Impact Of KRAS Mutation Status Research Articles

Real-world impact of KRAS mutations on clinical outcomes in metastatic colorectal cancer treated with trifluridine-tipiracil in the USA.

e15566 Background: Defining the impact of KRAS mutation status on outcomes to standard of care treatments in metastatic colorectal cancer (mCRC) is of increasing clinical relevance. We interrogated a large real-world genomic database to further explore the association between KRAS mutations and benefit to trifluridine-tipiracil (FTD-TPI) in patients with mCRC. Methods: 19,364 patients with mCRC and known KRAS mutation status were analyzed by next-generation sequencing (NextSeq, 592 Genes; NovaSeq, whole exome sequencing (WES)) at Caris Life Sciences. Real-world overall survival (rwOS) and time on treatment (ToT) was inferred from insurance claims data and calculated from time of start of treatment with FTD-TPI to last contact and time from first to last treatment with FTD-TPI with comparison done by the Kaplan-Meier test, respectively. Chi-square test was applied where appropriate, with p-value adjusted for multiple comparisons (p < 0.05). Results: 764 of 10,571 (7.2%) patients with wild-type (WT) KRAS, 768 of 6,984 (11%) with KRAS G12 mutation, and 170 of 1,809 (9.4%) with KRAS G13 mutation received FTD-TPI. Age distribution was similar among groups. Sidedness of primary site was reported in 692 (40.3%) patients; an increased proportion of right-sided tumors was observed in KRAS G12 (53.4% vs. 28.3%, p < 0.0001) and G13 (56% vs 28.3%, p < 0.0001) groups compared to KRAS WT. An increased proportion of TP53 mutations in KRAS WT was observed compared to KRAS G12 mutation (87% vs. 70%, p < 0.0001) and KRAS G13 mutation groups (87% vs. 75%, p < 0.0001). KRAS G12 mutation was associated with shorter median rwOS compared to KRAS WT (7.33 vs. 8.43 months (mo), HR 1.13 (95% CI 1.11-1.42), p = 0.041). KRAS G13 mutation was associated with similar rwOS to KRAS WT. Median ToT was shorter in patients with KRAS G12 mutations than KRAS WT (1.8 vs. 2 mo, HR of 1.22 (95% CI 1.11-1.42), p < 0.001). Median ToT was longer in patients with KRAS G13 versus KRAS G12 (2.3 vs. 1.8 mo, HR 0.82 (95% CI 0.68-0.98), p = 0.032). Conclusions: To our knowledge, this is the largest primarily US-based cohort of mCRC treated with FTD-TPI to be reported. KRAS G12 mutation, but not KRAS G13 mutation, was associated with shorter rwOS and ToT compared to KRAS WT, despite enrichment of TP53 and BRAF mutations in the KRAS WT group. This finding is consistent with previously published analyses of large randomized prospective trials of FTD-TPI in mCRC and further support KRAS mutation status as a predictive biomarker in this setting. [Table: see text]

Assessing the prognostic value of KRAS mutation combined with tumor size in stage I-II non-small cell lung cancer: a retrospective analysis.

KRAS mutation status is a well-established independent prognostic factor in advanced non-small cell lung cancer (NSCLC), yet its role in early-stage disease is unclear. Here, we investigate the prognostic value of combining survival data on KRAS mutation status and tumor size in stage I-II NSCLC. We studied the combined impact of KRAS mutational status and tumor size on overall survival (OS) in patients with stage I-II NSCLC. We performed a retrospective study including 310 diagnosed patients with early (stage I-II) NSCLCs. All molecularly assessed patients diagnosed with stage I-II NSCLC between 2016-2018 in the Västra Götaland Region of western Sweden were screened in this multi-center retrospective study. The primary study outcome was overall survival. Out of 310 patients with stage I-II NSCLC, 37% harbored an activating mutation in the KRAS gene. Our study confirmed staging and tumor size as prognostic factors. However, KRAS mutational status was not found to impact OS and there was no difference in the risk of death when combining KRAS mutational status and primary tumor size. In our patient cohort, KRAS mutations in combination with primary tumor size did not impact prognosis in stage I-II NSCLC.

