KRAS Mutations In Patients Research Articles

Association between Texture Analysis Parameters and Molecular Biologic KRAS Mutation in Non-Mucinous Rectal Cancer.

PurposeTo evaluate the association between magnetic resonance imaging (MRI)-based texture parameters and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation in patients with non-mucinous rectal cancer.Materials and MethodsSeventy-nine patients who had pathologically confirmed rectal non-mucinous adenocarcinoma with or without KRAS-mutation and had undergone rectal MRI were divided into a training (n = 46) and validation dataset (n = 33). A texture analysis was performed on the axial T2-weighted images. The association was statistically analyzed using the Mann-Whitney U test. To extract an optimal cut-off value for the prediction of KRAS mutation, a receiver operating characteristic curve analysis was performed. The cut-off value was verified using the validation dataset.ResultsIn the training dataset, skewness in the mutant group (n = 22) was significantly higher than in the wild-type group (n = 24) (0.221 ± 0.283; -0.006 ± 0.178, respectively, p = 0.003). The area under the curve of the skewness was 0.757 (95% confidence interval, 0.606 to 0.872) with a maximum accuracy of 71%, a sensitivity of 64%, and a specificity of 78%. None of the other texture parameters were associated with KRAS mutation (p > 0.05). When a cut-off value of 0.078 was applied to the validation dataset, this had an accuracy of 76%, a sensitivity of 86%, and a specificity of 68%.ConclusionSkewness was associated with KRAS mutation in patients with non-mucinous rectal cancer.

Visualizing Human Colorectal Cancer Intratumor Heterogeneity with Phylogeography.

Phylogeography combines ancestry with location and can be translated to intratumor heterogeneity (ITH) to visualize how tumors spread. ITH is common in human tumors, with many genetic and phenotypic differences between regions. The roles of ITH in progression are uncertain because many subclones lack discernable driver mutations. ITH can be visualized by mapping mutations onto microscopic sections, where subclones are directly associated with phenotypes, especially the deeper areas with the more invasive cells that confer worst clinical outcomes. Instead of a stepwise hierarchy where subclones segregate by phenotype with later branching subclones in more invasive areas, multiple subclones share superficial and invasive phenotype and are jigsaw arrayed in vertical columns. Phylogeography shows that both early and late subclones extend from the surface to the invasive front, suggesting that founder cells start with phenotypic plasticity and essentially all the drivers necessary to rapidly grow into large invasive tumors.

Anlotinib Exerts Anti-Cancer Effects on KRAS-Mutated Lung Cancer Cell Through Suppressing the MEK/ERK Pathway.

BackgroundWith a high frequency of 30%, KRAS mutations in patients with non-small cell lung cancer (NSCLC) often lead to their poor response to most anti-cancer therapies. As a multi-target tyrosine kinase inhibitor, Anlotinib shows clinical efficacy against several types of cancer. However, its effects on KRAS mutant NSCLC and the underlying molecular mechanisms remain unclear.Materials and MethodsCell counting Kit-8 assay, colony formation assay, flow cytometry analysis, wound healing scratch assay, Transwell assay and xenograft mouse model were used to evaluate the anti-cancer effects of Anlotinib. The potential molecular mechanisms were determined by immunohistochemistry (IHC) and Western blotting.ResultsAnlotinib inhibited proliferation of KRAS mutant lung cancer cells and induced apoptosis in vitro. In addition, the migration and invasion abilities of these cells were also decreased after treatment with Anlotinib. It significantly suppressed tumor growth in vivo and prolonged the survival of the xenograft-bearing mice, which correlated to lower expression levels of Ki67 in the tumor tissues. Mechanistically, Anlotinib downregulated MEK and ERK as well as their phosphorylated forms in the KRAS mutant lung cancer cells.ConclusionAnlotinib inhibits the growth of KRAS mutant lung cancer cells partly via the suppression of the MEK/ERK pathway. Our findings provide novel insights into treating recalcitrant KRAS mutated NSCLC.

