KRAS Status Research Articles

Comprehensive data of 4502 patients newly diagnosed with colorectal liver metastasis between 2015 and 2017, and prognostic data of 2427 patients newly diagnosed with colorectal liver metastasis in 2013 and 2014: Third report of a nationwide survey in Japan.

To improve treatment outcomes in patients with colorectal liver metastasis (CRLM), the Joint Committee for Nationwide Survey on CRLM was established by the Japanese Society for Cancer of the Colon and Rectum and the Japanese Society of Hepato-Biliary-Pancreatic Surgery. The aim of the study was to evaluate transition in the characteristics and treatment strategy in CRLM patients and analyze prognostic factors using large-scale data. The present study summarizes the data of patients newly diagnosed between 2015 and 2017 and presents prognostic data of patients newly diagnosed in 2013 and 2014. Survival curves were generated by the Kaplan-Meier method and compared by log-rank test. Multivariate analyses were carried out using Cox proportional hazard modeling. The data of 4502 patients newly diagnosed with CRLM between 2015 and 2017 and the prognostic data of 2427 patients diagnosed in 2013 and 2014 are included. Regarding the 2013 and 2014 prognostic data, the 5-year overall survival (OS) rates of patients who underwent hepatectomy alone was 59.8%. Multivariate analyses identified age at diagnosis of CRLM ≥70 years, concomitant extrahepatic metastasis at diagnosis of CRLM, tumor depth of primary lesion ≥subserosa/pericolic or perirectal tissue, mutant KRAS status, number of CRLM ≥5, maximum diameter of CRLM >5 cm, and surgical curability R1/R2 as independent predictors of OS. Analysis of the latest nationwide database of patients diagnosed with CRLM revealed changes in patients and oncological characteristics, a transition in treatment strategy, and different independent prognosticators to those reported previously.

WIN Symposium 2022 - Abstract Poster Presentations.

WIN Symposium 2022 - Abstract Poster Presentations.

The Impact of KRAS Mutation and PD-L1 Status on Outcomes of Definitive Stereotactic Body Radiation (SBRT) for Stage I Non-Small Cell Lung Cancer (NSCLC)

<h3>Purpose/Objective(s)</h3> Mutational and PD-L1 status of non-small cell lung cancer (NSCLC) correlate with response to systemic therapy. KRAS mutations have been implicated in radio-resistance of both colorectal liver metastasis as well as NSCLC after stereotactic body radiation (SBRT), while the effect of PD-L1 status on outcomes after SBRT is unknown. Here we examine the relationship of these molecular markers on outcomes after SBRT for stage I NSCLC. <h3>Materials/Methods</h3> Reflexive testing for mutations associated w NSCLC (EGFR, ALK, KRAS, ROS1, BRAF, RET, HER2, MET) was gradually implemented at our institution beginning in 2016, followed by PD-L1 testing in 2018, provided biopsy samples were obtained internally and adequate tissue for molecular testing was available. We cross-referenced an institutional database of all patients treated with definitive intent SBRT for stage I NSCLC from 1/2015-12/2020 in order to correlate mutational/PD-L1 testing along with other patient, tumor and treatment factors on local recurrence (LR), disease recurrence (AR) and overall survival (OS) after SBRT. Gray's test was used to compare cumulative incidence rates of LR and AR, and OS rates were compared using the log rank test. No patients received adjuvant systemic therapy of any kind. <h3>Results</h3> 148 patients with known mutational status were identified, of which 62 (41.9%) had known KRAS mutations. Other mutations (EGFR 16, ALK 3, BRAF 9, MET 4, ROS1 1, RET 1, and HER2 0) were identified too infrequently for analysis. PD-L1 status was known for 161 patients and was analyzed in the following groups (0% in 58, 1-49% in 60, and 50-100% in 43 patients) as well as a continuous variable. SBRT regimen was at physician discretion; 34 Gy/1 fx in 30.6%, 48-50 Gy/4-5 fx in 30.6%, 54-60 Gy/ 3 fx in 37.1%, and 60 Gy/8fx in 1.6% of patients. KRAS and PD-L1 groups were balanced for known prognostic factors, except KRAS mutated was a/w higher SBRT dose. At median follow-up of 25.7 months 55% of patients were living. By Gray's test KRAS mutation status was not associated with a difference in LR (2-year cumulative incidence of 1.3% versus 1.6%, p=0.25), AR (2-year cumulative incidence of 27.2% v 24.8%, p=0.70) or OS (5-year survival 44.9% v 49.1%, p=0.34) for wild-type versus mutant status respectively. There was a trend towards higher LR in the PD-L1 0% group with 2y LR of 10.2%, 5.2%, and 2.9% and 5y LR of 19.5, 10.9 and 9.2% in the three PD-L1 groups respectively (P=0.085), however PD-L1 did not correlate with LR as a continuous variable (p=0.15). The PD-L1 1-49% group experienced the lowest risk of 2y AR (28% v 20% v 36%, p=0.11) and greatest 5y OS (37% v 44.% v 28%, p=0.06) however PD-L1 was not correlated to AR (p=0.79) or OS (p=0.25) as a continuous variable. <h3>Conclusion</h3> Unlike prior series suggesting increased LF after SBRT in KRAS mutated adenocarcinoma, KRAS status was not correlated with LF in this series of patients of whom 70% received BED 149 or higher dose SBRT. Whether PD-L1 status is correlated with LR, AR or OS after SBRT for stage I NSCLC requires a larger sample for study.