The Impact of KRAS Mutational Status on Long-Term Survival following Liver Resection for Hilar Cholangiocarcinoma.

Simple SummaryThe reported frequency of KRAS mutations and their prognostic impact in patients resected for hilar cholangiocarcinoma are controversial. The aim of this study was to evaluate the rate of KRAS mutations in a single-center homogeneous population resected for hilar cholangiocarcinoma and the impact on prognosis. The frequency of KRAS mutations was 22.2%. KRAS mutation was not related with pathologic characteristics of the tumor. Patients with a KRAS mutation presented zero 5-year OS that was significantly lower than that observed in patients with KRAS wild type (5-year OS = 49.2%, p = 0.003). In the multivariable analysis, KRAS mutation was an independent strong predictor of poor OS. KRAS mutation analysis should be included in the routine pathologic evaluation of resected hilar cholangiocarcinoma in order to better stratify prognosis.KRAS mutation is reportedly associated with poor prognosis in patients with different cancer types. However, mutational data on hilar cholangiocarcinoma are few and controversial. The aim of this study was to evaluate the rate of KRAS mutations in a single-center homogeneous population resected for hilar cholangiocarcinoma and the subsequent impact on prognosis. KRAS mutation status was evaluated in 54 patients undergoing major hepatectomy combined with resection of the main biliary confluence and regional lymphadenectomy for hilar cholangiocarcinoma between 2001 and 2019. Among these 54 patients, 12 (22.2%) had a KRAS mutation. KRAS mutation was not related with pathologic characteristics of the tumor. Five-year overall survival (OS) in patients with KRAS mutation was significantly lower than that observed in patients with KRAS wild type (0 vs. 49.2%, respectively; p = 0.003). In the multivariable analysis; independent predictors of poor OS were KRAS mutation (HR = 5.384; p = 0.003) and lymph node metastases (HR = 2.805; p = 0.023). The results of our study suggested that KRAS mutation in hilar cholangiocarcinoma was not rarely observed. KRAS mutation was an independent strong predictor of poor OS. KRAS mutation analysis should be included in the routine pathologic evaluation of resected hilar cholangiocarcinoma in order to better stratify prognosis

Molecular Characteristics and the Effect of KRAS Mutation on the Prognosis of Immunotherapy in Non-Small Cell Lung Cancer in Xinjiang, China.

PurposeNon-small cell lung cancer (NSCLC) is a malignant tumor with high mortality. The Kirsten rat sarcoma vial oncogene (KRAS) gene can affect patient prognosis. In this study, we aim to explore the impact of KRAS mutation status on the clinical prognosis of NSCLC immunotherapy.Patients and MethodsCollected tumor samples from the Affiliated Cancer Hospital of Xinjiang Medical University and 220 patients with stage III–IV NSCLC were included the study. All patients are on first- or second-line therapy and not on targeted therapy. Based on the molecular profiles and clinical features, we analysis of the effect of KRAS mutation on the treatment outcome of NSCLC.ResultsIn this study, the main mutant subtypes of KRAS were G12C, G12D, and G12V. In the KRAS mutation group, the highest mutation frequency other than KRAS was TP53, followed by STK11 and KMT2C. We found that among patients received immunotherapy, KRAS-mutant patients were more sensitive to immunotherapy, with an objective response rate (ORR) of 65% and a disease control rate (DCR) of 80%. Survival analysis found that patients with KRAS mutation had better prognosis with immunotherapy than the non-KRAS mutation patients by comparing the overall survival (OS) (median OS: 18.1 months vs 12.2 months, p=0.0032) and progression-free survival (PFS) (media PFS: 7.9 months vs 3.6 months, p=0.01). We found that the patients with KRAS mutation had better prognosis with immunotherapy than with chemotherapy (median OS: 18.1 months vs 12.3 months, p=0.039, PFS 7.9 months vs 4.1 months, p=0.001). Patients with the KRAS G12C mutation had better results with immunotherapy than chemotherapy, but there was no significant difference in outcome between the two groups (OS: p=0.26 PFS: p=0.055). KRAS and TP53 co-mutation and KRAS and KMT2C co-mutation may improve response to immunotherapy.ConclusionOur results suggested that the gene mutation profile of NSCLC in KRAS mutation group and non-KRAS mutation group were different. The patients with KRAS mutation will have better prognosis with immunotherapy.