The Impact of KRAS Mutation on the Presentation and Prognosis of Non-Metastatic Colon Cancer: an Analysis from the National Cancer Database

IntroductionApproximately 40% of colorectal cancers have a KRAS mutation. The prognostic significance of KRAS mutations in patients with non-metastatic colon cancer has not been well elucidated. The National Cancer Database (NCDB) was used to analyze factors associated with KRAS mutation as well as its impact on the presentation and survival of patients with stages I–III colon cancer. MethodsThe NCDB was queried to identify patients diagnosed with stages I–III adenocarcinoma of the colon from 2004 to 2015. ResultsA total of 19,877 patients with known KRAS status were identified: mutation rates were 33% in stage I, 35% in stage II, and 38% in stage III patients (p < 0.01). On multivariable analysis, black race and right-sided location were independently associated with KRAS-mutated cancers (all p < 0.01). On univariate analysis for overall survival (OS), KRAS mutation was not significantly associated with a worse 5-year OS for stages I and II patients (p = 0.60 and 0.88, respectively). However, stage III KRAS-mutated colon cancers had a lower OS as compared with KRAS wild type cancers both on univariate and multivariable analysis. Right-sided colon cancers were independently associated with a worse prognosis compared with left-sided lesions (p < 0.01). ConclusionsKRAS-mutated colon cancers were more frequently observed in black patients, right-sided locations, and higher-stage tumors. These mutations had a negative prognostic impact for stage III patients, suggesting that the incorporation of genotypic data into colon cancer staging may help to guide systemic therapy and prognostication of colon cancer patients.

Deep Learning Features Improve the Performance of a Radiomics Signature for Predicting KRAS Status in Patients with Colorectal Cancer

We assess the performance of a model combining a deep convolutional neural network and a hand-crafted radiomics signature for predicting KRAS status in patients with colorectal cancer (CRC). The primary cohort consisted of 279 patients with clinicopathologically confirmed CRC between April 2011 and April 2015. Portal venous phase computed tomographic images were analyzed to extract traditional hand-crafted radiomics features as well as deep learning features. A Wilcoxon rank sum test, the minimum redundancy maximum relevance algorithm, and multivariable logistic regression analysis were used to select features and build a radiomics signature. A combined model was then developed using multivariable logistic regression analysis. An independent validation cohort of 119 patients from May 2015 to April 2016 was used to confirm the combined model's predictive performance. The C-index of hand-crafted radiomics signature's discriminative ability was 0.719 (95% confidence interval, CI: 0.658-0.776) for the primary cohort and 0.720 (95% CI: 0.625-0.813) for the validation cohort. The C-index of the deep radiomics signature's discriminative ability was 0.754 (95% CI: 0.696-0.813) for the primary cohort and 0.786 (95% CI: 0.702-0.863) for the validation cohort. The combined model, which merged the hand-crafted radiomics features and deep radiomics features, achieve a C-index of 0.815 (95% CI: 0.766-0.868) for the primary cohort and 0.832 (95% CI: 0.762-0.905) for the validation cohort. This study presents a model that incorporates the hand-crafted and deep radiomics signature, which can be used for individualized preoperative prediction of KRAS mutations in patients with CRC.

KRAS codon 12 and 13 mutations may guide the selection of irinotecan or oxaliplatin in first-line treatment of metastatic colorectal cancer

ABSTRACTBackground: In this study, we aimed to investigate the frequency, prognostic effect of codon, and amino acid-specific KRAS mutations in patients with metastatic colorectal cancer (mCRC) and their predictive effect on irinotecan and oxaliplatin during first-line treatment.Methods: The data of 304 mCRC patients were retrospectively evaluated between 2010 and 2018. Patients were categorized according to the most prominent codon and amino acid mutation and their prognostic features were analyzed.Results: In total, 274 patients were included in the study and 128 patients (47%) revealed KRAS mutation. Median follow-up time was 19.8 months (range; 1.6–96). The median overall survival rates for patients with codons 12 and 13 mutations were 25.4 and 22.2 months, respectively (p = 0.4). Moreover, the median overall survival for the codon 12 mutant patients who received irinotecan-based chemotherapy in the first-line treatment was 42.7 months, whereas for the codon 13 mutant and KRAS wild-type patients, it was 18.3 and 23.9 months, respectively (codon 12 vs. codon 13; HR: 0.31, p = 0.03, codon 12 vs. wild-type; HR: 0.45, p = 0.03).Conclusion: The significant survival advantage was observed in patients with codon 12 mutations who received irinotecan-based chemotherapy as a first-line treatment.