Immunotherapy combined with chemotherapy improved clinical outcomes over bevacizumab combined with chemotherapy as first-line therapy in adenocarcinoma patients.

No definite conclusion has yet to be reached for the first-line treatment combined with chemotherapy for advanced adenocarcinoma NSCLC patients with negative driver genes. This study sought to compare the clinical outcomes of Beva+ChT and IO+ChT as first-line treatment for this population and investigated whether the statuses of BM, PD-L1 expression, and KRAS and TP53 mutations could influence the results. The clinical data of patients with adenocarcinoma NSCLC who received first-line therapy were retrospectively collected and the patients were assigned to the IO+ChT and Beva+ChT groups. The disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were evaluated between the two groups. The survival effects of BM, PD-L1 expression, and KRAS and TP53 mutations were also evaluated. From April 2018 to October 2020, a total of 105 patients with first-line therapy were included in our analysis; 54 (51.4%) patients were included in the IO+ChT group and 51 (48.6%) patients were included in the Beva+ChT group. The results showed that OS (NR vs. 18.3 m, p= 0.011) and PFS (14.9m vs. 6.3 m, p <0.001) were superior in patients in the IO+ChT group than in patients in the Beva+ChT group. Further analysis revealed that the OS (median OS: NR vs. 14.7 months, p= 0.039) and PFS (median PFS: 18.5 vs. 5.5 months, p< 0.001) advantages of the IO+ChT group were also seen in the PD-L1 > 1% subgroup but were not seen in the PD-L1 < 1%, BM or KRAS mutation subgroups. ICIs combined with ChT improved clinical outcomes over Beva combined with ChT as first-line therapy for adenocarcinoma patients without driver gene alterations, especially in patients with PD-L1 ≥ 1%.

KRAS, NRAS, BRAF, PIK3CA, and AKT1 signatures in colorectal cancer patients in south-eastern Romania.