Impact of KRAS mutation status on the efficacy of immunotherapy in lung cancer brain metastases

Immune checkpoint inhibitors (ICIs) have resulted in improved outcomes in non-small cell lung cancer (NSCLC) patients. However, data demonstrating the efficacy of ICIs in NSCLC brain metastases (NSCLCBM) is limited. We analyzed overall survival (OS) in patients with NSCLCBM treated with ICIs within 90 days of NSCLCBM diagnosis (ICI-90) and compared them to patients who never received ICIs (no-ICI). We reviewed 800 patients with LCBM who were diagnosed between 2010 and 2019 at a major tertiary care institution, 97% of whom received stereotactic radiosurgery (SRS) for local treatment of BM. OS from BM was compared between the ICI-90 and no-ICI groups using the Log-Rank test and Cox proportional-hazards model. Additionally, the impact of KRAS mutational status on the efficacy of ICI was investigated. After accounting for known prognostic factors, ICI-90 in addition to SRS led to significantly improved OS compared to no-ICI (12.5 months vs 9.1, p < 0.001). In the 109 patients who had both a known PD-L1 expression and KRAS status, 80.4% of patients with KRAS mutation had PD-L1 expression vs 61.9% in wild-type KRAS patients (p = 0.04). In patients without a KRAS mutation, there was no difference in OS between the ICI-90 vs no-ICI cohort with a one-year survival of 60.2% vs 54.8% (p = 0.84). However, in patients with a KRAS mutation, ICI-90 led to a one-year survival of 60.4% vs 34.1% (p = 0.004). Patients with NSCLCBM who received ICI-90 had improved OS compared to no-ICI patients. Additionally, this benefit appears to be observed primarily in patients with KRAS mutations that may drive the overall benefit, which should be taken into account in the development of future trials.

Impact of KRAS mutational status on outcomes in patients with pancreatic cancer (PDAC).

4142 Background: KRAS mutations (m) (KRASm) are present in over 90% of pancreatic adenocarcinomas (PDAC) with a predominance of G12 substitutions. KRAS wildtype (WT) PDAC relies on alternate oncogenic drivers, and the prognostic impact of these remains unknown. We evaluated alterations in WT PDAC and explored the impact of specific KRASm and WT status on survival. Methods: WGS and RNAseq were performed on 570 patients (pts) ascertained through our translational research program from 2012-2021, of which 443 were included for overall survival (OS) analyses. This included 176 pts with resected and 267 pts with advanced PDAC enrolled on the COMPASS trial (NCT02750657). The latter cohort underwent biopsies prior to treatment with first line gemcitabine-nab-paclitaxel or mFOLFIRINOX as per physician choice. The Kaplan-Meier and Cox proportional hazards methods were used to estimate OS. Results: KRAS WT PDAC (n = 52) represented 9% of pts, and these cases trended to be younger than pts with KRASm (median age 61 vs 65 years p = 0.1). In resected cases, the most common alterations in WT PDAC (n = 23) included GNASm (n = 6) and BRAFm/fusions (n = 5). In advanced WT PDAC (n = 27), alterations in BRAF (n = 11) and ERBB2/3/4 (n = 6) were most prevalent. Oncogenic fusions (NTRK, NRG1, BRAF/RAF, ROS1, others) were identified in 9 pts. The BRAF in-frame deletion p.486_491del represented the most common single variant in WT PDAC, with organoid profiling revealing sensitivity to both 3rd generation BRAF inhibitors and MEK inhibition. In resected PDAC, multivariable analyses documented higher stage (p = 0.043), lack of adjuvant chemotherapy (p &lt; 0.001), and the KRAS G12D variant (p = 0.004) as poor prognostic variables. In advanced disease, neither WT PDAC nor KRAS specific alleles had an impact on prognosis (median OS WT = 8.5 mths, G12D = 8.2, G12V = 10.0, G12R = 12.0, others = 9.2, p = 0.73); the basal-like RNA subtype conferred inferior OS (p &lt; 0.001). A targeted therapeutic approach following first line chemotherapy was undertaken in 10% of pts with advanced PDAC: MMRd (n = 1), homologous recombination deficiency (HRD) (n = 19), KRASG12C (n = 1), CDK4/6 amplification (n = 3), ERBB family alterations (n = 2), BRAF variants (n = 2). OS in this group was superior (14.7 vs 8.8 mths, p = 0.04), mainly driven by HRD-PDAC where KRASm were present in 89%. Conclusions: In our dataset, KRAS G12D is associated with inferior OS in resected PDAC, however KRAS mutational status was not prognostic in advanced disease. This suggests that improved OS in the WT PDAC population can only be achieved if there is accelerated access to targeted drugs for pts.