Prognostic Impact of BRAF and KRAS Mutation in Patients with Colorectal and Appendiceal Peritoneal Metastases Scheduled for CRS and HIPEC

BackgroundKRAS and BRAF mutations are prognostic and predictive tools in metastatic colorectal cancer, but little is known about their prognostic value in patients scheduled for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Therefore, we analyzed the prognostic impact of KRAS and BRAF mutations in patients with peritoneal metastases scheduled for CRS and HIPEC.Patients and MethodsIn a consecutive series of 399 patients scheduled for CRS and HIPEC between 2009 and 2017, 111 subjects with peritoneal metastases from primaries of the appendix, colon, or rectum were analyzed for KRAS mutation and 92 for BRAF mutation.ResultsMutation in KRAS was present in 51/111 (46%), and mutated BRAF was found in 10/92 (11%). There was no difference in overall survival between KRAS mutation tumors and KRAS wild type, whereas BRAF mutation was associated with short survival. No subject with BRAF mutation survived 2 years. On multivariate analysis, completeness of cytoreduction score (CCS, p = 0.000001), presence of signet cell differentiation (p = 0.000001), and BRAF mutation (p = 0.0021) were linked with poor prognosis.ConclusionsBRAF mutation is a marker of poor prognosis in patients with appendiceal and colorectal peritoneal metastases scheduled for CRS and HIPEC, whereas survival outcome in subjects with mutated KRAS does not differ from wild-type KRAS. This finding suggests that those with BRAF mutation should be considered for alternative treatment options.

GEFT protein expression in digestive tract malignant tumors and its clinical significance.

Guanine nucleotide exchange factor T (GEFT), a member of the Rho guanine nucleotide exchange factor family, is expressed in a variety of tumors. In the present study, the expression and clinical significance of GEFT in malignant digestive tract tumors was assessed. Tumor and adjacent control samples from 180 patients were tested. Positive GEFT expression rates were 80, 83.33 and 86.67% in esophageal squamous carcinoma (ESCC), gastric carcinoma (GC) and colorectal cancer (CRC), respectively. GEFT expression was associated with diffuse type carcinoma according to the Lauren classification (χ2=12.525, P=0.002) and tumor-node-metastasis (TNM) stages III/IV (χ2=4.033, P=0.045) in GC, and with vessel carcinoma embolus (χ2=7.890, P=0.005) and lymph node metastasis (χ2=5.455, P=0.020) in CRC, but was not associated with other clinicopathological parameters. Patients with high levels of GEFT protein expression had a less favorable outcome compared with patients with low levels of GEFT expression in patients with CRC (χ2=3.876, P=0.049). However, a significant association was not found between GEFT expression and overall survival in patients with ESCC (χ2=0.040, P=0.842) or GC (χ2=0.501, P=0.479). The rate of human epidermal growth factor receptor 2 upregulation in patients with GC was 13.33% and it was associated with nerve invasion (χ2=4.005, P=0.045) and TNM stages III/IV (χ2=5.600, P=0.018). Mismatch repair protein (MMRP) defect was observed in six cases, and the KRAS mutation rate was 26.67% in patients with CRC. GEFT expression was significantly correlated with MMRP (r=-0.285, P=0.027) and KRAS mutation in patients with CRC (r=0.697, P<0.001). These findings revealed frequent GEFT upregulation in malignant digestive tract tumors, which may have promoted tumor development. GEFT expression in CRC may be associated with microsatellite instability and KRAS mutation status, suggesting that GEFT may be a potential therapeutic target for patients with CRC.

Changes in KRAS mutations in patients with oral mucosa and tongue cancer (OMTC) undergoing medical treatment with cetuximab (Cet).

