Types Of KRAS Mutations Research Articles

Multi-targeting of K-Ras domains and mutations by peptide and small molecule inhibitors.

K-Ras activating mutations are significantly associated with tumor progression and aggressive metastatic behavior in various human cancers including pancreatic cancer. So far, despite a large number of concerted efforts, targeting of mutant-type K-Ras has not been successful. In this regard, we aimed to target this oncogene by a combinational approach consisting of small peptide and small molecule inhibitors. Based on a comprehensive analysis of structural and physicochemical properties of predominantly K-Ras mutants, an anti-cancer peptide library and a small molecule library were screened to simultaneously target oncogenic mutations and functional domains of mutant-type K-Ras located in the P-loop, switch I, and switch II regions. The selected peptide and small molecule showed notable binding affinities to their corresponding binding sites, and hindered the growth of tumor cells carrying K-RasG12D and K-RasG12C mutations. Of note, the expression of K-Ras downstream genes (i.e., CTNNB1, CCND1) was diminished in the treated Kras-positive cells. In conclusion, our combinational platform signifies a new potential for blockade of oncogenic K-Ras and thereby prevention of tumor progression and metastasis. However, further validations are still required regarding the in vitro and in vivo efficacy and safety of this approach.

A multicenter phase II trial to assess the efficacy and safety of bevacizumab plus mFOLFOX6 as induction chemotherapy toward R0 surgical resection in advanced colorectal liver metastases with mutant-type KRAS: NEXTO-mt trial.

450 Background: The oncological benefit of bevacizumab plus mFOLFOX6 in advanced colorectal liver metastases (CRLMs) in terms of conversion to curative resection remains unknown. This multicenter phase II trial aimed to evaluate the efficacy and safety of bevacizumab plus mFOLFOX6 as induction chemotherapy for advanced CRLMs harboring mutant-type KRAS. Methods: Patients who had advanced CRLMs (tumor number of ≥5 and/or technically unresectable) harboring mutant-type KRAS were included in this study. The induction chemotherapy of bevacizumab plus mFOLFOX6 was administered and assessed for resectability every 4 cycles. If the unresectable CRLMs were converted to be resectable, liver resection was planned after a waiting period of 4–6 weeks and followed by postoperative chemotherapy up to 12 cycles. The primary endpoint was R0 resection rate. The secondary endpoints were safety, recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS). The trial was conducted following approval from the Institutional Ethics Review Board of all institutions and registered in the University Hospital Medical Information Network Clinical Trials Registry (registration number: UMIN000009530). Results: Between February 2013 and December 2017, 29 patients from six centers were enrolled in this trial. The rates of complete and partial responses were 0% and 62.1%, respectively. R0 and R1 resections were performed in 19 and 1 patient, respectively (R0 resection rate: 65.5%). No mortality after liver resection occurred. During the median follow-up of 30.7 months (range, 7.2–82.6 months), the median OS for the 29 patients was 49.1 months. The 3-year PFS and OS rates were 7.4%, and 64.4%, respectively. The 3-year RFS rate was 10.0% in 20 patients who achieved R0 or R1 resections. Conclusions: Bevacizumab plus mFOLFOX6 achieved a high R0 resection rate with a favorable survival for patients with advanced CRLMs harboring mutant-type KRAS. Clinical trial information: UMIN000009530.

