Age-dependent prognostic value of KRAS mutation in metastatic colorectal cancer

2021 ◽  
Author(s):  
Muhammet Ozer ◽  
Suleyman Yasin Goksu ◽  
Nina Niu Sanford ◽  
Chul Ahn ◽  
Muhammad Shaalan Beg ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Kras Mutation ◽  
Prognostic Value ◽  
Age Groups ◽  
Prognostic Impact ◽  
Kras Gene ◽  
Kras Mutations ◽  
Kras Status ◽  
Age Dependent

Background: The age-dependent prognostic impact of KRAS status in metastatic colorectal cancer (mCRC) is unknown. Materials & Methods: We used the National Cancer Database to evaluate the survival by KRAS status for age-groups <50, 50–69 and ≥70, adjusting for relevant patient and tumor characteristics. Results: mCRC patients (n = 26,095; 33.5%) had KRAS status reported, and 11,338 of these patients (43.4%) had mutations in the KRAS gene. Patients with KRAS mutations had worse overall survival than wild-type KRAS patients. In age-groups <50 years (23 vs 29 months; p < 0.001) and 50–69 (21 vs 23.4 months; p < 0.001), KRAS mutations were significantly associated with worse survival, whereas in the ≥70-year age-group, there was no significant association (14 vs 14 months; p = 0.34). Conclusion: We conclude that the age of patients influences the prognostic value of KRAS mutation in metastatic colorectal cancer.

INVESTIGATION KRAS MUTATION IN CIRCULATION TUMOR DNA IN DIFFERENT STAGES OF COLORECTAL CANCER

2019 ◽  
Vol 65 (5) ◽  
pp. 701-707
Author(s):  
Vitaliy Shubin ◽  
Yuriy Shelygin ◽  
Sergey Achkasov ◽  
Yevgeniy Rybakov ◽  
Aleksey Ponomarenko ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Plasma Volume ◽  
Kras Mutation ◽  
Stage Iv ◽  
Circulating Tumor Dna ◽  
Stage Ii ◽  
Kras Gene ◽  
Kras Mutations ◽  
Droplet Pcr ◽  
Tumor Dna

To determine mutations in the plasma KRAS gene in patients with colorectal cancer was the aim of this study. The material was obtained from 44 patients with colorectal cancer of different stages (T1-4N0-2bM0-1c). Plasma for the presence of KRAS gene mutation in circulating tumor DNA was investigated using digital droplet polymerase chain reaction (PCR). KRAS mutations in circulating tumor DNA isolated from 1 ml of plasma were detected in 13 (30%) patients with cancer of different stages. Of these, with stage II, there were 3 patients, with III - 5 and with IV - 5. Patients who did not have mutations in 1 ml of plasma were analyzed for mutations of KRAS in circulating tumor DNA isolated from 3 ml of plasma. Five more patients with KRAS mutations were found with II and III stages. The highest concentrations of circulating tumor DNA with KRAS mutation were found in patients with stage IV. The increase in plasma volume to 3 ml did not lead to the identification of mutations in I stage. This study showed that digital droplet PCR allows identification of circulating tumor DNA with the KRAS mutations in patients with stage II-IV of colon cancer. The results can be used to determine the degree of aggressiveness of the tumor at different stages of the disease, but not the 1st, and it is recommended to use a plasma volume of at least 3 ml.

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.

KRAS mutation is highly predictive of cetuximab resistance in metastatic colorectal cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10502-10502 ◽  
Author(s):  
F. Di Fiore ◽  
F. Le Pessot ◽  
A. Lamy ◽  
F. Charbonnier ◽  
J. Sabourin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Predictive Factors ◽  
Kras Mutation ◽  
Copy Number ◽  
Gene Copy Number ◽  
Gene Mutations ◽  
Gene Copy ◽  
Kras Gene ◽  
Egfr Gene

