001) and high frequency of microsatellite instability (p < 0.001). BRAF mutation was also correlated with poor overall survival in all cases of patients (p = 0.009). Overall, the background of KRAS and BRAF mutation was almost similar between CRCs of Western countries and those of Japanese. However, KRAS mutation status was considered to be helpful to predict recurrence in Japanese patients with stage II CRC. Conclusions: Our findings indicate that BRAF and K-RAS mutation plays an important role in the tumorigenesis of colorectal cancer. These results indicate that molecular analysis for BRAF and K-RAS may be a useful biomarker for identifying patients with right-sided colon cancer with poor outcome who may benefit from a more individualized course of therapy.

Prognostic value of RAS, BRAF, and PIK3CA mutations in early-stage colorectal cancer.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 594-594
Author(s):  
Jennifer Elizabeth Byer ◽  
Nishi Kothari ◽  
TzuHua Juan ◽  
Jamie K. Teer ◽  
Michael J. Schell ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Survival Data ◽  
Braf Mutation ◽  
Prognostic Value ◽  
Early Stage ◽  
Stage I ◽  
Braf V600e ◽  
Pik3ca Mutations ◽  
1000 Genomes ◽  
Braf Mutant

594 Background: Activating mutations in the KRAS, BRAF and PIK3CA oncogenes deregulate growth-factor pathways and promote metastasis in colorectal cancer (CRC). The prognostic value of these mutations has been reported with conflicting results in early CRC. We evaluated RAS, BRAF, and PIK3CA mutations as prognostic biomarkers in early stage (stage I-III) colorectal cancer (CRC) patients. Methods: Tumor samples collected from 302 early stage CRC patients diagnosed between 1998 and 2010 were analyzed as part of a multi-institutional observational study. Targeted exome sequencing was performed using the Illumina NGS platform with 50-100X coverage of mutations. The BWA/GATK pipeline was used to identify variants and indels. Matched normal samples were not available for comparison to identify somatic mutations, therefore 1000 Genomes was used to filter normal variants. Variants identified in 1000 Genomes with an MAF <0.01 were filtered. Overall survival data was collected via retrospective chart review. Extended RAS, BRAF V600E, and PIK3CA (exon 9 and 20) mutations were evaluated. The log-rank test was used to compare survival distributions. Results: 302 patients were eligible for analysis (53 stage I, 125 stage II, 124 stage III). 109 patients had RAS mutations (KRAS or NRAS), 41 patients had BRAF mutations, and 29 patients had PIK3CA mutations. Of the 247 patients with microsatellite stability (MSS) 98 were RAS mutant, 10 were BRAF mutant, and 19 were PIK3CA mutant. Of the 55 patients with microsatellite instability high (MSI-H) 11 were RAS mutant, 31 were BRAF mutant, and 10 were PIK3CA mutant. BRAF mutation was prognostic for decreased OS (p= 0.0245), particularly in patients with MSS tumors (p=0.0141). RAS and PIK3CA mutations did not have prognostic value for OS (p =0.72 and 0.23 respectively). Conclusions: In early stage colorectal cancer, we confirmed BRAF mutation is prognostic for OS particularly in MSS patients. RAS and PIK3CA mutations did not confer prognostic value.

Evaluation of BRAF mutation as a powerful prognostic factor in advanced and recurrent colorectal cancer.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 413-413
Author(s):  
T. Yokota ◽  
T. Ura ◽  
N. Shibata ◽  
D. Takahari ◽  
K. Shitara ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Prognostic Factors ◽  
Braf Mutation ◽  
Kras Mutation ◽  
Clinicopathological Features ◽  
Wild Type ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Braf Mutant