Characterization With KRAS Mutant Is a Critical Determinant in Immunotherapy and Other Multiple Therapies for Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is a frequent type of cancer, which is mainly characterized clinically by high aggressiveness and high mortality. KRAS oncoprotein is the most common molecular protein detected in NSCLC, accounting for 25% of all oncogenic mutations. Constitutive activation of the KRAS oncoprotein triggers an intracellular cascade in cancer cells, leading to uncontrolled cell proliferation of cancer cells and aberrant cell survival states. The results of multiple clinical trials have shown that different KRAS mutation subtypes exhibit different sensitivities to different chemotherapy regimens. Meanwhile, anti-angiogenic drugs have shown differential efficacy for different subtypes of KRAS mutated lung cancer. It was explored to find if the specificity of the KRAS mutation subtype would affect PD-L1 expression, so immunotherapy would be of potential clinical value for the treatment of some types of KRAS mutations. It was discovered that the specificity of the KRAS mutation affected PD-L1, which opened up immunotherapy as a potential clinical treatment option. After several breakthrough studies, the preliminary test data of many early clinical trials showed that it is possible to directly inhibit KRAS G12C mutation, which has been proved to be a targeted treatment that is suitable for about 10%–12% of patients with advanced NSCLC, having a significant impact on the prolongation of their survival and the improvement of their quality of life. This article reviews the latest progress of treatments for NSCLC with KRAS mutation, in order to gain insight into the biological diversity of lung cancer cells and their potential clinical implications, thereby enabling individualized treatment for patients with KRAS-mutant NSCLC.

Prevalence and type of KRAS mutations in endometrial endometrioid carcinoma

Prevalence and type of KRAS mutations in endometrial endometrioid carcinoma

Selected Articles from This Issue

Dysregulation of the protein arginine methyltransferase 5 (PRMT5) is associated with lymphomas, lung cancers, and breast cancers. In this First Disclosure, Brehmer and colleagues outline JNJ-64619178, an inhibitor of PRMT5 with potent anti-proliferative activity. JNJ-64619178 occupies the SAM and substrate pockets of PRMT5, trapping it in a catalytically inactive state. PMRT5 inhibition by JNJ-64619178 increased alternatively spliced events and resulted in the killing of primary AML samples ex vivo. Taken together, the results support the continued clinical study of JNJ-64619178 (NCT03573310).The approval of Trastuzumab deruxtecan demonstrates the potency of the DNA topoisomerase I inhibitor DXd in antibody-drug conjugates (ADCs). DXd-ADCs exhibit a short systemic half-life and ability to optimize the drug-antibody ratio. In this First Disclosure, Okajima and colleagues outline the design of another DXd-containing ADC targeting Trophoblast cell surface antigen 2 (TROP2). Datopotamab deruxtecan is designed to have a shorter half-life than sacituzumab govitecan, a TROP2-directed ADC approved by the FDA for TNBC. Dato-DXd showed potent anti-tumor activity and was absent of severe gastrointestinal toxicity. The results support the first-in-human phase 1 study for patients with advanced solid tumors (NCT03401385).Chromosome region maintenance 1 is overexpressed in ovarian cancer and its inhibition has been shown to achieve a 30% disease control rate in recurrent disease. Here, Handley and colleagues seek to enhance the effects of selinexor through synergistic drug combinations. Their screen found the PARP inhibitor olaparib as the most likely candidate. Selinexor decreased the expression of DNA damage repair proteins, generating an increased susceptibility to PARP inhibitors. The combination reduced tumor nodules and weight in vivo in a mouse model. Their results outline an actionable combination for advanced ovarian cancer patients.The advent of KRAS inhibitors, as well as the disagreement between retrospective studies in immunotherapy and KEYNOTE-189, demonstrate the need to characterize the KRAS mutational landscape of non-small cell lung cancer (NSCLC). Therefore, Judd and colleagues sequenced 592 genes from 17,095 NSCLC specimens to assess co-occuring genomic alterations, tumor mutational burden (TMB), and PD-L1 expression. They demonstrate the rate of co-mutation depends on the KRAS mutation type. Mutated KRAS was significantly increased in PD-L1 expression compared to wild type, with KRAS G12C the most likely to be PD-L1 positive. These studies inform future therapeutic intervention for KRAS-mutated NSCLC.

Characterization of KRAS Mutation Subtypes in Non-small Cell Lung Cancer.