Impact of KRAS mutation status on outcomes of metastatic colorectal cancer treated with anti-angiogenic agents: a meta-analysis

The impact of KRAS mutation status on outcomes of metastatic colorectal cancer (mCRC) treated with anti-angiogenic agents is controversial. A total of 4,066 mCRC patients from nine randomized controlled trials (RCTs) were included for analysis. The pooled results showed that the use of anti-angiogenic agents significantly improved progression-free survival (PFS) in mCRC patients with KRAS wide type (HR 0.63, 95%CI: 0.53–0.75, p<0.001) or mutated (HR 0.55, 95%CI: 0.38–0.79, p=0.001). In addition, the use of anti-angiogenic agents significantly improved overall survival (OS) in mCRC patients with KRAS wide type (HR 0.78, 95%CI: 0.70–0.86, p<0.001) or KRAS mutant status (HR 0.87, 95%CI: 0.77–0.98, p=0.018). No publication bias was detected for OS and PFS in mCRC patients. The findings of this study show that the use of anti-angiogenic agents significantly improved PFS and OS in mCRC independent of K-RAS gene status. KRAS gene status does not significantly influence the activity of antiangiogenic agents.

Prognostic Impact of KRAS Mutational Status in Patients with Colorectal Cancer Liver Metastases Differs According to the Location of the Primary Tumor

Prognostic Impact of KRAS Mutational Status in Patients with Colorectal Cancer Liver Metastases Differs According to the Location of the Primary Tumor

Prognostic impact of K-RAS mutational status and primary tumor location in patients undergoing resection for colorectal cancer liver metastases: an update.

Aim: To determine the impact of KRAS mutation status on survival in patients undergoing surgery for colorectal liver metastases (CLM). Patients & methods: Patients with resected CLM and KRAS mutations. Survival was compared between mt-KRAS and wt-KRAS. Results: Of 662 patients, 174 (26.3%) were mt-KRAS and 488 (73.7%) wt-KRAS. mt-KRAS patients had significantly lower recurrence-free survival (HR: 1.42; 95% CI: 1.10-1.84). There were no differences between the groups for sidedness. Poorer survival was associated with mt-KRAS with positive lymph nodes, >1 metastases, tumors >5cm, synchronous tumors and R1-R2. Conclusion: KRAS mutation status can help predict recurrence-free survival. Primary tumor location was not a prognostic factor after resection. KRAS mutation status can help design a multidisciplinary approach after curative resection of CLM.

The ALPPS approach for colorectal liver metastases: impact of KRAS mutation status in survival

The ALPPS approach for colorectal liver metastases: impact of KRAS mutation status in survival

The ALPPS approach for colorectal liver metastases: impact of KRAS mutation status in survival

The ALPPS approach for colorectal liver metastases: impact of KRAS mutation status in survival

P-271 - Prognostic impact of K-RAS mutational status and primary tumour location in patients undergoing resection for colorectal cancer liver metastases: A METHEPAR analysis (multicentre study in Argentina)

P-271 - Prognostic impact of K-RAS mutational status and primary tumour location in patients undergoing resection for colorectal cancer liver metastases: A METHEPAR analysis (multicentre study in Argentina)

187P - Impact of KRAS mutational status and primary tumor location on the efficacy of aflibercept plus FOLFIRI in Japanese patients with metastatic colorectal cancer: An exploratory analysis in a phase II study