Somatic mutations in the oncogenes of the epidermal growth factor receptor signaling pathway play vital roles in colorectal carcinogenesis and have been closely linked with clinical resistance to monoclonal therapy. In this study, we have analyzed the mutation frequencies of 5 genes and compared the genetic findings with clinicopathological variables in order to determine diagnostically relevant alterations and compare these findings with those of other studies In our Sanger sequencings, KRAS (exons 2, 3, and 4), NRAS (exons 2, 3, and 4), PIK3CA (exons 9 and 20), BRAF (exon 15), AKT1 (exon 2) genes, and microsatellite instability (MSI) status were analyzed using an ABI 3500 analyzer in a cohort of 58 Romanian colorectal cancer (CRC) patients who underwent surgical resection at Emergency County Clinical Hospital in Constanța, Romania. In our series, mutation rates of KRAS, BRAF, PIK3CA, and AKT1 genes were 39.63%, 8.62%, 6.88%, and 3.44%, respectively. By contrast, we did not find any tumor harboring mutation in the NRAS gene. Notably, the KRAS and PIK3CA mutations were not mutually exclusive, 1 patient harbored 2 mutations in exon2, codon 12 (Gly12Val) of KRAS and exon 20, codon 1047 (His1047Arg) of PIK3CA. The finding of our study are generally consistent with data found in the literature. Regarding to clinicopathological variables, mutation of KRAS was associated with distant metastasis at the time of diagnosis, while mutation of BRAF was significantly associated with MSI-H in contrast with MSI-L/MSS tumors. Moreover, PIK3CA mutation tends to be located in the proximal segment of the colon and to be well/moderately differentiated compared to wild-type tumors. In conclusion, the assessment of these mutations suggests that CRC patients from southeast Romania exhibit a mutation profile similar to other populations. These results could contribute to creating a better method of qualifying patients for molecularly targeted therapies and obtaining better screening strategies.

Practical Implications of KRAS Mutation Status and Sidedness of Primary Tumour in Patients with Colorectal Cancer and Synchronous Liver Metastases: A Subset Analysis of the CoSMIC Study.

Simple SummaryPatients presenting with liver metastases at the time of diagnosis of their colorectal cancer (termed ‘synchronous disease’) have a worse outcome than those whose disease is limited to the primary bowel tumour. There is evidence to show that patients with tumours on the right side of the colon have worse survival. Furthermore, mutations in the KRAS gene have also been shown to adversely affect outcome. This study explores the association between the side of the primary colorectal tumour in patients with synchronous disease and mutations in the KRAS gene on survival. We analyse a specific cohort of patients from the previously published CoSMIC study who presented with colorectal cancer and synchronous liver metastases and who had their colorectal tumour analysed for KRAS mutations. We find that for this cohort, neither mutations in the KRAS gene nor the side of the colon tumour influenced survival.Patients with colorectal cancer presenting with synchronous liver metastases have less favourable outcomes than those with primary-only disease. There is evidence of different genetic mutational signatures according to the sidedness of the primary tumour. KRAS mutations are key driver mutations in colorectal cancer progression. This post hoc analysis of the previously reported CoSMIC inception cohort explores the association between primary tumour sidedness and KRAS mutational status on the outcome of patients with colorectal cancer and synchronous liver metastases. Patients diagnosed with synchronous disease were recruited between April 2014 and March 2017 and, after exclusions, 83 patients undergoing colorectal primary KRAS mutation testing constituted the final study population. Data were collected prospectively on demographic profiles, treatment, and outcomes. Twenty-one patients (25%) had right-sided tumours and 62 (75%) had left-sided tumours, with 46 (55%) and 37 (45%) exhibiting wildtype and mutated KRAS, respectively. There was no difference in distribution of liver metastases by KRAS status (unilobar vs. bi-lobar; p = 0.58; Fisher’s Exact test) and no difference in 5-year survival according to KRAS mutation status (Log-rank test, p = 0.82) or tumour sidedness (p = 0.16). In summary, in this cohort of patients with colorectal cancer and synchronous liver metastases, neither KRAS mutation status nor tumour sidedness influenced survival.

The Prognostic Utilities of DNA Mismatch Repair Status and KRAS and BRAF Mutation in Korean Colorectal Cancer Patients: The KASID Multicenter Study

Introduction: KRAS, BRAF, and DNA mismatch repair (MMR) mutations aid clinical decision-making for colorectal cancer (CRC) patients. To ensure accurate predictions, the prognostic utilities of these biomarkers and their combinations must be individualized for patients with various TNM stages. Methods: Here, we retrospectively analyzed the clinicopathological features of 904 Korean CRC patients who underwent CRC surgery in three teaching hospitals from 2011 to 2013; we also assessed the prognostic utilities of KRAS, BRAF, and MMR mutations in these patients. Results: The overall frequencies of KRAS and BRAF mutations were 35.8% and 3.2%, respectively. Sixty-nine patients (7.6%) lacking expression of ≥1 MMR protein were considered MMR protein deficient (MMR-D); the remaining patients were considered MMR protein intact. KRAS mutations constituted an independent risk factor for shorter overall survival (OS) in TNM stage I–IV and stage III patients. BRAF mutations were associated with shorter OS in TNM stage I–IV patients. MMR-D status was strongly positive prognostic in TNM stage I–II patients. Discussion/Conclusion: To our knowledge, this is the first multicenter study to explore the prognostic utilities of KRAS, BRAF, and MMR statuses in Korean CRC patients. Various combinations of KRAS, BRAF, and DNA MMR mutations serve as genetic signatures that affect tumor behavior; they are prognostic in CRC patients.