KRAS is the most commonly mutated oncogene in NSCLC and development of direct KRAS inhibitors has renewed interest in this molecular variant. Different KRAS mutations may represent a unique biologic context with different prognostic and therapeutic impact. We sought to characterize genomic landscapes of advanced, KRAS-mutated non-small cell lung cancer (NSCLC) in a large national cohort to help guide future therapeutic development.Molecular profiles of 17,095 NSCLC specimens were obtained using DNA next-generation sequencing of 592 genes (Caris Life Sciences) and classified on the basis of presence and subtype of KRAS mutations. Co-occurring genomic alterations, tumor mutational burden (TMB), and PD-L1 expression [22C3, tumor proportion score (TPS) score] were analyzed by KRAS mutation type.Across the cohort, 4,706 (27.5%) samples harbored a KRAS mutation. The most common subtype was G12C (40%), followed by G12V (19%) and G12D (15%). The prevalence of KRAS mutations was 37.2% among adenocarcinomas and 4.4% in squamous cell carcinomas. Rates of high TMB (≥10 mutations/Mb) and PD-L1 expression varied across KRAS mutation subtypes. KRAS G12C was the most likely to be PD-L1 positive (65.5% TPS ≥ 1%) and PD-L1 high (41.3% TPS ≥ 50%). STK11 was mutated in 8.6% of KRAS wild-type NSCLC but more frequent in KRAS-mutant NSCLC, with the highest rate in G13 (36.2%). TP53 mutations were more frequent in KRAS wild-type NSCLC (73.6%).KRAS mutation subtypes have different co-occurring mutations and a distinct genomic landscape. The clinical relevance of these differences in the context of specific therapeutic interventions warrants investigation.

P59.20 Natural History of KRAS Mutant Non-Small-Cell Lung Cancer in the Immunotherapy Era: A Single-Centre Retrospective Study

KRAS mutated NSCLC represents the main subgroup of oncogene-addicted tumors. Relevantly the clinical behaviour of patient with different types of KRAS mutations may differ. In this retrospective real-world cohort, we report about clinical characteristics and survival data of patients with KRAS-mutation positive advanced NSCLC diagnosed at our Institution.

Prognostic Value of KRAS Gene Mutation on Survival of Patients with Peritoneal Metastases of Colorectal Adenocarcinoma.

Objective The main objective of the study was to determine the effect of the presence of mutation in the KRAS gene on the survival in patients with colorectal cancer (CRC) and peritoneal metastases (PM). Materials and Methods A retrospective cohort study was performed. Patients diagnosed with CRC with synchronous or metachronous PM between January 2006 and December 2019 were included. Data on the histopathological, clinical, and treatment factors were collected. The effect of each variable on survival was evaluated by Cox regression. Results A total of 149 patients were included (64 women (43%) and 85 men (57%); mean age, 63 years). The long-term survival rate at 36 months was 24% (median, 21 months). KRAS mutation was detected in 75 patients (50.3%). Kaplan–Meier analysis estimated that likelihood of survival was higher in patients with wild-type KRAS tumours (35%) than in mutated-type KRAS (14%) (median: 28 vs. 15, respectively) (P=0.001). Within the categories into which the peritoneal cancer index (PCI) was classified, survival at 36 months depended on the KRAS status. Survival in wild-type KRAS tumours with PCI 1–10 was 71% and with PCI 11–20 was 26%, while in mutant-type KRAS tumours, survival was 41% and 4%, respectively (P=0.025). In the multiple regression analysis, the KRAS mutation was revealed to have an independent prognostic value (HR: 2.144; 95% CI: 1.342–3.424). Conclusion The mutational status of the KRAS gene has demonstrated a strong association with survival and prognostic utility in patients with CRC with PM.