10502 Background: In metastatic colorectal cancer (MCRC), no molecular predictive markers to cetuximab response have been yet established. The aim was to evaluate whether KRAS gene mutations, EGFR immunochemistery (IHC) and EGFR gene copy number correlate with response to cetuximab. Methods: 59 patients with MCRC treated by cetuximab between July 2004 and December 2005 were retrospectively included. Clinical data were collected and tumour response was evaluated according to RECIST criteria. EGFR IHC was performed using the Dako kit. The EGFR gene copy number was determined by FISH (Fluorescence in-Situ Hybridization). Detection of KRAS gene mutations on exon 2 was performed by sequencing of extracted paraffin-embedded DNA and then by 2 methods, SNaPshot and PCR-LCR, specifically developed to detect small fractions of mutated tumor cells. Response to cetuximab was studied according to clinical data, IHC, FISH and KRAS mutation analysis using the Fischer exact test. Predictive factors of response were determined by logistic regression. Skin reactions were collected but not considered for this analysis as regards the lack of accurate grading in a retrospective study. Times to progression (TTP) were calculated using the Kaplan-Meier method and compared with log-rank test. Results: 12 patients (20.3%) responded to cetuximab (2 patients with complete response and 10 patients with partial response), 19 (32.2%) had stable disease and 28 (47.5%) were in disease progression. A KRAS mutation was detected in 22/59 tumours and, in 6 cases, was missed by sequencing analysis but detected using the SNaPshot and PCR-LCR assays. No KRAS mutation was found in responders patients. KRAS mutation was associated with disease progression (p = 0.0005) and TTP was significantly decreased in mutated KRAS patients (3 vs 5.5 months, p = 0.015). There was no correlation between EGFR IHC and cetuximab response. No EGFR gene copy number increase was detected in responders patients. Predictive factors of cetuximab resistance were KRAS mutation (p=0.003; OR:0.10; 95IC:0.22–0.40) and age<60 (p=0.024; OR:0.13; 95IC:0.02–0.77). Conclusions: KRAS mutation is highly predictive of cetuximab resistance in MCRC. Our study also highlights the need of sensitive methods to ensure an efficient mutation detection. No significant financial relationships to disclose.

scholarly journals KRAS gene mutation in patients with primary colorectal cancer

Acta Medica ◽  
2019 ◽  
Vol 50 (1) ◽  
pp. 20-25
Author(s):  
Minh Thuc Vu Thi ◽  
Van Thieu Le ◽  
Quang Huy Huynh ◽  
Minh Duc Nguyen
Keyword(s):  
Colorectal Cancer ◽  
Gene Mutation ◽  
Kras Mutation ◽  
Pcr Amplification ◽  
Colorectal Cancers ◽  
Kras Gene ◽  
Kras Mutations ◽  
Exon 2 ◽  
Mutational Status ◽  
Keywords Colorectal Cancer

Objective: KRAS mutation occurs in 30% to 50% of colorectal cancers. The aim of our study was to determine the frequency of KRAS mutations among patients with colorectal cancer; and the relationship with clinicopathologic features. Materials and Methods: 79 colorectal cancer cases at a hospital in Hai Phong of Vietnam were collected, including 45 colon cancer and 34 rectal cancer during January 2010 and July 2012. PCR amplification and DNA sequencing were used to detect mutations in exon 2 of KRAS gene. The study was based on informed consent and approval by the Ethics Committee of Viet Tiep Hospital. Results: KRAS mutation was found in 40.4% (225/557) colorectal cancer. All mutation locations were in codon 12. There was significant association (p < 0.05) between KRAS mutations, tumor size and tumor stage. No significant association was observed between KRAS mutations and gender, tumor location, tumor grade or histologic presence of mucin (p>0.05). Conclusion: Determining the KRAS mutational status of tumor samples has become an essential tool for managing patients with colorectal cancers Keywords: colorectal cancer, KRAS gene mutation, clinicopathology.

Age-dependent prognostic value of KRAS mutation in metastatic colon cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16085-e16085
Author(s):  
Muhammet Ozer ◽  
Suleyman Yasin Goksu ◽  
Nina Niu Sanford ◽  
Todd Anthony Aguilera ◽  
Radhika Kainthla ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Kras Mutation ◽  
Prognostic Value ◽  
Cox Regression ◽  
Categorical Variables ◽  
Metastatic Colon Cancer ◽  
Tumor Characteristics ◽  
Wild Type ◽  
Kras Status ◽  
Age Dependent

e16085 Background: KRAS mutation is associated with poor prognosis in metastatic colon cancer (mCC). However, the age-dependent prognostic value of KRAS status is unknown. We aimed to confirm if the prognostic impact of KRAS is dependent on the age of diagnosis in mCC. Methods: We identified adult patients with mCC diagnosed between 2004 and 2016 using the NCDB. We compared patients with KRAS mutation and KRAS wild type, stratified according to age group < 50, 50-70, and ≥70. Categorical variables were compared using the chi-square test. We performed the Kaplan-Meier and Cox regression methods for survival analyses. We adjusted for patient and tumor characteristics (included KRAS status, MSI, 18q loss of heterozygosity, side of the primary tumor). Results: A Total of 19,875 patients had KRAS status reported; 43% had KRAS mutation, and 57% were KRAS wild type. Patients with KRAS mutation were more likely to be female, black, have elevated CEA, and have right-sided tumors (all p < .001). In the overall population, patients with KRAS mutation had significantly worse OS compared to patients with KRAS wild type (20 vs. 22 months, p < .001), and this difference was maintained after multivariable Cox regression analysis ( p < .001) (Table). Young patients ( < 50 years) with KRAS mutation had a worse prognosis than those with KRAS wild type in the tumor (23 vs. 29 months, p < .001). KRAS status did not maintain its prognostic value among older age (≥70 years) patients (14 vs. 14 months, p = NS). Conclusions: In this analysis of a national cancer registry, we confirmed that KRAS mutation was an independent poor prognostic factor for mCC. This effect persisted after adjusting for patient and tumor characteristics, including sidedness and MSI status. However, we identified that this prognostic value of KRAS mutation is significant in young mCC patients < 50 years, as compared to older patients. [Table: see text]