Evaluating the time toxicity of cancer treatment in the CCTG CO.17 randomized clinical trial (RCT).

248 Background: Most individual treatments for advanced cancer are associated with modest survival benefits. The time spent in pursuing these treatments can be substantial. We have previously developed a pragmatic and patient-centered metric of these time costs, which we term ‘’time toxicity’’, as any day with physical healthcare system contact. This includes outpatient visits (e.g., for bloodwork, scans, infusions, urgent care), emergency room visits, and overnight stays in a healthcare facility. Herein we sought to assess time toxicity in a completed RCT. Methods: We conducted a secondary analysis of the Canadian Cancer Trials Group CO.17 RCT that evaluated weekly cetuximab infusions vs supportive care alone in 572 patients with advanced colorectal cancer. CO.17 recruited participants in Canada, Australia and New Zealand. Initial results reported a 6-week improvement in median overall survival (OS) with cetuximab (6.1 vs 4.6 months, p = 0.005). Subsequent analyses reported that OS benefit was restricted to and significantly more in patients with K-ras wild-type tumors. We calculated patient-level time toxicity by analyzing treatment, follow-up, and resource utilization forms. We considered a day without physical healthcare contact as a ‘’home day’’. Thus, for a patient, OS was time toxic days + home days. We compared medians of time measures across arms, and stratified results by K-ras status. Results: In the overall population, median time toxic days were higher in the cetuximab arm (28, vs 10, p &lt; 0.001), although median home days were not statistically different (140, vs 121, p = 0.09). The proportion of time toxic days (time toxic days/OS) were significantly more with cetuximab (18%, vs 6%, p &lt; 0.001). Of the 28 time toxic days in the overall cetuximab arm, 14 (50%) were protocol-related (e.g., scheduled infusions etc). Stratified results are in the table. Conclusions: Time toxicity can be extracted through secondary analyses of RCTs. In CO.17, despite an overall OS-benefit with cetuximab, home days were statistically similar across arms. In the K-ras-mutated group, cetuximab was associated with numerically similar OS but more time toxic days. In the K-ras-wild type group, cetuximab was associated with higher home days. Thus, time toxicity data need not always be sobering. Time toxicity measures can supplement traditional survival endpoints in RCTs to guide patient-oncologist decision-making. Cooperative group RCTs are well positioned for such analyses. Clinical trial information: NCT00079066. [Table: see text]

383P An exosome-based liquid biopsy assay for predicting therapeutic outcomes in patients with metastatic colorectal cancer treated with anti-EGFR therapy: Results from prospective, first-line, PULSE and POSIBA trials

Metastatic colorectal cancer (mCRC) remains the third leading cause of cancer-related deaths worldwide. Wild-type (WT) K-RAS status is a major determinant for the efficacy of anti-EGFR therapy; however, as many as 40-60% patients (pts) even with this genetic background do not benefit from these regimens. While circulating cell-free miRNAs (cf-miRNAs) have emerged as an important class of cancer biomarkers, reent data suggests that miRNAs within the tumor-derived exosomal cargo (exo-miRNAs) might offer higher cancer specificity.

