Prevalence Of KRAS Mutations Research Articles

Additional impact of genetic ancestry over race/ethnicity to prevalence of KRAS mutations and allele-specific subtypes in non-small cell lung cancer

KRAS mutation is the most common oncogenic driver in patients with non-small cell lung cancer (NSCLC). However, the detailed understanding of how self-reported race and/or ethnicity (SIRE), genetically inferred ancestry (GIA), and their interaction affect KRAS mutation is largely unknown. Here, we investigated the associations between SIRE, quantitative GIA, and KRAS mutation and its allele-specific subtypes in a multi-ethnic cohort of 3918 patients from the Boston Lung Cancer Survival cohort and the Chinese OrigiMed cohort with an independent validation cohort of 1450 patients with NSCLC. This comprehensive analysis included detailed covariates including age at diagnosis, sex, clinical stage, cancer histology, and smoking status. We report that SIRE is significantly associated with KRAS mutations, modified by sex, with SIRE-Asian patients showing lower rates of KRAS mutation, transversion substitution, and the allele-specific subtype KRASG12C compared to SIRE-White patients, after adjusting for potential confounders. Moreover, GIA was found to correlate with KRAS mutations, where patients with a higher proportion of European ancestry had an increased risk of KRAS mutations, especially more transition substitutions and KRASG12D. Notably, among SIRE-White patients, an increase in European ancestry was linked to a higher likelihood of KRAS mutations, whereas an increase in Admixed American ancestry was associated with a reduced likelihood, suggesting that quantitative GIA offers additional information beyond SIRE. The association of SIRE, GIA, and their interplay with KRAS driver mutations in NSCLC highlights the importance of incorporating both into population-based cancer research, aiming to refine clinical decision-making processes and mitigate health disparities.

The genomic, transcriptomic, and immunological profile of patients with recurrent/refractory NSCLC.

8039 Background: Lung cancer is the leading cause of cancer-related deaths worldwide, and often presents at advanced stages, with > 50% of patients presenting as stage III or IV. Patients with recurrent stage III NSCLC (R/R) previously treated with definitive chemoradiation and immunotherapy consolidation may have a difference in overall survival compared to de novo stage IV (DN). In this study, we aim to compare the molecular and immune landscapes of these two patient populations to identify potential genomic patterns and biomarkers of resistance. Methods: 3728 NSCLC specimens underwent sequencing of DNA (592-gene panel or whole exome) or RNA (whole transcriptome) or immunohistochemistry at Caris Life Sciences (Phoenix, AZ). Patients were classified as R/R (n = 26) if they received Durvalumab and chemoradiation within 12 months (m) before tissue collection and treated with Pembrolizumab within 6 m after tissue collection. Patients treated with Pembrolizumab within 6 months after tissue collection and had no prior (or post) treatment with Durvalumab and chemoradiation at any point in time were classified as DN (n = 3702). Tumor microenvironment (TME) cell fractions were estimated from bulk RNA sequencing using QuanTIseq. Significance was determined using chi-square, Mann Whitney U and adjusted for multiple comparisons where applicable (q < 0.05). Results: TP53 (91 vs 68%) and KEAP1 (30 vs. 14%, both p < 0.05, q > 0.05) mutation prevalence was higher in R/R, whereas a decreased prevalence of KRAS mutations was noted in this group (13 vs. 33%) as compared to the DN group. Compared to DN patients, R/R patients were associated with an increased prevalence of mutations in BCL2 (4.3 vs. 0%, q < 0.05), BCL9 (4.3 vs. 0.2%, q < 0.05), HNF1A (4.3 vs. 0.2%), TNFAIP3 (4.3 vs. 0.2%), AKT1 (4.3 vs. 0.4%), MAP3K1 (4.3 vs. 0.5%), and SPEN (4.3 vs. 0.6%; all p < 0.05, q > 0.05). Further, copy number amplification of NUTM1 (4.5 vs. 0%), SMO (4.3 vs. 0.5%), CHIC2 (4.5 vs. 0.2%; all q < 0.05), PIK3CA (9 vs. 1.2%) and FLCN (4.5 vs. 0.3%; both p < 0.05, q > 0.05) was more common in R/R compared to DN. R/R TME was associated with decreased B cell (2.9 vs 4.4%, q < 0.05) and regulatory T cell fractions (1.3 vs. 2.6%, p < 0.05, q > 0.05). Conclusions: R/R patient tumors had distinct molecular alterations and immune landscapes, including an increased prevalence of biomarkers associated with immunotherapy resistance ( TP53 and KEAP1 mutations) and lower tumor B- and T reg- cell fractions, which may suggest decreased likelihood of response to immunotherapy compared to patients with DN NSCLC. The RR population had a lower-than-expected percentage of KRASmutations. These distinct molecular differences highlight the need for NGS testing in the recurrent setting, despite initial NGS testing at diagnosis. Molecularly targeted interventions may be options in the future for patients with R/R Stage III NSCLC.

