KRASMutations As an Independent Prognostic Factor in Patients With Advanced Colorectal Cancer Treated With Cetuximab

2008 ◽  
Vol 26 (3) ◽  
pp. 374-379 ◽  
Author(s):  
Astrid Lièvre ◽  
Jean-Baptiste Bachet ◽  
Valérie Boige ◽  
Anne Cayre ◽  
Delphine Le Corre ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Prognostic Factor ◽  
Kras Mutation ◽  
Prognostic Value ◽  
Advanced Colorectal Cancer ◽  
Progression Free Survival ◽  
Skin Toxicity ◽  
Independent Prognostic Factor ◽  
Allelic Discrimination ◽  
Kras Mutations

PurposeCetuximab is efficient in advanced colorectal cancer (CRC). We previously showed that KRAS mutations were associated with resistance to cetuximab in 30 CRC patients. The aim of this study was to validate, in an independent larger series of 89 patients, the prognostic value of KRAS mutations on response to cetuximab and survival.Patients and MethodsEighty-nine metastatic CRC patients treated with cetuximab after treatment failure with irinotecan-based chemotherapy were analyzed for KRAS mutation by allelic discrimination on tumor DNA. The association between KRAS mutations and tumor response, skin toxicity, progression-free survival (PFS) and overall survival (OS) was analyzed.ResultsA KRAS mutation was present in 27% of the patients and was associated with resistance to cetuximab (0% v 40% of responders among the 24 mutated and 65 nonmutated patients, respectively; P < .001) and a poorer survival (median PFS: 10.1 v 31.4 weeks in patients without mutation; P = .0001; median OS: 10.1 v 14.3 months in patients without mutation; P = .026). When we pooled these 89 patients with patients from our previous study, the multivariate analysis showed that KRAS status was an independent prognostic factor associated with OS and PFS, whereas skin toxicity was only associated with OS. In a combined analysis, median OS times of patients with two, one, or no favorable prognostic factors (severe skin toxicity and no KRAS mutation) was of 15.6, 10.7, and 5.6 months, respectively.ConclusionThese results confirm the high prognostic value of KRAS mutations on response to cetuximab and survival in metastatic CRC patients treated with cetuximab.

Should KRAS Mutations Be Considered an Independent Prognostic Factor in Patients With Advanced Colorectal Cancer Treated With Cetuximab?

2008 ◽  
Vol 26 (15) ◽  
pp. 2600-2600 ◽  
Author(s):  
Marina Chiara Garassino ◽  
Gabriella Farina ◽  
Antonio Rossi ◽  
Olga Martelli ◽  
Valter Torri
Keyword(s):  
Colorectal Cancer ◽  
Prognostic Factor ◽  
Advanced Colorectal Cancer ◽  
Independent Prognostic Factor ◽  
Kras Mutations

KRASandBRAFMutations in Advanced Colorectal Cancer Are Associated With Poor Prognosis but Do Not Preclude Benefit From Oxaliplatin or Irinotecan: Results From the MRC FOCUS Trial

2009 ◽  
Vol 27 (35) ◽  
pp. 5931-5937 ◽  
Author(s):  
Susan D. Richman ◽  
Matthew T. Seymour ◽  
Philip Chambers ◽  
Faye Elliott ◽  
Catherine L. Daly ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Prognostic Factor ◽  
Braf Mutation ◽  
Poor Prognosis ◽  
Advanced Colorectal Cancer ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Poor Prognostic Factor ◽  
Minimal Impact ◽  
The Impact

PurposeActivating mutation of the KRAS oncogene is an established predictive biomarker for resistance to anti–epidermal growth factor receptor (anti-EGFR) therapies in advanced colorectal cancer (aCRC). We wanted to determine whether KRAS and/or BRAF mutation is also a predictive biomarker for other aCRC therapies.Patients and MethodsThe Medical Research Council Fluorouracil, Oxaliplatin and Irinotecan: Use and Sequencing (MRC FOCUS) trial compared treatment sequences including first-line fluorouracil (FU), FU/irinotecan or FU/oxaliplatin in aCRC. Tumor blocks were obtained from 711 consenting patients. DNA was extracted and KRAS codons 12, 13, and 61 and BRAF codon 600 were assessed by pyrosequencing. Mutation (mut) status was assessed first as a prognostic factor and then as a predictive biomarker for the benefit of adding irinotecan or oxaliplatin to FU. The association of BRAF-mut with loss of MLH1 was assessed by immunohistochemistry.ResultsThree hundred eight (43.3%) of 711 patients had KRAS-mut and 56 (7.9%) of 711 had BRAF-mut. Mutation of KRAS, BRAF, or both was present in 360 (50.6%) of 711 patients. Mutation in either KRAS or BRAF was a poor prognostic factor for overall survival (OS; hazard ratio [HR], 1.40; 95% CI, 1.20 to 1.65; P < .0001) but had minimal impact on progression-free survival (PFS; HR, 1.16; 95% CI, 1.00 to 1.36; P = .05). Mutation status did not affect the impact of irinotecan or oxaliplatin on PFS or OS. BRAF-mut was weakly associated with loss of MLH1 staining (P = .012).ConclusionKRAS/BRAF mutation is associated with poor prognosis but is not a predictive biomarker for irinotecan or oxaliplatin. There is no evidence that patients with KRAS/BRAF mutated tumors are less likely to benefit from these standard chemotherapy agents.