1056P KRAS and LKB1 mutation conferring prognostic and predictive role on liquid biopsy in advanced NSCLC

Liquid biopsy (LB) is a feasible tool able to detect genomic alterations in cancer at baseline and also as a longitudinal monitoring to identify resistance mutations. In patients (pts) with mNSCLC, when tissue biopsy remains a difficult procedure, LB might be crucial for therapeutical options, especially in the immunotherapy (IO) and target therapy era. The aim of this bicentric study is to assess the prognostic value of LB in mNSCLC. Data from mNSCLC with any gene alteration/PD-L1 expression were collected at Istituto Nazionale Tumori of Milan and Policlinico Universitario of Naples. Liquid biopsy was performed by 73-gene Guardant360® CDx / 29-gene Archer® LiquidPlex™panels. Effects of circulating genomic alterations on Overall Survival (OS) (from 4-stage diagnosis to death/last FUP) were assessed using Cox proportional hazard model cell free. Kaplan-Meier curves were performed to assess OS between IO and non-IO treatments arms. Of 488 pts underwent LB, most were male (56.9%), former smoker (46.3%), with adenocarcinoma (73.6%) and PD-L1 > 1% (55.6%). 301/488 patients (62.6%) were treated with IO alone or in combination with chemotherapy, in first (47.0%) or second line (102 – 29.2%). In 133 (32.1%) cases, LB was performed at IO baseline, while in 101 (24.5%) cases at IO progression. Among the most relevant genes, STK11+/LKB1+ confers the worst OS (HR for OS 2.12 months, CI 95% 1.26 – 3.56; p = 0.005), regardless treatments. LKB1+/KRAS+ have a poorer OS than LKB1-/KRAS- (OS: 13 vs 24 m, HR 2.34 95% IC 1.19 – 4.61) and LKB1-/KRAS+ (OS: 13 vs 34 m HR 2.99 95% IC 1.36-6.54). When analyzing the effect of KRAS on IO and non-IO arms, KRAS-/IO have the best prognosis compared to KRAS+/non-IO which have the worst prognosis, while KRAS+/IO seems to have a similar prognosis to KRAS-/non-IO pts (HR 0.82 95% IC 0.43 – 1.58). Results reported on LB confirmed previous reports on tissue: STK11+ pts, have the worst prognosis regardless treatments. KRAS+ compare to STK11+/KRAS+ pts and STK11-/KRAS- pts seems to have the best prognosis. IO seems to play a relevant role on survival regardless KRAS status, in fact when using IO the negative prognostic effect of KRAS+ pts decreases and becomes similar to KRAS-/non-IO pts.

EP08.02-088 Mutational Status of KRAS, STK11 and CDKN2A Genes as Predictors of Response to Antiangiogenic Agents in Non-small Cell Lung Cancer Patients

Lung cancer is the leading cause of cancer deaths worldwide. Antiangiogenic agents have been established as one of the various treatment options for this type of tumor. However, it has not been possible to establish a biomarker that allows the selection of patients who will most benefit from this treatment. Recent publications suggest that the response to antiangiogenic agents is influenced by the presence of KRAS, TP53 or STK11/LKB1 gene mutations. The aim of this study was to establish the relationship between the presence of tumor mutations and the response to antiangiogenic agents.

Cytotoxicity of combinations of the pan-KRAS SOS1 inhibitor BAY-293 against pancreatic cancer cell lines

KRAS is mutated in approximately 25% of cancer patients and first KRAS G12C-specific inhibitors showed promising responses. Pancreatic cancer has the highest frequency of KRAS mutations but the prevailing KRAS G12D mutation is difficult to target. Inhibition of the GTP exchange factor (GEF) SOS1—KRAS interaction impairs oncogenic signaling independently of the specific KRAS mutations. In general, cell lines exhibiting KRAS mutations show specific alterations in respect to glucose utilization, signal transduction and stress survival. The aim of this investigation was to check the putative synergy of the SOS1 inhibitor BAY-293 with modulators targeting specific vulnerabilities of KRAS-mutated cell lines in vitro. The cytotoxicity of BAY-293 combinations was tested against MIA PaCa-2 (G12C), AsPC1 (G12D) and BxPC3 (KRAS wildtype) cell lines using MTT tests and calculation of the combination indices (CI) according to the Chou-Talalay method. The results show that BAY-293 synergizes with modulators of glucose utilization, inhibitors of the downstream MAPK pathway and several chemotherapeutics in dependence of the specific KRAS status of the cell lines. In particular, divergent responses for BAY-293 combinations between pancreatic and NSCLC cell lines were observed for linsitinib, superior inhibitory effects of trametinib and PD98059 in NSCLC, and lack of activity with doxorubicin in case of the pancreatic cell lines. Phosphoproteome analysis revealed inhibition of distinct signaling pathways by BAY-293 for MIA PaCa-2 on the one hand and for Aspc1 and BH1362 on the other hand. In conclusion, BAY-293 exhibits synergy with drugs in dependence of the tumor type and specific KRAS mutation.