413 Background: Alterations in the RAS/RAF/ERK signaling pathways frequently occur in colorectal cancer (CRC). KRAS mutations preclude responsiveness to EGFR-targeted therapies for CRC patients. However, prognostic significance of KRAS mutation is still controversial. The aim of this study is to investigate clinicopathological features of KRAS mutation in codon 12 and 13 as well as of BRAF mutation, and to validate prognostic impact of KRAS/BRAF mutation in advanced and recurrent CRC. Methods: The population consisted of 230 unselected patients who had undergone first-line chemotherapy for advanced and recurrent CRC between November 2002 and June 2010. Cycleave PCR was performed to detect a point mutation at codon 12, 13 or 61 in KRAS, and the V600E mutation in BRAF. Prognostic factors associated with survival were identified using univariate and multivariate logistic and/or Cox proportional hazards analyses. Results: KRAS mutations were present in 34.8% (n= 80) of patients, including 23.5% (n = 54) in codon 12, 11.3% (n = 26) in codon 13, and 0% in codon 61. 6.5% (n = 15) of patients had BRAF mutation. None of the CRC patients carried both KRAS and BRAF mutations. The primary tumor lesions were located on the right side of the colon in 60% of the BRAF mutant patients (p=0.0371). Furthermore, BRAF mutant was significantly associated with the pathological subtypes of poorly differentiated adenocarcinoma/mucinous carcinoma (p<0.0001) and peritoneal metastasis (p=0.0059). The median overall survival for BRAF mutant and KRAS 13 mutant patients was 11.0 and 27.7 months, respectively, which was significantly worse than that for KRAS wild-type (wt)/BRAF wt (40.6 months) (BRAF; HR=3.89, 95% CI 1.83-8.24, p<0.001, KRAS13; HR=2.03, 95% CI 1.10-3.74, p=0.024). After adjustment for significant features by multivariate Cox regression analysis, BRAF mutation was associated with poor overall survival (HR, 3.70, 95% CI, 1.48-9.28; p=0.005), together with performance status 2. Conclusions: This retrospective analysis shows that clinicopathological features of CRC patients with BRAF mutations seem to be distinct from those with wild type BRAF. BRAF mutation is one of the most powerful prognostic factors in advanced and recurrent CRC. No significant financial relationships to disclose.

Relationship between oncogenic mutations (RAS, BRAF and PIK3CA) and tumor location and prognosis in colorectal cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15109-e15109
Author(s):  
Daisuke Inagaki ◽  
Manabu Shiozawa ◽  
Tetta Satoyoshi ◽  
Yosuke Atsumi ◽  
Masaaki Murakawa ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Braf Mutation ◽  
Cox Regression ◽  
Pik3ca Mutation ◽  
Tumor Location ◽  
Kras Mutations ◽  
Mutation Status ◽  
Cox Regression Analysis ◽  
Oncogenic Mutation

e15109 Background: Several studies have reported that right-sided colon cancers (RCC) and left-sided colorectal cancers (LCRC) differ in several factors including genetic features. We investigated the difference in clinicopathological characteristics and oncogenic mutation status between patients with RCC and LCRC in all stages and assessed outcome. Methods: This study was a prospective, observational study. Patients were recruited from November 2014 to February 2016. Formalin-fixed paraffin-embedded tissue blocks were collected and DNA wes extracted from tissue sections from 227 cases. There was no double cancer. Mutations in KRAS, NRAS, HRAS, BRAF and PIK3CA were detected by next-generation DNA sequencer. Tumors from cecum to transverse colon were defined as RCC, and tumors from descending colon to rectum were defined as LCRC. The median follow-up period was 521 days. Results: KRAS, NRAS, BRAF and PIK3CA mutations were present in 95 patient (41.9%), 7 patients (3.1%), 10 patients (4.4%) and 23 patients (10.1%) respectively, and there was no HRAS mutation in all patients. RCC was 68 patients and LCRC was 159 patients. Poorly differentiated adenocarcinoma and mutinous adenocarcinoma were significantly more frequent in RCC compared to LCRC (P = 0.031). KRAS mutations were detected in 37 patients with RCC (54.4%) and in 58 patients with LCRC (36.5%). BRAF mutations were detected in 7 patient with RCC (10.3%) and in 3 patients with LCRC (1.9%). KRAS and BRAF mutation in RCC were significantly more frequent than in LCRC (P = 0.012 and P = 0.005, respectively). The incidence of NRAS and PIK3CA mutation was no difference between two groups. In all patients, overall survival was evaluated. On univariate Cox regression analysis, BRAF mutation was associated with significantly poorer overall survival than BRAF wild type (HR = 4.831, P = 0.013). Other oncogenic mutation status and tumor location weren’t associated with overall survival. Conclusions: KRAS and BRAF mutation were more frequent in the patients with RCC compared to those with LCRC in all stages. This study suggested BRAF mutation correlated with poor outcomes in patients with colorectal cancer.