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.

Methylated circulating tumor DNA (Met-DNA) as an independent prognostic factor in metastatic pancreatic adenocarcinoma (mPAC) patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4136-4136 ◽  
Author(s):  
Daniel Pietrasz ◽  
Shufang Wang-Renault ◽  
Laetitia Dahan ◽  
Julien Taieb ◽  
Karine Le Malicot ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Prognostic Factor ◽  
Prognostic Value ◽  
Progression Free Survival ◽  
Circulating Tumor Dna ◽  
Independent Prognostic Factor ◽  
Oncologic Outcomes ◽  
Phase Ii Trials ◽  
Training Cohort ◽  
Tumor Dna

4136 Background: Circulating tumor DNA has emerged as prognostic biomarker in oncology. Many different genes can be mutated within a tumor, complicating procedures, even with highly sensitive next-generation sequencing (NGS). DNA methylation in promotor of specific genes is an early key epigenetic change during oncogenesis. Specific methylated genes could be a potential relevant cancer biomarker that may substitute for NGS panels. The aim of this study was to assess the prognostic value of Met-DNA in mPAC. Methods: Prognostic value of Met-DNA was assessed in a prospective cohort (PLAPAN) of mPAC (training cohort), correlated with NGS, then in two prospective independent validation cohorts from two randomized phase II trials (PRODIGE 35 and 37). Plasma samples were collected before chemotherapy on EDTA-coated tubes. Met-DNA was quantified using two specific markers of pancreatic DNA methylation by digital droplet PCR and correlated with prospectively registered patient (pts) characteristics and oncologic outcomes (progression free survival (PFS) and overall survival (OS)). Results: 330 patients (pts) were enrolled. 60% (n = 58) of the 96 pts of the training cohort had at least one Met-DNA marker. The correlation with NGS assessment was R = 0.93 (Pearson; p < 0.001). 59.5% (n = 100/168) and 59% (n = 39/66) of pts had detectable Met-DNA in the 2 validation cohorts. In the training cohort, Met-DNA was correlated with poor OS (HR = 1.82; 95%CI 1.07-2.42; p = 0.026). In validation cohorts, Met-DNA was a prognostic factor of PFS (HR = 1.62; 95%CI 1.17-2.25, p = 004) and OS (HR = 1.79; 95%CI 1.28-2.49, p < 0.001) in PRODIGE 35, as in PRODIGE 37: PFS HR = 1.79 (95%CI 1.07-2.99; p = 0.026) and OS HR = 2.08 (95%CI [1.18-3.68], p = 0.01), respectively. In multivariate analysis adjusted on gender, age, CA19-9 > 40UI.mL, treatment arm, number of metastatic sites and stratified on center, Met-DNA was independently associated with poor OS in both trials: HR = 1.81 (95%CI 1.10-2.98; p = 0.02) and HR = 3.62 (95%CI: 1.32-9.93; p = 0.01). Conclusions: This study demonstrates that Met-DNA is a strong independent prognostic factor in mPAC. These results argue for patient’s stratification on ctDNA status for further randomized trials. Clinical trial information: NCT02827201 and NCT02352337.

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.