187P - Impact of KRAS mutational status and primary tumor location on the efficacy of aflibercept plus FOLFIRI in Japanese patients with metastatic colorectal cancer: An exploratory analysis in a phase II study

The ALPPS Approach for Colorectal Liver Metastases: Impact of KRAS Mutation Status in Survival

Background/Aims: Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations influence survival after hepatectomy for colorectal liver metastases (CRLM). However, their prognostic significance has never been evaluated in patients who undergo Associating Liver Partition and Portal vein occlusion for Staged hepatectomy (ALPPS). Methods: Between June 2011 and March 2016, 26 patients underwent ALPPS for CRLM. Complications were classified according to the Clavien-Dindo classification. Bi- and multivariate cox analyses were performed to evaluate variables potentially associated with survival. Results: Overall, morbidity grade ≥3a and 90-day mortality were 38.5 and 0%, respectively. The median follow-up from the time of discharge was 21.5 months (interquartile range 9.6-35.6). One- and 3-year overall survival (OS) was 83.4 and 48.9%, respectively. Patients with mutated (MT) KRAS had a median OS of 15.3 vs. 38.3 months for those with wild-type (WT) KRAS (p < 0.0001). Median disease-free survival was 7.9, 5.6 vs. 12.3 months for MT and WT KRAS, respectively (p = 0.023). KRAS mutation was found to be an independent risk factor for OS (hazard ratio 7.15, 95% CI 1.50-34.11; p = 0.014). Conclusion: KRAS mutation is an independent predictor of poor survival after ALPPS. This finding will help to optimize patient selection, both avoiding futile surgical indication and maximizing the benefit for patients with extensive disease who are otherwise subjected to high-risk aggressive surgery.

Kras mutation is a marker of worse oncologic outcomes after percutaneous radiofrequency ablation of colorectal liver metastases.

BackgroundKras mutation has been associated with shorter overall survival and time to disease recurrence after resection of colorectal liver metastases (CLM). This study evaluated the prognostic value of Kras mutation in patients with CLM treated by percutaneous radiofrequency ablation (RFA).MethodsThis is an IRB waived retrospective analysis of the impact of KRAS mutation status on oncologic outcomes after CLM RFA. The endpoints were overall survival (OS), local tumor progression (LTP) rates, and incidence of new liver, lung, and peritoneal metastases. Survival times were calculated using Kaplan-Meier methodology from the time of RFA.ResultsThe study enrolled 97 patients. Kras exon 2 mutation was detected in 39% (38/97) of patients. On univariate analysis, Kras mutation (P=0.016) (HR: 1.8; 95% CI: 1.1 – 2.9) was a significant predictor of OS and retained significance on multivariate analysis. Kras mutation was a significant predictor of new liver metastases (P=0.037) (SHR: 2.0; CI: 1.0-3.7) and peritoneal metastases (P=0.015) (sHR: 3.0; 95% CI: 1.2-7.2) on multivariate analysis. Kras mutation was a significant predictor of LTP after RFA of CLM ablated with margins of 1-5 mm (P=0.018) (SHR: 3.0; 95% CI: 1.2-7.7) with an LTP rate of 80% (12/15) versus 41% (11/27) for wild type.ConclusionKras mutation is a significant predictor of overall survival, new liver, and peritoneal metastases after RFA of CLM. A minimal radiographic ablation margin ≥ 6 mm is essential for local tumor control especially for mutant CLM.

207P Impact of K-RAS mutation status on disease behavior and treatment outcome in metastatic colorectal cancer patients

207P Impact of K-RAS mutation status on disease behavior and treatment outcome in metastatic colorectal cancer patients

207P Impact of K-RAS mutation status on disease behavior and treatment outcome in metastatic colorectal cancer patients

207P Impact of K-RAS mutation status on disease behavior and treatment outcome in metastatic colorectal cancer patients

Predictive value of KRAS mutation status in metastatic colorectal cancer (mCRC) patients treated with capecitabine and bevacizumab (CAP-B) maintenance treatment vs observation in the phase III CAIRO3 study.