Clinical and Genomic Landscape of RAS Mutations in Gynecologic Cancers.

We aimed to describe RAS mutations in gynecologic cancers as they relate to clinicopathologic and genomic features, survival, and therapeutic implications. Gynecologic cancers with available somatic molecular profiling data at our institution between February 2010 and August 2022 were included and grouped by RAS mutation status. Overall survival was estimated by the Kaplan-Meier method, and multivariable analysis was performed using the Cox proportional hazard model. Of 3,328 gynecologic cancers, 523 (15.7%) showed any RAS mutation. Patients with RAS-mutated tumors were younger (57 vs. 60 years nonmutated), had a higher prevalence of endometriosis (27.3% vs. 16.9%), and lower grades (grade 1/2, 43.2% vs. 8.1%, all P < 0.0001). The highest prevalence of KRAS mutation was in mesonephric-like endometrial (100%, n = 9/9), mesonephric-like ovarian (83.3%, n = 5/6), mucinous ovarian (60.4%), and low-grade serous ovarian (44.4%) cancers. After adjustment for age, cancer type, and grade, RAS mutation was associated with worse overall survival [hazard ratio (HR) = 1.3; P = 0.001]. Specific mutations were in KRAS (13.5%), NRAS (2.0%), and HRAS (0.51%), most commonly KRAS G12D (28.4%) and G12V (26.1%). Common co-mutations were PIK3CA (30.9%), PTEN (28.8%), ARID1A (28.0%), and TP53 (27.9%), of which 64.7% were actionable. RAS + MAPK pathway-targeted therapies were administered to 62 patients with RAS-mutated cancers. While overall survival was significantly higher with therapy [8.4 years [(95% confidence interval (CI), 5.5-12.0) vs. 5.5 years (95% CI, 4.6-6.6); HR = 0.67; P = 0.031], this effect did not persist in multivariable analysis. RAS mutations in gynecologic cancers have a distinct histopathologic distribution and may impact overall survival. PIK3CA, PTEN, and ARID1A are potentially actionable co-alterations. RAS pathway-targeted therapy should be considered.

Abstract 2151: Additional impact of genetic ancestry over self-reported race/ethnicity to prevalence of KRAS mutations and allele-specific subtypes in non-small cell lung cancer