1250P Differences of immune microenvironment among NSCLC patients with various KRAS mutation types

KRAS is the most common oncogenic driver in NSCLC. Researchers previously reported that only KRAS mutation and KRAS co-mutated with STK11 define distinct subgroups of NSCLC, which response differently to immune checkpoint inhibitors (ICI). Herein, by means of evaluating the tumor immune microenvironment (TME) and some biomarkers, to explore the mechanism of different efficacy of ICI showed in these subgroup of Chinese NSCLC patients.

Tumor microenvironment-adjusted prognostic implications of the KRAS mutation subtype in patients with stage III colorectal cancer treated with adjuvant FOLFOX

Several studies have reported that the prognostic effect of KRAS mutations on colorectal cancers (CRCs) varies depending on the type of mutation. Considering the effect of KRAS mutations on tumor microenvironment, we analyzed the prognostic significance of KRAS mutation types after adjusting for the tumor-infiltrating lymphocytes (TIL) and tumor-stromal percentage (TSP) statuses. In two independent cohorts, KRAS mutations were analyzed by Sanger sequencing and/or next-generation sequencing. TIL density and the TSP were quantified from whole-slide immunohistochemical images. KRAS-mutant CRCs were divided into three subgroups (G12D/V, other codon 12 mutations and codon 13 mutations) to examine their differential effect on TIL density, the TSP and recurrence-free survival (RFS). Among the KRAS mutations, only the G12D/V subgroups showed significantly less TIL infiltration than the wild-type CRCs. According to survival analysis, G12D/V mutations were associated with short RFS; codon 13 mutations showed discordant trends in the two cohorts, and other codon 12 mutations showed no significant association. Multivariate analysis further supported the prognostic value of G12D/V mutations. This result is not only consistent with a recent study suggesting the immunosuppressive effect of mutant KRAS but also provides insight into the type-specific prognostic effect of KRAS mutations.

P86.18 Prevalence, Clinical Characteristics and Survival of Patients with KRAS Mutant Lung Cancer in Argentina.

Between 20-35% of lung adenocarcinomas harbor a KRAS gene mutations (KRASm), most commonly in codon 12. With the development of KRAS G12C covalent inhibitors as novel targeted therapies in this population, there is renewed interest in understanding the clinical features and outcomes of patients with KRAS mutant non-small cell lung cancer (NSCLC) worldwide. Clinical and pathologic data were collected for patients with KRAS mutant lung cancer in two academic hospital, CEMIC and Hospital Italiano de Buenos Aires (HIBA) in Argentina. Molecular profiling of tumor samples was done in a cohort of patients using targeted next generation sequencing (NGS) with Oncomine Focus Assay (ThermoFisher) at both institutions (CEMIC/HIBA). Patients with KRAS mutational status assessed by PCR/sanger sequencing at CEMIC were also included. We estimated the prevalence and type of KRAS mutations using both testing methods. We estimated the overall survival (OS) of patients from the date of metastatic disease diagnosis using Kaplan-Meier. The prevalence of KRAS mutations using NGS was 23% (35/150) and was 19% (16/84) using PCR/sanger sequencing. The prevalence of KRAS G12C was 10,6% (16/150) with NGS and 6% (5/84) using sanger sequencing. KRAS G12C accounted for 41% of KRAS mutations in the entire cohort of, followed by G12V (24%), G12D (8%), G13C (6%) and G12A (6%), G12S (4%), G13D (4%), G13S (4%), Q61H (2%) and one commutation (2%). In the 51 patients with KRASm NSCLC included, the median age (IQR) was 66 years (61-72.5), there was a higher proportion of male patients (65%) and smoking history (94%), and the most tumor histology was adenocarcinomas (94%). In total, 39 patients had metastatic disease of which 90% received treatment. First line treatment included chemotherapy (n=33, 94%), immunotherapy (n=2, 6%). 20 patients (51%) received second line treatment with immunotherapy (n=15) and chemotherapy (n=5). With a follow up median of 38 months (IC 95%: 21.6-47.9), the median overall survival of patients with metastatic disease was 14.2 months (IC 95%: 7.7-30.3). KRAS mutations occur in about 23% of patients with NSCLC and KRAS G12C mutations in 10.6% of patients using NGS. This is similar to previously reported data in other western countries, and higher than reported in overall in Latin America. Extensive molecular profiling of lung cancer can identify potentially targetable KRAS G12C mutations and help to select a subgroup of patients that can benefit with clinical trials targeting KRAS.