350P Postoperative histopathological, clinical and molecular risk score for patients with colorectal liver metastases

Hepatic resection is considered the optimal potentially curative treatment for colorectal liver metastases (LM). The Genetic And Morphological Evaluation (GAME) score, which includes KRAS status, tumor burden score, CEA, lymph node metastases and extrahepatic disease, has been proposed as a preoperative tool to select patients (pts) for liver resection. Nevertheless, histological characteristics of LM have been presented as potential prognostic biomarkers to be considered after resection. This study aimed to create a postoperative score including histological characteristics. Clinical and pathological data were collected from 146 metastatic colorectal cancer pts undergoing liver resection between 2004 and 2019 at Hospital de Sant Pau. Histopathological changes in liver parenchyma such as immune phenotype (IP) and histological growth pattern (HGP) were documented to identify potential prognostic factors. We calculated the GAME score of each patient and added the histological characteristics that had a prognostic value in the multivariable analysis. Of the 146 LM analyzed, twenty-three pts had a desmoplastic HGP (16%), thirty-one (22%) had a desertic IP and a fibrotic capsule was described in 22.5% of the cases. In the univariable analysis, the desmoplastic HGP and the fibrotic capsule was associated with a better overall survival (OS) (102 vs 49.3 months, HR 0.44 95% CI 0.23-0.86; p= 0.013 and 89.3 vs 46.9 months; HR 0.56 95% CI 0.33-0.98; p=0.037). The desertic IP was associated with a shorter OS (34.2 vs 58.3 months; HR 1.77 CI 1.1-2.8; p= 0.01) and remained significant in the multivariable analysis (HR 1.95, CI 95% 1.16-3.23; p= 0.012). We added 1 point to the original GAME score if a desertic immune phenotype was observed, and pts were classified in three risk groups with significant differences in survival. The high-risk group (score ≥4) had a recurrence free survival (RFS) and OS of 12.7 and 36.6 months vs 30.7 and 89.3 months in the low-risk group (score 0-1), respectively (p<0.001 and p=0.007). The desertic immune phenotype in liver metastasis of CRC has a bad prognostic value and could be considered to assess adjuvant treatment after hepatic resection.

KRAS mutation status between left- and right-sided colorectal cancer: are there any differences in computed tomography?

To investigate the differences in clinicopathological and imaging features according to KRAS mutation status in left- and right-sided colorectal cancer. A total of 157 patients with pathologically proven colorectal cancer and preoperative contrast-enhanced multidetector CT examinations were enrolled. According to the tumor location and KRAS status, they were divided into two groups: the left-sided colorectal cancer (LCC) group (wild type, mutant type) and the right-sided colorectal cancer (RCC) group (wild type, mutant type). Clinicopathological and imaging features were recorded in each group. The imaging observation indicators included short axis diameter (SAD), longitudinal tumor length (LTL), tumor shape, pericolic fat stranding, bowel stenosis, intratumoral low-density range, enhancement pattern, and bowel obstruction. Univariate and multivariate logistic regression analyses were performed to compare the difference in KRAS mutation status between groups. In the LCC group, SAD, tumor shape, degree of pericolic fat stranding, and bowel obstruction were significant indicators for predicting KRAS status (P < 0.05). In the RCC group, CA19-9, SAD, and intratumoral low-density range were significant indicators for predicting KRAS status (P < 0.05.). The area under the curve (AUC) of the combination image indicators in the LCC group was 0.802 [cutoff point 0.372, 95% confidence interval (CI) 0.718-0.888, sensitivity 85.4%, specificity 72.0%]. The AUC in the RCC group was 0.828 (cutoff point 0.647, 95% CI 0.726-0.931, sensitivity 79.5%, specificity 75.0%). The CT imaging features associated with KRAS mutation status in the LCC and RCC groups were different. The combination of tumor location and imaging features can help to further improve the predictive value of KRAS status.