Abstract Background: KRAS mutation is the most common oncogenic driver in patients with non-small cell lung cancer (NSCLC). However, the interplay between self-reported race and/or ethnicity (SIRE) and genetically inferred ancestry (GIA) on KRAS mutations and allele-specific subtypes is largely unknown. Methods: A total of 3918 NSCLC patients from the Chinese OrigiMed (OM) cohort (n=2039) and Boston Lung Cancer Survival (BLCS) cohort (n=1879) were included, all of whom had baseline covariates including age, sex, clinical stage, SIRE, histology and smoking status. KRAS mutation and subtypes were determined by targeted NGS panels in each cohort, and KRAS mutation outcomes, including KRAS mutation, KRAS subtypes, and KRAS transversion and transition were analyzed. GIA was inferred from paired germline data for patients in the BLCS cohort. Multivariable and multinomial logistic regressions were employed to assess the associations between SIRE, GIA and KRAS outcomes. Results: In the entire cohort, 804 (20.5%) patients harbored KRAS mutation, with a considerably higher prevalence of 31.5% observed in BLCS compared to 10.4% in OM cohort. Patients with self-identified Asian was associated with a significantly lower rate of KRAS mutation (OR = 0.44, 95% CI:0.22 - 0.81, P = 0.01), transversion substitutions (OR = 0.24, 95% CI:0.10 - 0.62, P = 0.003) and KRASG12C (OR = 0.17, 95% CI:0.04 - 0.72, P = 0.02) compared to SIRE-White patients after adjusting for confounders including smoking status, sex and histology. The association of SIRE and KRAS driver mutation was further modified by sex, with Asian women demonstrating lower risk compared to Asian men, while the opposite trend was observed in SIRE-White patients. Increased European ancestry was associated with a higher risk of KRAS mutation (OR per 10% increase = 1.05, 95% CI:1.00 - 1.09, P = 0.03), particularly with more transition substitutions (OR per 10% increase = 1.10, 95% CI:1.01 - 1.21, P = 0.03) and KRASG12D (OR per 10% increase = 1.18, 95% CI:1.04 - 1.34, P = 0.01). This association was even more pronounced in patients of increased Northern European ancestry. Furthermore, even among SIRE-White patients, a 10% increase in European ancestry was associated with an additional 6% increase in the likelihood of KRAS mutations (OR = 1.06, 95% CI: 1.01 - 1.12, P = 0.03), while a 10% increase in Admixed American ancestry was associated with a 6% decreased likelihood of KRAS mutations (OR = 0.94, 95% CI: 0.88 - 0.99, P = 0.04). Results were validated in an independent cohort of 1450 patients. Conclusion: Self-reported race/ethnicity and genetic ancestry are both associated with KRAS driver mutations and allele-specific subtypes of NSCLC. This work highlights the significance of integrating both into population-based cancer research, aiming to refine clinical decision-making processes and mitigate health disparities. Citation Format: Xinan Wang, Kangcheng Hou, Biagio Ricciuti, Joao V. Alessi, Xihao Li, Federica Pecci, Rounak Dey, Jia Luo, Mark M. Awad, Alexander Gusev, Xihong Lin, Bruce E. Johnson, David C. Christiani. Additional impact of genetic ancestry over self-reported race/ethnicity to prevalence of KRAS mutations and allele-specific subtypes in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2151.

Prevalence of K-RAS mutation in carcinoma gallbladder-a cross-sectional observational analysis

Prevalence of K-RAS mutation in carcinoma gallbladder-a cross-sectional observational analysis

RAS/RAF/MAPK Pathway Mutations as Predictive Biomarkers in Middle Eastern Colorectal Cancer: A Systematic Review.

This review article aims to investigate the prevalence and spectrum of rat sarcoma (RAS) and V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF) mutations, and their connection with geographical location, clinicopathological features, and other relevant factors in colorectal cancer (CRC) patients in the Middle East. A systematic literature review, employing the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework, was conducted to investigate the association between the frequency of relevant mutations and the descriptive clinicopathological characteristics of CRC patients. Multiple electronic databases, including PubMed, Science Direct, Web of Science, Scopus, and Google Scholar, were searched to analyze the relevant literature. A total of 19 eligible studies comprising 2960 patients with CRC were included in this review. A comprehensive analysis of the collected literature data as well as descriptive and methodological insights is provided. Men were predominant in reviewed studies for the region, accounting for 58.6%. Overall, RAS mutation prevalence was 38.1%. Kirsten RAS Viral Oncogene Homolog (KRAS) mutations were the most common, accounting for 37.1% of cases and distributed among different exons, with the G12D mutation being the most frequent in exon 2 (23.2%) followed by G12V (13.7%), G13D (10.1%), G12C (5.1%), G12A (5.04%), and G12S (3.6%). Neuroblastoma RAS Viral Oncogene Homolog (NRAS) mutations were identified in 3.3% of tumor samples, with the most common mutation site located in exons 2, 3, and 4, and codon 61 being the most common location for the region. The total mutation frequency in the BRAF gene was 2.6%, with the V600E mutation being the most common. The distribution patterns of RAS and BRAF mutations among CRC patients exhibit notable variations across diverse ethnic groups. Our study sheds light on this phenomenon by demonstrating a higher prevalence of KRAS mutations in CRC patients from the Middle East, as compared with those from other regions. The identification of these mutations and geographical differences is important for personalized treatment planning and could potentially aid in the development of novel targeted therapies. The distinct distribution patterns of RAS and BRAF mutations among CRC patients across different ethnic groups, as well as the regional variability in mutation prevalence, highlight the need for further research in this area.