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

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

BRAF and KRAS mutations in papillary thyroid carcinoma in the United Arab Emirates.

BackgroundPapillary thyroid carcinoma (PTC) is the most common malignant thyroid neoplasm comprising 80–90% of all thyroid malignancies. Molecular changes in thyroid follicular cells are likely associated with the development of PTC. Mutations in serine/threonine-protein kinase (BRAF) and Rat sarcoma viral oncogene homolog (RAS) are commonly seen in PTC.MethodsIn total, 90 cases of PTC are randomly selected from archive paraffin blocks and 10μm sections were cut and processed for DNA extraction. BRAF V600E mutation and 8 types of KRAS mutations were investigated using Real Time PCR.ResultsBRAF V600E mutation was identified in 46% of PTC while KRAS mutations were seen in 11% of PTC. There was significant correlation between BRAF V600E mutation and PTC larger than 5cm in diameter, positive surgical margin and lymph node metastasis. BRAF V600E mutation was significantly higher in patients with less than 55-year of age than those more than 55-year of age. BRAF V600E mutation was significantly higher in patients with family history of thyroid cancer than those without. There was no significant difference in BRAFV600E mutation between males and females, PTC classic and follicular variants, unifocal and multifocal PTC. There was a significant higher percentage of BRAF V600E mutation in classic PTC than papillary microcarcinoma variant. There was no significant age, gender, histologic type, tumor size, lymph node metastasis, tumor focality, and surgical margin status differences between KRAS mutated and non-mutated PTC.ConclusionBRAF V600E and KRAS mutation are seen in a significant number of PTC in the UAE. BRAF mutation is significantly correlated with large tumor size, positive surgical margins and lymph node metastasis suggesting an association between BRAF V600E mutation and tumor growth and spread.

Abstract C058: Vitamin C preferentially induces growth inhibition and cell death in KRAS G12D-mutant pancreatic cancer cells

Abstract Vitamin C (L-Ascorbic acid, VC), an anti-oxidant has been studied as the possible potent chemotherapeutic drug in various cancers including colorectal cancer, breast cancer, ovarian cancer, prostate cancer and lung cancer. In particular, it is recently reported that VC kills efficiently colorectal cancer cells with KRAS or BRAF mutations. Give fact that pancreatic cancer has high frequency of KRAS mutation rate and is one of the most aggressive and lethal cancers with lack of effective therapy targeting the KRAS mutations, we would like to investigate whether VC effectively kills pancreatic cancer cells with various types of KRAS mutation. We first tested cytotoxicity and cell growth inhibition effect of VC on pancreatic cancer cell lines. In growth inhibition and colony formation assay, VC showed differential effect on cell growth and colony formation according to the KRAS genotypes. Treatment of the pancreatic cancer cell lines harboring KRAS G12D mutation with VC resulted in marked decrease of cell survival and colony formation, while same treatment of the cell lines with other KRAS mutations or wild type had no growth inhibitory effect. Interestingly, although there was no dramatic difference in well-known VC transporters, Glut1 expression according to the KRAS genotypes, sodium-dependent vitamin c transporter 2 (SVCT2) expression was relatively lower in KRAS G12D-mutant pancreatic cancer cells than other cells. To study possible mechanisms of VC-induced growth inhibition and cell death, we also tested whether glycolysis was inhibited or not though extracellular acidification rate (ECAR) measurement. After 1mM VC injection, ECAR decreased dramatically in KRAS G12D-mutant pancreatic cancer cells compared to the other genotypes. In cell cycle phospho-antibody array analysis, the results indicated that VC significantly increased the expression of DNA damage-associated proteins. Finally, we also found that cell death measured by apoptosis increased in KRAS G12D-mutant pancreatic cancer cells with VC through annexin V-PI staining FACS analysis. In conclusion, we showed VC selectively induces the apoptosis and cell growth inhibition in KRAS G12D-mutant pancreatic cancer cells than other KRAS mutations by inhibition of glycolysis and induction of DNA damage-associated proteins. Our findings suggest that VC is needed to further investigate as the potential novel agent with cytotoxic chemotherapies for the treatment of pancreatic cancer. Citation Format: Hye-Lim Jang, Jung Yong Hong, Seung Tae Kim, Jeeyun Lee, Se Hoon Park, Young Suk Park, Ho Yeong Lim, Won Ki Kang, Joon Oh Park. Vitamin C preferentially induces growth inhibition and cell death in KRAS G12D-mutant pancreatic cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C058. doi:10.1158/1535-7163.TARG-19-C058