scholarly journals Therapeutic Targets of KRAS in Colorectal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6233
Author(s):  
Shafia Rahman ◽  
Shimon Garrel ◽  
Michael Gerber ◽  
Radhashree Maitra ◽  
Sanjay Goel
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Metastatic Colorectal Cancer ◽  
Unmet Need ◽  
Therapeutic Strategies ◽  
Personalized Therapy ◽  
Prognostic Impact ◽  
Kras Mutations ◽  
Therapy Approach ◽  
Predictive Role

Patients with metastatic colorectal cancer have a 5-year overall survival of less than 10%. Approximately 45% of patients with metastatic colorectal cancer harbor KRAS mutations. These mutations not only carry a predictive role for the absence of response to anti-EGFR therapy, but also have a negative prognostic impact on the overall survival. There is a growing unmet need for a personalized therapy approach for patients with KRAS-mutant colorectal cancer. In this article, we focus on the therapeutic strategies targeting KRAS- mutant CRC, while reviewing and elaborating on the discovery and physiology of KRAS.

scholarly journals The Prognostic Effect of KRAS Mutations in Non-Small Cell Lung Carcinoma Revisited: A Norwegian Multicentre Study

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4294
Author(s):  
Sissel Gyrid Freim Wahl ◽  
Hong Yan Dai ◽  
Elisabeth Fritzke Emdal ◽  
Thomas Berg ◽  
Tarje Onsøien Halvorsen ◽  
...  
Keyword(s):  
Kras Mutation ◽  
Clinical Characteristics ◽  
Small Cell Lung Carcinoma ◽  
Progression Free Survival ◽  
Small Cell ◽  
Prognostic Impact ◽  
Small Cell Lung ◽  
Kras Mutations ◽  
Cell Lung Carcinoma ◽  
Kras Status

Background: due to emerging therapeutics targeting KRAS G12C and previous reports with conflicting results regarding the prognostic impact of KRAS and KRAS G12C in non-small cell lung cancer (NSCLC), we aimed to investigate the frequency of KRAS mutations and their associations with clinical characteristics and outcome. Since mutation subtypes have different preferences for downstream pathways, we also aimed to investigate whether there were differences in outcome according to mutation preference for the Raf, PI3K/Akt, or RalGDS/Ral pathways. Methods: retrospectively, clinicopathological data from 1233 stage I–IV non-squamous NSCLC patients with known KRAS status were reviewed. KRAS’ associations with clinical characteristics were analysed. Progression free survival (PFS) and overall survival (OS) were assessed for the following groups: KRAS wild type (wt) versus mutated, KRAS wt versus KRAS G12C versus KRAS non-G12C, among KRAS mutation subtypes and among mutation subtypes grouped according to preference for downstream pathways. Results: a total of 1117 patients were included; 38% had KRAS mutated tumours, 17% had G12C. Among KRAS mutated, G12C was the most frequent mutation in former/current smokers (45%) and G12D in never smokers (46%). There were no significant differences in survival according to KRAS status, G12C status, among KRAS mutation subtypes or mutation preference for downstream pathways. Conclusion: KRAS status or KRAS mutation subtype did not have any significant influence on PFS or OS.

EGFR and KRAS mutations during anti-EGFR monoclonal antibody treatment in metastatic colorectal cancer: Clinically relevant?