scholarly journals Combination of microsatellite instability and BRAF mutation status for subtyping colorectal cancer

2015 ◽  
Vol 112 (12) ◽  
pp. 1966-1975 ◽  
Author(s):  
T T Seppälä ◽  
J P Böhm ◽  
M Friman ◽  
L Lahtinen ◽  
V M J Väyrynen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Braf Mutation ◽  
Mutation Status

scholarly journals Microsatellite instability status delineates braf mutation classes and patterns of metastases in braf-mutant colorectal cancer

HPB ◽  
2021 ◽  
Vol 23 ◽  
pp. S607
Author(s):  
A. Lakoma ◽  
T. Lenko ◽  
Y. Wang ◽  
A. Gomez ◽  
C. Maedler-Kron ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Braf Mutation ◽  
Braf Mutant

Prognostic Role of KRAS and BRAF in Stage II and III Resected Colon Cancer: Results of the Translational Study on the PETACC-3, EORTC 40993, SAKK 60-00 Trial

2010 ◽  
Vol 28 (3) ◽  
pp. 466-474 ◽  
Author(s):  
Arnaud D. Roth ◽  
Sabine Tejpar ◽  
Mauro Delorenzi ◽  
Pu Yan ◽  
Roberto Fiocca ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Multivariate Analysis ◽  
Braf Mutation ◽  
Kras Mutation ◽  
Prognostic Value ◽  
Tumor Stage ◽  
Stage Ii ◽  
Kras Mutations ◽  
Exon 2 ◽  
Mutation Status

Purpose Mutations within the KRAS proto-oncogene have predictive value but are of uncertain prognostic value in the treatment of advanced colorectal cancer. We took advantage of PETACC-3, an adjuvant trial with 3,278 patients with stage II to III colon cancer, to evaluate the prognostic value of KRAS and BRAF tumor mutation status in this setting. Patients and Methods Formalin-fixed paraffin-embedded tissue blocks (n = 1,564) were prospectively collected and DNA was extracted from tissue sections from 1,404 cases. Planned analysis of KRAS exon 2 and BRAF exon 15 mutations was performed by allele-specific real-time polymerase chain reaction. Survival analyses were based on univariate and multivariate proportional hazard regression models. Results KRAS and BRAF tumor mutation rates were 37.0% and 7.9%, respectively, and were not significantly different according to tumor stage. In a multivariate analysis containing stage, tumor site, nodal status, sex, age, grade, and microsatellite instability (MSI) status, KRAS mutation was associated with grade (P = .0016), while BRAF mutation was significantly associated with female sex (P = .017), and highly significantly associated with right-sided tumors, older age, high grade, and MSI-high tumors (all P < 10−4). In univariate and multivariate analysis, KRAS mutations did not have a major prognostic value regarding relapse-free survival (RFS) or overall survival (OS). BRAF mutation was not prognostic for RFS, but was for OS, particularly in patients with MSI-low (MSI-L) and stable (MSI-S) tumors (hazard ratio, 2.2; 95% CI, 1.4 to 3.4; P = .0003). Conclusion In stage II-III colon cancer, the KRAS mutation status does not have major prognostic value. BRAF is prognostic for OS in MS-L/S tumors.

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