Kirsten Rat Sarcoma Viral Oncogene Homologue (KRAS) Mutations in the Occurrence and Treatment of Pancreatic Cancer.

Pancreatic cancer is a highly malignant tumor with a 5-year survival rate of less than 6%, and incidence increasing year by year globally. Pancreatic cancer has a poor prognosis and a high recurrence rate, almost the same as the death rate. However, the available effective prevention and treatment measures for pancreatic cancer are still limited. The genome variation is one of the main reasons for the development of pancreatic cancer. In recent years, with the development of gene sequencing technology, in-depth research on pancreatic cancer gene mutation presents that a growing number of genetic mutations are confirmed to be in a close relationship with invasion and metastasis of pancreatic cancer. Among them, KRAS mutation is a special one. Therefore, it is particularly important to understand the mechanism of the KRAS mutation in the occurrence and development of pancreatic cancer, and to explore the method of its transformation into clinical tumor molecular targeted treatment sites, to further improve the therapeutic effect on pancreatic cancer. Therefore, to better design chemical drugs, this review based on the biological functions of KRAS, summarized the types of KRAS mutations and their relationship with pancreatic cancer and included the downstream signaling pathway Raf-MEK-ERK, PI3K-AKT, RalGDS-Ral of KRAS and the current medicinal treatment methods for KRAS mutations. Moreover, drug screening and clinical treatment for KRAS mutated cell and animal models of pancreatic cancer are also reviewed along with the prospect of targeted medicinal chemistry therapy for precision treatment of pancreatic cancer in the future.

P2.01-67 Are KRAS Mutations Predictive of Response to Immunotherapy in Non Small-Cell Lung Cancer? A Single Center Experience