e17524 Background: Mutations in KRAS are known to be predictors of anti-EGFR therapy efficacy. Besides the mutation status of the treatment-naive tumors the changes in the level of mutant DNA during medical treatment are also of clinical interest for the individualization of the treatment. The purpose of the study was to detect somatic single nucleotide polymorphism (SNP) activating mutations in KRAS exon 2 in patients (pts) with OMTC undergoing chemotherapy (CT)±Cetuximab (Cet). Methods: Extracellular DNA samples were obtained from plasma of pts with OMTC (T3-4No-1Mo) undergoing CT (CDDP+5FU)+Cet (group A) before treatment and in 2 weeks after. Patients undergoing CT (CDDP+5FU, no Cet) were included in Group B. 7 activating mutations in KRAS exon 2 were detected by Droplet Digital PCR method (DD PCR) with "KRAS Screening Multiplex Kit" (BioRad, USA). Results: Samples from 28 pts were included. The frequency of SNP activating in KRAS exon 2 before treatment was 25%. In the group A (n = 12) KRAS mutations were not found or the level of mutant DNA did not exceed 1%. No significant changes were found in this group after treatment. The group B (n = 16) had some KRAS variations the majority of which did not change after treatment. However, 2 pts had a sharp increase in mutant DNA: from 0.03% before CT in both cases to 17.04% and 56.38% -after treatment (p &lt; 0.01). Conclusions: Medical treatment, especially CT, could cause the changes in activating mutations in KRAS exon 2 in pts with OMTC. Revealing of these changes is of great importance for the following treatment options. Detection of mutant extracellular DNA by DD PCR could be valuable to monitor their status during the treatment.

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

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.

Role of KRAS Mutations in Patients with Metastatic Colorectal Cancer Who Receive Regorafenib Plus FOLFIRI as a Salvage Therapy

目的：本研究的目的在於評估KRAS基因的角色在接受regorafenib及irinotecan劑量調整過的FOLFIRI當作救援治療的轉移性大腸直腸癌病人。方法：以單一醫學中心，從2013年10月至2017年6月，總共收錄了21位病人。回顧性的記錄其臨床特徵及以regorafenib及irinotecan劑量調整過的FOLFIRI當作救援治療的療效。其無進展生存期、總生存期依據KRAS基因做出分組分析。結果：經過10.0個月(1.3-38.6個月)中位數追蹤時間，全部病人的中位數無進展生存期及總生存期分別為7.0及10.0個月。疾病控制率為61.9%，其中包含有9.5%的病人疾病程度為部分改善及52.4%為穩定疾病。在KRAS基因野生型及突變型之間，兩個族群的中位數無進展生存期(野生型7.0個月對比突變型5.5個月，p值等於0.494)及中位數總生存期(野生型13.0個月對比突變型9.5個月，p值等於0.249)。兩組病人的性別、年齡、UGT1A1基因型、irinotecan劑量、治療反應、疾病控制率及手足症候群發生率亦均無統計學上的顯著差異。結論：針對轉移性大腸直腸癌病人以regorafenib及irinotecan劑量調整過的FOLFIRI的合併治療可以得到較好的疾病控制率及較長的無進展生存期及總生存期。而KRAS基因野生型的轉移性大腸直腸癌病人在接受此合併療法後顯示出無統計學上差異但仍有較好的治療趨勢。

The Role of KRAS in Endometrial Cancer: A Mini-Review.

Endometrial cancer (EC) is the most common cancer of the female genital tract, resulting annually in 76,000 related deaths worldwide. EC originates either from oestrogen-related proliferative endometrium (type I, endometrioid), or from atrophic endometrium (type II, non-endometrioid). Each type of EC is characterized by different molecular profile alterations. The Kirsten rat sarcoma viral oncogene homolog (KRAS) gene encodes a signalling protein which moderates response to various extracellular signals via down-regulation of the mitogen-activated protein kinase (MAPK) or phosphoinositide-3-kinase/v-akt murine thymoma viral oncogene (PI3K/AKT) pathways. This article reviews the role of KRAS in predicting transition from hyperplastic endometrium to early-stage well-differentiated EC, as well as further invasive proliferation of the tumour to advanced-stage disease. KRAS seems to be directly associated with type I EC, and most studies support its early involvement in carcinogenesis. Current evidence correlates KRAS mutations with increased cell proliferation and apoptosis, as well as up-regulation of endometrial cell oestrogen receptors. Tumours positive for KRAS mutation can harbour hypermethylation-related changes in genome expression, and this can be the cause of concurrent loss of DNA repair proteins. Despite some evidence that KRAS mutation status affects cancer progression, a consensus is yet to be reached. Based on the available evidence, we suggest that screening for KRAS mutations in patients with hyperplastic endometrium or early-stage type I EC, may provide important information for prognosis stratification, and further provision of personalised treatment options.