Deep Neural Network for the Prediction of KRAS Genotype in Rectal Cancer.

KRAS mutation can alter the treatment plan after resection of colorectal cancer. Despite its importance, the KRAS status of several patients remains unchecked because of the high cost and limited resources. This study developed a deep neural network (DNN) to predict the KRAS genotype using hematoxylin and eosin (H&E)-stained histopathological images. Three DNNs were created (KRAS_Mob, KRAS_Shuff, and KRAS_Ince) using the structural backbone of the MobileNet, ShuffleNet, and Inception networks, respectively. The Cancer Genome Atlas was screened to extract 49,684 image tiles that were used for deep learning and internal validation. An independent cohort of 43,032 image tiles was used for external validation. The performance was compared with humans, and a virtual cost-saving analysis was done. The KRAS_Mob network (area under the receiver operating curve [AUC] 0.8, 95% CI 0.71 to 0.89) was the best-performing model for predicting the KRAS genotype, followed by the KRAS_Shuff (AUC 0.73, 95% CI 0.62 to 0.84) and KRAS_Ince (AUC 0.71, 95% CI 0.6 to 0.82) networks. Combing the KRAS_Mob and KRAS_Shuff networks as a double prediction approach showed improved performance. KRAS_Mob network accuracy surpassed that of two independent pathologists (AUC 0.79 [95% CI 0.64 to 0.93], 0.51 [95% CI 0.34 to 0.69], and 0.51 (95% CI 0.34 to 0.69]; p < 0.001 for all comparisons). The DNN has the potential to predict the KRAS genotype directly from H&E-stained histopathological slide images. As an algorithmic screening method to prioritize patients for laboratory confirmation, such a model might possibly reduce the number of patients screened, resulting in significant test-related time and economic savings.

EP-334 The Impact of Combined DNA Repair and Oncogene Mutations in Colorectal Cancer Survival

Abstract Aims To examine the coexistent effect of either KRAS or BRAF gene status with MMR gene status on patient outcomes in a rural population of colorectal cancer patients. Methods Using a colorectal cancer database, results for patient mutation status for mismatch repair genes and other oncogenes, obtained by DNA sequencing and immunohistochemical analysis, were assessed to see if there were significant differences in survival probability in patients with and without single and combined risk factors. Kaplan-Meier survival analyses were performed to examine overall survival probability in the different groups of patients. Results Comparison of survival outcomes in patients with and without KRAS and MLH1 mutations showed a significant difference (p=0.018). Pairwise analysis reveals that this difference is mostly between the group with wild-type status for both genes and a patient with mutant KRAS and EGFR status with wildtype MLH1 status (p=0.062 with bonferroni correction). Combined KRAS and PMS2 status results in a borderline insignificant (p=0.056) survival difference as well. The effects of mutations in other combinations of oncogenes, as well as sex or tumour sidedness and mutation statuses, were not significant on survival probability. Conclusions These preliminary results should be interpreted with caution owing to the relatively small sample size. This study supports previous findings that mutant oncogenes, combined with altered MMR genes can be predictive of colorectal cancer survival outcome.

The Screening and COnsensus Based on Practices and Evidence (SCOPE) Program Results of a Survey on Daily Practice Patterns for Patients with Metastatic Colorectal Cancer-A Swiss Perspective in the Context of an International Viewpoint.