Lung cancer is the leading cause of cancer-related mortality. In the last decade, the treatment landscape has evolved for non-small-cell lung cancer (NSCLC), in large part thanks to two therapeutic advances: targeted therapy for oncogene driven tumours and immune checkpoint-inhibitors (ICI). The latter can lead to very long survival, but only in a limited number of patients. Post-hoc analyses and preclinical data suggest KRAS mutated NSCLC may respond better to ICI. We retrospectively analysed all stage IV NSCLC patients treated in our center with immunotherapy from January 2016 to December 2017 and compared KRAS mutated to wildtype patients. The clinical outcomes analysed were disease control rate (DCR), partial response (PR), progression free survival (PFS) and overall survival (OS). We performed an exploratory analysis on the impact of KRAS mutation type and concurrent mutations. 45 patients treated with ICI. 7 were excluded due to insufficient data. 38 were included. 27 patients (71%) with nivolumab, 9 patients (24%) with pembrolizumab and 2 patients (5%) with atezolizumab. 22 patients (58%) were male and 16 (42%) female. The median age was 63. 21 patients (55%) presented KRAS mutations, of which 4 (19%) had concurrent p53 mutations and 1 (5%) an EGFR mutation. 17 patients (45%) were KRAS wild-type, of which 4 (24%) had EGFR mutations and 1 (6%) had a BRAF V600E mutation. In the KRAS mutated subgroup 59% were male and 41% were female, the median age was 61 years and all patients had PS 0-1. All patients received second line immunotherapy except for 2, one in third line, one fifth line. In the intention to treat population (ITT) the DCR was 71% with 55% PR, PFS was 11.3 months, and OS 17.7 month. In the KRAS wild-type subgroup DCR was 59% with 49% PR, the PFS was 8.4 months and OS 16.8 months. In the KRAS mutated subgroup, DCR was 81%, with 62% PR, PFS was 13.6 months and OS 18.5 months. An exploratory analysis based on KRAS mutation types or co-mutations was performed. The average PFS for G12C, G13C, G12V, G61H and other mutations was 19.1, 7.8, 9.4, 2.2, 13.9 months respectively. PFS for p53 co-mutated KRAS NSCLC was 23.5 months. Further analyses for STK11 co-mutations are ongoing, as these confer resistance to ICI. At the time of analysis 7 patients were still receiving immunotherapy. In our retrospective study, KRAS mutations in NSCLC were predictive of numerically superior response to ICI compared to wildtype patients. Currently, the data is conflicting and larger clinical trials are needed to clarify this hypothesis and ascertain whether and how KRAS should be part of the treatment algorithm for the selection of ICI patients. Furthermore, more research is needed to confirm the potential role of mutation types and clinical impact of co-mutations in KRAS.

KRAS Mutation as Predictor Factor in Locally Advanced Rectal Cancer

Introduction: Standard treatment of locally advanced rectal cancer (LARC) includes neoadjuvant chemo-radiotherapy followed by total mesorectal excision (TME). The role of KRAS as a biomarker in rectal cancer remains equivocal. We evaluate the Tumor Regression Grade (TRG), Relapse-Free Survival (RFS) and Overall Survival (OS) according to the KRAS oncogene status in LARC. Material and Method: We evaluated the KRAS status in 23 patients with LARC. Tumor DNA was obtained from pretreatment biopsy tissues. Results: KRAS mutation was found in 30,4% of the patients. TRG (1-2) after CRT were 56,2% and 42,8%, for wild-type and mutant KRAS groups (p= NS). After a median follow-up of 31 months, there was no difference in RFS (47,7 vs 23,3 months) or OS (51,5 vs 30 months) between wild-type and mutant-type KRAS groups, respectively. Conclusions: Although KRAS status seems to have slightly better prognosis in LARC, it does not reach significant results (probably due to insufficient sample) in TRG, RFS or OS.

Multiple KRAS mutations in the non-mucinous epithelial lining in the majority of mucinous cystic neoplasms of the pancreas.

Mucinous cystic neoplasms (MCNs) of the pancreas are cystic neoplasms lined by mucinous lining epithelium (MLE) with associated ovarian-type stroma. Although a non-MLE (NMLE) can be observed in some MCNs, whether cystic neoplasms with ovarian-type stroma and NMLE should be classified as MCNs or separately designated is debated. To test this, NMLEs were defined as flat or cuboidal epithelial cells without intracytoplasmic mucin. A total of 112 MCNs were reviewed, and the epithelium was classified as NMLE or MLE. A total of 110 females and two males with a mean age of 46.5±12.3years were included in this study. At least focal NMLE was noted in 76.8% (86/112) of MCNs. The mean percentage of the neoplastic epithelium that was NMLE in these 86 cases was 46%. NMLE was predominant (>50%) in 38.4% (43/112) of cases. MCNs with NMLE were smaller (42±21mm) than those with MLE (60±36mm, P<0.001), and all NMLEs had low-grade dysplasia. Twelve MCNs with NMLE or MLE were selected for KRAS mutation analysis with droplet digital polymerase chain reaction after laser capture microdissection. All 12 MCNs showed multiple types of KRAS mutation, which were detected in 92% (11/12) of NMLE foci and 89% (8/9) of MLE foci. Predominant NMLE was common in small MCNs with low-grade dysplasia. Clonal KRAS mutations were observed in both NMLE and MLE, supporting the hypothesis that MCNs with NMLE should be classified as MCNs.