Role of KRAS Mutations in Patients with Metastatic Colorectal Cancer Who Receive Regorafenib Plus FOLFIRI as a Salvage Therapy

Role of KRAS Mutations in Patients with Metastatic Colorectal Cancer Who Receive Regorafenib Plus FOLFIRI as a Salvage Therapy

Diffusion kurtosis imaging-derived histogram metrics for prediction of KRAS mutation in rectal adenocarcinoma: Preliminary findings.

Although histological examination is the standard method for assessing genetic status, the development of a noninvasive method, which can display the heterogeneity of the whole tumor to supplement genotype analysis, might be important for personalized treatment strategies. To evaluate the potential role of diffusion kurtosis imaging (DKI)-derived parameters using histogram analysis derived from whole-tumor volumes for prediction of the status of KRAS mutations in patients with rectal adenocarcinoma. Retrospective. In all, 148 consecutive patients with histologically confirmed rectal adenocarcinoma who were treated at our institution. DKI was performed with a 3.0 T MRI system using a single-shot echo-planar imaging sequence with b values of 0, 700, 1400, and 2100 sec/mm2 . D, K, and apparent diffusion coefficient (ADC) values were measured using whole-tumor volume histogram analysis and were compared between different KRAS mutations status. Student's t-test or Mann-Whitney U-test, and receiver operating characteristic (ROC) curves were used for statistical analysis. All the percentile metrics of ADC and D values were significantly lower in the mutated group than those in the wildtype group (all P < 0.05), except for the minimum value of ADC and D (both P > 0.05), while K-related percentile metrics were higher in the mutated group compared with those in the wildtype group (all P < 0.05). Regarding the comparison of the diagnostic performance of all the histogram metrics, K75th showed the highest AUC value of 0.871, and the corresponding values for sensitivity, specificity, positive predictive value, and negative predictive value were 81.43%, 78.21%, 77.03%, and 82.43%, respectively. DKI metrics with whole-tumor volume histogram analysis is associated with KRAS mutations, and thus may be useful for predicting the KRAS status of rectal cancers for guiding targeted therapy. 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:930-939.

Comparison of PANAMutyper and PNAClamp for Detecting KRAS Mutations from Patients With Malignant Pleural Effusion.

KRAS is one of the frequently mutated genes in human cancers and often relates with drug resistance and poor prognosis. PANAMutyper™ is a novel technology that integrates PNAClamp™ and PANA S-Melting™. In the present study, PANAMutyper™ and PNAClamp™ were compared for the detection of KRAS mutations using different samples of patients with malignant pleural effusion. A total of 103 patients (including 56 lung adenocarcinoma, 10 lung squamous carcinoma, 17 small cell lung cancer, 3 large cell lung cancer, 3 stomach cancer, 2 ovarian cancer, and others) with malignant pleural effusion were investigated using matched tumor tissue, cell block, and pleural effusion samples. The diagnostic performance of these two methods was compared. KRAS mutations were detected in 18 (17.5%) of 103 patients using tissue, cell block, and pleural effusion samples. All 18 patients with KRAS mutations were detected by PANAMutyper™ using any sample type, however, only 7 cases were detected by PNAClamp™. Among the subtypes of KRAS mutations, substitution in codon 12, 35G>T was the most frequent, followed by substitution in codon 12, 35G>A and codon 12, 34G>A. In pleural effusion specimens, PANAMutyper™ showed a better diagnostic performance compared to PNAClamp™. PANAMutyper™ had a diagnostic superiority for the detection of KRAS mutations in patients with malignant pleural effusion compared to PNAClamp™, although there was a concordance between PANAMutyper™ and PNAClamp™ results. Therefore, PANAMutyper™ can be used for a more sensitive and accurate detection of KRAS mutations.

The Prognostic Impact of KRAS Mutation in Patients Having Curative Resection of Synchronous Colorectal Liver Metastases