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3513-3513
Author(s):  
Lucie Karayan-Tapon ◽  
Aurelie Ferru ◽  
Ulrich Cortes ◽  
Claire Villalva ◽  
Jean Marc Tourani ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Monoclonal Antibody ◽  
Disease Control ◽  
Metastatic Colorectal Cancer ◽  
Primary Tumor ◽  
Kras Mutation ◽  
Wild Type ◽  
Antibody Treatment ◽  
Kras Mutations ◽  
Primary Tumors

3513 Background: It is well-established that only patients with wild-type KRAS metastatic colorectal cancer (mCRC) benefit from treatment with an epidermal growth factor receptor monoclonal antibody (anti-EGFR mAb). Recently, in patients with tumor progression after anti-EGFR mAb, occurrence of EGFR mutation (n=2/10) [Montagut C et al., Nat Med 2012] or KRAS mutation (n=6/10) [Misale S et al., Nature 2012] in metastases has been identified. These mutations could explain treatment resistance but still need to be confirmed with simultaneous analysis of KRAS and EGFR mutations. Methods: We analyzed 37 tumor samples after anti-EGFR mAb treatment for mCRC (34 from metastasis lesions and 3 from primary tumors). We analyzed KRAS (codons 12 and 13), BRAFV600E and EGFRS492R mutations using a highly sensitive technique, pyrosequencing (TheraScreen KRAS Pyro Kit, Qiagen). All tumors were KRAS, BRAFV600E and EGFRS492Rwild-type before anti-EGFR mAb treatment. Results: The majority of patients were treated using anti-EGFR mAb in first-line chemotherapy (70%) and combined with cytotoxic chemotherapy (96%). Cetuximab was used in 86% and panitumumab in 14% of the cases. Among the 37 tumor specimens, 8 were collected after disease progression, and the others after disease control. No EGFRS492R mutation was detected. No tumors developed BRAF mutation but one tumor acquired a KRAS mutation. Nevertheless, the KRAS mutation in this patient (G12V) was detected, after 5-fluorouracil plus cetuximab therapy, only in the primary tumor in the colon but not in the liver metastasis. Moreover, there was a disease control (partial response). Conclusions: Our results suggest that EGFRS492R and acquired KRAS mutations during anti-EGFR mAb therapy are not the only factors accounting for anti-EGFR resistance. Moreover, occurrence of KRAS mutation during anti-EGFR therapy could differ between primary tumor and metastases.

Impact of KRAS mutational status on clinical outcomes in patients receiving capecitabine based chemotherapy.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 436-436
Author(s):  
Nirit Yarom ◽  
Gillian Gresham ◽  
Nana Boame ◽  
Derek J. Jonker
Keyword(s):  
Clinical Outcomes ◽  
Kras Mutation ◽  
Hazard Ratio ◽  
Prognostic Impact ◽  
Kras Gene ◽  
Kras Mutations ◽  
Mutation Status ◽  
Mutational Status ◽  
Kras Mutation Status ◽  
Line Chemotherapy

436 Background: Mutations affecting the KRAS gene are established predictive markers of outcome with anti–epithelial growth factor receptor antibodies in metastatic colorectal cancer (mCRC). The relevance of these markers for chemotherapy has not been established. This analysis was performed to assess the predictive impact of KRAS mutation status in patients receiving chemotherapy. Methods: KRAS mutational status was available for 223 patients treated for mCRC. Predictive analysis of mutational status by type of fluoropyrmidine the 1st-line regimen contained (either capecitabine [C] based chemotherapy or infusional 5Fluorouracil [I-5Fu]) for clinical outcomes: progression-free survival (PFS), time to chemotherapy resistance (TTCR) and overall survival (OS). Results: KRAS mutations were observed in 43.5% of the patients. 165 patients received I-5Fu, 44 patients received C. KRAS mutation status (wild type [WT] v mutated [MT]) had no prognostic impact for OS (hazard ratio [HR], 0.81; CI, 0.69 to 1.1 p=0.17) for PFS (hazard ratio [HR], 0.87; CI, 0.66 to 1.14 p=0.3) and TTCR (hazard ratio [HR], 0.85; CI, 0.65to 1.12 p=0.26). C based 1st-line chemotherapy vs. I- 5FU based was predictive of PFS (hazard ratio [HR], 0.52; CI, 0.37 to 0.74 p=0.0003) and TTCR (hazard ratio [HR], 0.54; CI, 0.38 to 0.75p=0.0005) and not of OS (hazard ratio [HR], 0.74; CI, 0.52 to 1.1 p=0.1). KRAS mutational status had predictive impact in patients receiving C based 1st-line chemotherapy on OS (hazard ratio [HR], 0.47; CI, 0.23 to 0.948 p<0.0001) TTCR (hazard ratio [HR], 0.49; CI, 0.25 to 0.97 p=0.0398) and was not predictive of PFS (hazard ratio [HR], 0.78; CI, 0.4 to 1.53 p=0.47) Conclusions: KRAS gene mutation status was predicitve for OS and for TTCR in patients who received C based 1st-line chemotherapy.

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