3525Background: The impact of KRAS mutation status in mCRC treated with anti-VEGF therapy is controversial. The randomized phase 3 CAIRO3 study showed benefit of first-line CAP-B maintenance treatm...

KRAS Mutations in Codon 12 or 13 Are Associated With Worse Prognosis in Pancreatic Ductal Adenocarcinoma

Mutations in the KRAS and P53 genes belong to the most frequently observed genetic alterations in pancreatic ductal adenocarcinoma. The aim of this study was to examine the frequency and prognostic impact of KRAS mutations. In addition, we attempted to define molecular subgroups with distinct biologic behavior by combination of KRAS sequencing data with p53 protein expression data. KRAS mutational analyses were performed in a study group of 153 patients by Sanger sequencing. Immunohistochemistry for p53 was performed on tissue microarrays. KRAS mutations in codon 12 or 13 were found in 68% of cases. Nuclear staining for p53 was detectable in 110 (68%) of 162 evaluable cases. We found no correlation between KRAS mutational status and p53 expression. KRAS mutational status but not p53 immunohistochemistry was an independent prognostic factor in the study group (P = 0.02). In a stratified analysis according to KRAS mutational status, p53 expression failed to define prognostic groups beyond the impact of KRAS mutational status. Our results support the crucial role of KRAS mutational status in pancreatic cancer biology. KRAS mutational status may serve as a prognostic marker. However, its predictive role for targeted therapies remains to be evaluated.

KRAS mutation status-stratified randomized phase II trial of GEMOX with and without cetuximab in advanced biliary tract cancer (ABTC): The TCOG T1210 trial.

4018 Background: Gemcitabine/platinum combination is considered as globally acceptable standard care in patients with ABTC. Two recently published randomized trials showed adding EGFR antagonist, either erlotinib or cetuximab, does not further improve the clinical outcomes of gemcitabine/oxaliplatin (GEMOX)-treated ABTC patients. However, the impact of KRAS mutation status on the results of both studies was not properly addressed. Methods: A prospective, multicenter randomized, phase II trial to evaluate the therapeutic efficacies of adding cetuximab to GEMOX in patients with ABTC, in which eligible patients were stratified by status of KRAS mutation and ECOG PS, and tumor location then randomized to receive either GEMOX (gemcitabine 800 mg/m2, fixed-rate infusion and oxaliplatin 85 mg/m2, i.v., Q 2 weeks) or GEMOX plus cetuximab (500 mg/m2, i.v., Q 2 weeks, C-GEMOX). The primary endpoint was overall response rate (ORR). As an exploratory trial, 120 (60 per arm) patients was estimated to detect a two-tailed 10% difference in ORR (20% in GEMOX and 30% in C-GEMOX) with a significant level of a=0.2 and b=0.5. Results: Between Nov 2010 and May 2012, a total of 122 patients were accrued. The demography was male: 47.5%, median age: 60 y/o, ECOG PS 0/1: 28.7%/71.3%, IHCC/EHCC/GBC: 71.3%/16.4%/12.3%, KRAS mutation: 36.1%, with locally advanced/metastatic diseases: 32.0%/68.0%, and prior surgical resection: 41.8%. On intent-to-treat analysis, the ORR and DCR in the C-GEMOX (N=62) and GEMOX (N-60) arms was 27.3% vs 15.0% (p=0.1223) and 82.2% vs 60.0% (p=0.0090), respectively (Fisher’s exact test); while the median PFS was 7.1 vs 4.0 months (p= 0.0069) and median OS was 10.3 vs 8.8 months (p=0.4057), respectively (log-rank test). Planned subgroup analysis showed the 43 patients with KRAS mutated tumors benefited more from cetuximab therapy, with a DCR of 78.3% vs 38.1% (p=0.0132), median PFS of 7.0 vs 1.9 months (p=0.0351) and median OS of 10.3 vs 6.6 months (p=0.6924). Conclusions: Adding cetuximab significant improves the DCR and PFS of GEMOX in ABTC patients, notably in subpopulation with KRAS mutated tumors. Larger-scale phase III trial is warranted. Clinical trial information: NCT01267344.