Backgroundm-KRAS has been recently reported to be a significant prognostic factor in patients undergoing resection of colorectal liver metastases. This is due to the lack of response to monoclonal epithelial growth factor receptor antibodies, and potentially as a result of a more aggressive tumor biology. MethodsThe National Cancer Database was queried to identify patients with known KRAS status presenting with colorectal cancer and liver metastases who underwent resection of the primary tumor and metastatic disease between 2010 and 2015. ResultsA total of 2655 patients were identified of which 1116 (42%) had m-KRAS. Tumor size, lymph node involvement rates, and margin status of the primary tumor were similar between patients with m-KRAS and wild-type KRAS (wt-KRAS). In the multivariable analysis, African-American race and right-sided colon cancers were independently associated with m-KRAS (both p < 0.001). m-KRAS patients had a significantly lower overall survival (OS) than those with wt-KRAS, with a 3- and 5-year OS of 51 vs. 64% and 31 vs. 42%, respectively (p < 0.001). After adjustment for available prognostic confounders, factors independently associated with worse OS were increasing age, receipt of monoagent chemotherapy, tumor size, positive lymph node, and resection margin status of the primary tumor, right-sided cancers, and m-KRAS. Conclusionsm-KRAS is associated with worse OS in patients presenting with colorectal cancer and liver metastases undergoing resection of the primary tumor and metastatic disease. Right-sided lesions and African-American race were associated with m-KRAS. However, while right-sided remained an independent prognostic factor for OS, race did not.

Urinary cell-free DNA as a prognostic marker for KRAS-positive advanced-stage NSCLC.

KRAS mutations are prevalent in non-small cell lung cancer (NSCLC) but its clinical implications remain to be determined. Continual profiling of KRAS mutations in patients is challenging, and the study aims to determine the potential use of urinary DNA in disease predictions. A total of 150 patients were recruited. To ascertain the clinical relevance of urinary DNA, matched tumor profiles were analyzed. Serial measurements were taken to gauge the reliability of the assay. These results were correlated to overall survival using the Kaplan-Meier estimate. A good overall concordance of 93% (consolidated results from serial measurements) was achieved between tumor tissue and urinary DNA profiling. Of the discordant KRAS cases, we observed subsequent positive detection during monitoring and very low concentrations of mutant DNA. In addition, we noted that KRAS-positive patients detected using urinary DNA have good prognostic utility. Interestingly, we also observed that the trend is highly correlative of the rate of change in KRAS mutant DNA concentrations and the period of monitoring. Urinary DNA offered a non-invasive approach to probe NSCLC dynamics, and in our study we showed that it had predictive capabilities for KRAS-positive patients. Serial monitoring of urinary samples showed that it had a predictive role in identifying patients with worse outcome.

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.

Detection of KRAS Exon 2 Mutations in Circulating Tumor Cells Isolated by the ISET System from Patients with RAS Wild Type Metastatic Colorectal Cancer

INTRODUCTION: The presence of KRAS mutations in patients with metastatic colorectal cancer (mCRC) predicts poor response to agents targeting the EGFR. Even in patients with RAS wild type (WT) tumors, resistance eventually develops due to multiple mechanisms, including the expansion of previously undetected KRAS mutated clones. In this feasibility study, we aimed to detect KRAS exon 2 mutations in serial samples of circulating tumor cells (CTCs) of RAS WT patients with mCRC captured by the Isolation by Size of Epithelial Tumor cells (ISET) system. METHODS: CTC isolation using the ISET system was performed from prospectively collected blood samples obtained from patients with RAS and BRAF WT mCRC prior to first-line therapy initiation, at first imaging assessment and on disease progression. CTCs were enumerated using hematoxylin & eosin and CD45 double stain on a single membrane spot. DNA was extracted from 5 spots and KRAS exon 2 mutations were detected using a custom quantitative Polymerase Chain Reaction (qPCR) assay. RESULTS: Fifteen patients were enrolled and 28 blood samples were analyzed. In 9 (60%) patients, at least one sample was positive for the presence of a KRAS exon 2 mutation. In 11 out of 28 samples (39.2%) with detectable CTCs a KRAS mutation was detected; the corresponding percentages for baseline and on progression samples were 27% and 37.5%, respectively. The most commonly detected mutations were G13D and G12C (n=3). The presence of KRAS mutated CTCs at baseline was not prognostic for either PFS (P=.950) or OS (P=.383). CTC kinetics did not follow tumor response patterns. CONCLUSION: The results demonstrate that using a qPCR-based assay, KRAS exon 2 mutations could be detected in CTCs captured by the ISET system from patients with RAS WT primary tumors. However, the clinical relevance of these CTCs remains to be determined in future studies.

Su1252 - Suitable Liquid Biopsy Samples for Detecting Kras Mutations in Patients with Pancreatic Cancer

Su1252 - Suitable Liquid Biopsy Samples for Detecting Kras Mutations in Patients with Pancreatic Cancer