Chemotherapy in KRAS-mutated chemotherapy naive non-small cell lung cancer patients: A phase III comparing cisplatin-pemetrexed with carboplatin-paclitaxel-bevacizumab: NVALT 22 (NCT02743923).

TPS9127 Background: In a retrospective analysis of KRAS mutated non-small cell lung cancer (NSCLC) patients response and progression free survival (PFS) to first line chemotherapy was better for carboplatin-paclitaxel-bevacizumab then other first line combinations (Mellema Lung Cancer, 2015:90:249-54). Methods: Trial Design: Multi-center open label randomized phase III study. After stratification for KRAS mutation (G12V versus G12C versus other), performance status (0-1 vs. 2) and brain metastasis (yes of no) patients will be 1:1 randomized to carboplatin-paclitaxel-bevacizumab or cisplatin-pemetrexed q3wks for up to six cycles. Continuation maintenance with bevacizumab and pemetrexed is allowed until progression. Study population: histologically or cytologically confirmed stage IIIB or stage IV KRAS mutated NSCLC patients who are eligible for platinum-based chemotherapy and are chemotherapy naïve. Previous anti-PD(L1) therapy for advanced disease is allowed (amendment 25.1.2018). Response will be assessed according to RECIST 1.1, CT scans will be made every 6 weeks until progression. Blood and archival tissue will be optionally collected for translational research. This may help to identify subgroups of patients who are likely better treated with a specific treatment regimen. Statistical analysis: The trial was designed to demonstrate superiority of the carboplatin-paclitaxel-bevacizumab treatment over cisplatin-pemetrexed with an assumed hazard ratio of 0.67. In total 201 events are required for the final analysis, corresponding to a total sample size of 240 patients to be accrued. There is a single interim analysis planned after 101 events have been observed. Primary endpoint: PFS defined by the response criteria in solid tumors (RECIST) and assessed by independent review. Secondary endpoints: Overall response rate, Overall Survival, outcome according to type of KRAS mutation, response assessed by CRABB criteria. Study progress: Currently 25 sites are open across the Netherlands and 170 of the 240 required patients are randomized (February 12, 2019). Clinical trial information: NCT02743923.

SUVmax and metabolic tumor volume: surrogate image biomarkers of KRAS mutation status in colorectal cancer.

PurposeThe objective of this study was to explore the association between KRAS mutation status and PET/CT metabolic parameters in colorectal cancer (CRC) patients.Materials and methodsOne hundred and sixty-four CRC patients were enrolled in this study and received PET/CT examination before operation, then KRAS mutation status was analyzed through pathologically confirmed CRC samples. The association between tumor clinical characteristics and PET/CT metabolic parameters, including maximum standardized uptake value (SUVmax), SUVmean, and metabolic tumor volume (MTV), and KRAS mutation status was analyzed using chi-squared tests, Mann–Whitney U tests, and logistic regression analysis.ResultsThe KRAS mutation type patients exhibited high MTV and high SUVmax using a threshold of 17.8 cm3 and 8.7 respectively and the predictive accuracy was 0.772 and 0.603 respectively. High MTV (P=0.001; 95% CI: 1.119–1.296) and high SUVmax (P=0.048; 95% CI: 0.564–0.985) were independent predictors for KRAS mutation status.ConclusionMTV and SUVmax were associated with KRAS mutation type in CRC patients. PET/CT metabolic parameters can be used for supplementing KRAS mutation status prediction in CRC patients.