Highly sensitive quantitative detection of circulating tumor DNA in urine and plasma from advanced colorectal cancer patients in aid of early diagnosis of clinically relevant KRAS mutations.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 654-654 ◽  
Author(s):  
Jason C. Poole ◽  
Cecile Rose T. Vibat ◽  
Lucie Benesova ◽  
Barbora Belsanova ◽  
Saege Hancock ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Patients ◽  
Kras Mutation ◽  
Tumor Tissue ◽  
Advanced Colorectal Cancer ◽  
Circulating Tumor Dna ◽  
Plasma Samples ◽  
Kras Mutations ◽  
Clinical Sensitivity ◽  
Colorectal Cancer Patients

654 Background: Acquisition of point mutations in KRAS gene is causally associated with the onset of development of a resistance to anti-EGFR therapy in colorectal cancer. Newly acquired KRAS mutations can be detected in blood plasma months before radiographic detection. The objective of this study was to demonstrate feasibility of an ultrasensitive non-invasive method for detection of KRAS mutations in urine and plasma of patients with advanced colorectal cancer. Methods: Archived, matched urine and plasma samples (stored between 3-5 years prior to ctDNA extraction) from 20 treatment naïve, advanced stage cancer patients with known tumor tissue KRAS mutations determined by an accredited clinical laboratory, were used in a retrospective setting for a blinded concordance study. KRAS status in urine and plasma was compared to that in tumor tissue in order to assess clinical sensitivity of the ctDNA assay. An ultrashort-amplicon (31bp) assay for KRAS mutation enrichment and detection in highly fragmented urinary and plasma ctDNA was developed. The assay detected 1 copy of KRASG12A/C/D/R/S/V or G13D mutant allele in a background of wild-type DNA with a verified analytical sensitivity of 0.007% (7 copies per ~100,000 genome equivalents). Results: In a pilot study of 20 advanced stage colorectal cancer patients, 15 of 16 evaluable archived urine samples (94%) had KRAS mutation that was concordant with tissue biopsy. Of 20 archived plasma samples evaluated, 19 (95%) displayed the KRAS mutation concordant with tumor tissue. Of 16 paired urine and plasma samples, 15 (94%) had concordant KRAS mutation calls. Conclusions: This study demonstrates high clinical sensitivity (≥94%) of concordant KRAS mutation detection between urine, plasma and tissue specimens from advanced colorectal cancer patients. Early detection and monitoring of acquired KRAS mutations in circulating tumor DNA, and in particular urinary ctDNA, opens the possibility of a new paradigm for a truly non-invasive method of individualized care for colorectal cancer patients.

KRAS mutation as a predictor for cause-specific survival in early- versus late-onset colorectal cancer: A United States population-based study.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 580-580
Author(s):  
Albert Y. Lin ◽  
Amanda R Kahl ◽  
Jennifer Y. Pan ◽  
Joshua Lo ◽  
Winifred Tung ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Prognostic Factor ◽  
Kras Mutation ◽  
Late Onset ◽  
Incidence Rates ◽  
Cox Proportional Hazards ◽  
Kras Mutations ◽  
Poor Prognostic Factor ◽  
Rectal Cancers ◽  
Cause Specific Survival

580 Background: While the overall incidence rates for colorectal cancer (CRC) —the third leading cancer diagnosis in the U.S.—have been decreasing over the last several decades, incidence rates for early-onset (EO, age 20-49 years) CRC have shown an upward trend. Multiple studies have documented mutations in KRAS proto-oncogene (KRAS) as a poor prognostic factor in sporadic CRC, but its impact on EO versus late-onset (LO, age > 49 years) CRC is unclear. Methods: Surveillance, Epidemiology, and End Results (SEER) Program data were queried to identify pathologically-confirmed CRC cases tested for KRAS and diagnosed between 2010 and 2015. Demographic, histologic, and KRAS data were compared between EO and LO using Chi-square tests. Kaplan-Meier and Cox proportional hazards models were used to estimate cause-specific survival (CSS) and examine factors associated with CSS. Results: Of 202,173 CRC cases, 3,842 EO and 17,819 LO CRC cases had KRAS testing with a KRAS mutation frequency of 40% and 41%, respectively. Compared with LO tumors harboring mutated KRAS, EO tumors with KRAS mutations were more frequently found in females (52% vs. 45%, P < 0.001), left-sided (LS) or rectal cancers (62% vs. 48%, P < 0.001), stage III/IV (89% vs. 81%, P < 0.001), and grade III/IV (21% vs. 18%, P = 0.038). Compared to CSS in EO with KRAS mutation, LO with KRAS mutation was associated with worse prognosis—with an overall hazard ratio (HR) of 1.21 (95% CI, 1.15-1.27, P < 0.0001). Results [HR (95% CI)] from Cox analyses on the effects of KRAS mutation on CSS, stratified by sidedness, are shown below. Conclusions: Despite EO CRC carrying worse prognostic factors than LO CRC, it confers better CSS than LO CRC. EO CRC is distinct from LO CRC in clinical and pathological features, in addition to its response to mutant KRAS. Mutated KRAS is an independent prognostic factor in LS colon and rectal cancers among the LO, but not in the EO population. [Table: see text]

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