In Switzerland, physicians do not have national guidelines for metastatic colorectal cancer (mCRC) patient care and utilize international versions for management recommendations. Moreover, information about adherence to these guidelines and real-world practice patterns in Switzerland or other countries is lacking. The Screening and COnsensus based on Practices and Evidence (SCOPE) program were designed by an international expert panel of gastrointestinal oncologists to gather real-world insights in the current clinical setting to manage patients with mCRC who have received prior treatment. We sought to understand general practice patterns, the influence of molecular diagnostics (e.g., testing for KRAS, NRAS, BRAF, and MSI), tumor sidedness, and patient-centric factors on treatment selection utilizing in-person surveys and three hypothetical patient case scenarios. Here, we describe and evaluate the Swiss data from the SCOPE program within the context of an international viewpoint and discuss the findings of our analysis. In general, we find that the real-world clinical decisions of Swiss physicians (SWI) closely follow international (INT) recommendations and guidelines, largely paralleling their regional and international counterparts in using the two approved treatments in the third- and fourth-line settings, namely trifluridine-tipiracil and regorafenib. Finally, our data suggest a tendency toward the use of trifluridine-tipiracil (SWI: 79%; INT: 66%) over regorafenib (SWI: 18%; INT: 18%) as the preferred third-line treatment choice in mCRC patients regardless of KRAS status.

Healthy and unhealthy plant‐based diets in relation to the incidence of colorectal cancer overall and by molecular subtypes

BackgroundPlant‐based foods have been recommended for health. However, not all plant foods are healthy, and little is known about the association between plant‐based diets and specific molecular subtypes of colorectal cancer (CRC). We examined the associations of healthy and unhealthy plant‐based diets with the incidence of CRC and its molecular subtypes.MethodsWhile 123 773 participants of the Nurses’ Health Study and the Health Professionals Follow‐up Study had been followed up (3 143 158 person‐years), 3077 of them had developed CRC. Healthy and unhealthy plant‐based diet indices (hPDI and uPDI, respectively) were calculated using repeated food frequency questionnaire data. We determined the tumoural status of microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and BRAF and KRAS mutations.ResultsHigher hPDI was associated with lower CRC incidence (multivariable hazard ratio [HR] comparing extreme quartiles, 0.86, 95% confidence interval [CI]: 0.77, 0.96; P‐trend = .04), whereas higher uPDI was associated with higher CRC incidence (multivariable HR comparing extreme quartiles, 1.16, 95% CI: 1.04, 1.29; P‐trend = .005). The association of hPDI significantly differed by KRAS status (P‐heterogeneity = .003) but not by other tumour markers. The hPDI was associated with lower incidence of KRAS‐wildtype CRC (multivariable HR comparing extreme quartiles, 0.74, 95% CI: 0.57, 0.96; P‐trend = .004) but not KRAS‐mutant CRC (P‐trend = .22).ConclusionsWhile unhealthy plant‐based diet enriched with refined grains and sugar is associated with higher CRC incidence, healthy plant‐based diet rich in whole grains, fruits and vegetables is associated with lower incidence of CRC, especially KRAS‐wildtype CRC.

Assessment of KRAS and NRAS status in metastatic colorectal cancer: Experience of the National Institute of Oncology in Rabat Morocco

Introduction: RAS status is a predictive biomarker for anti-EGFR response in metastatic colorectal cancer (mCRC). The Idylla technology (IT) is a fully automated molecular testing system based on real-time PCR and provides rapid results in a very short preparation time. In this study, we aimed to evaluate the full RAS mutation status in Moroccan patients with mCRC.

Mutation of KRAS in colorectal adenocarcinoma in Greenland

KRAS mutation is one of the most frequent driver mutations in colorectal cancer (CRC) and is also a prognostic biomarker. The aim of the present study was to determine the frequency of KRAS mutations over time in the Greenlandic population diagnosed with CRC. In total, 578 patients with the diagnosis of adenocarcinoma between 1988 and 2017 were identified. The status of KRAS and the mutational subtypes of KRAS mutations were determined in 102 representative samples by the Idylla™ platform in the time periods 1988-1990, 2002-2004, and 2015-2017. The results showed that the frequency of the KRAS mutations increased significantly, from 27% in 1988-1990 to 43% in 2015-2017 (p < 0.001). Furthermore, the most frequent subtypes of KRAS mutations in Greenland were G12D (c.35G > A) with 14%, G12V (c.35G > T) with 7%, and G13D (c.38G > A) with 6%. In conclusion, this study showed that the frequency of KRAS mutations in CRC has been increasing in recent decades in the specific population of Greenland. The results of this study may be used in initiatives related to targeted therapy of CRC in specific ethnicities and in investigations focusing on the environmental factors of cancer-related somatic mutations.