Focusing on colorectal cancer in young adults (Review).

Colorectal cancer (CRC) ranks as the third leading cause of cancer-related mortality worldwide. Recent years have witnessed an increase in the incidence of CRC among adults <50 years old on a global scale. The increased incidence is associated with several modifiable risk factors, including obesity, type II diabetes, physical inactivity and frequent antibiotic use. In younger individuals, haematochezia and abdominal pain are the most common symptoms, predominantly affecting the left-side colon. While certain cases of early-onset CRC (eoCRC) are associated with a genetic predisposition, the majority result from sporadic mutations in the genes APC, KRAS, BRAF and TP53, which trigger uncontrolled cell proliferation and tumour formation. Colorectal carcinogenesis involves three major pathways: The chromosomal instability (CIN), microsatellite instability and CpG island methylator phenotype pathways. Dysregulation of the CIN pathway accounts for 85% of sporadic cases of eoCRC. Notably, eoCRC exhibits a distinctive molecular profile, characterized by a decreased prevalence of BRAF mutations, an increased prevalence of KRAS mutations and LINE-1 hypomethylation, and involvement of the Microsatellite and Chromosomal Stable pathway. Prevention strategies for eoCRC primarily centre on lifestyle modifications and the development of screening programs targeting younger populations. Further exploration into the molecular mechanisms involved in the identification of novel risk factors associated with eoCRC is imperative. These efforts, in conjunction with the development of specific screening strategies, hold the potential to reduce morbidity and mortality in the future.

Abstract C063: Frequency and spectrum of KRAS mutations in lung adenocarcinoma from Black/African American and White/European patients

Abstract Lung cancer is the most common cause of cancer death in the United States and a major source of cancer health disparity. Lung cancer incidence and mortality rates are higher in Black/African American (B/AA) men than in men from other racial/ethnic groups. Lung adenocarcinoma, arising in the alveoli or air sacs of the lung, is the most common subtype of lung cancer in all ethnic/racial groups. Genetic driver mutations can differ among racial/ethnic groups, in the identity of the mutated genes, their mutation frequencies, and the spectrum of mutations for each given gene. In addition, the same mutation could have different effects depending on an individual patient’s genetic background, resulting in differential responses to therapies. Therefore, it is important to identify the frequency and spectrum of driver mutations in different population groups. Protooncogenes from the RAS family, KRAS, NRAS, and HRAS, play a crucial role in cell growth regulation, cell proliferation, and survival. KRAS is frequently mutated in numerous cancer types, including lung adenocarcinoma, and has been reported to be the driver gene in ~30% of lung adenocarcinomas from White/European (W/E) patients. Due to the much lower number of lung cancer samples analyzed from B/AA patients, it has been unclear if the KRAS mutational frequency and spectrum in B/AA lung adenocarcinoma patients differs from that in W/E patients. Here we collected available existing data sets with mutational information on KRAS muations in lung adenocarcinoma from B/AA and W/E patients. We obtained data for 1555 B/AA and 13840 White lung adenocarcinoma patients. While B/AA lung adenocarcinoma patients had a lower prevalence of KRAS mutations (27% vs. 35%) than W/E patients, (χ2 p-value= 5.877e-10), KRAS was still the most frequently mutated cancer driver gene in both groups. The most common KRAS mutations in both B/AA and W/E patients were alterations of glycine 12 to cysteine (G12C), valine (G12V), aspartic acid (G12D), and alanine (G12A), as well as glutamine 61 to histidine (Q61H) and glycine 13 to cysteine (G13C). Given that a substantial proportion of lung adenocarcinoma patients carry a mutated KRAS gene, investigating new potential KRAS-targeting therapies remains especially urgent. To this end, we are investigating polyisoprenylated cysteinyl amide inhibitors (PCAIs), a group of potential cancer therapy agents designed to specifically disrupt and suppress hyperactive G-protein signaling, as caused by mutated RAS proteins. We are testing PCAI efficiacy on B/AA and W/E lung adenocarcinoma cell lines carrying various KRAS mutations. Citation Format: Daniel J. Mullen, Pablo E. Puente, Christopher Leon, Diana I. Romero, Kweku Ofosu-Asante, Yong Huang, Nazarius S. Lamango, Ite A. Offringa. Frequency and spectrum of KRAS mutations in lung adenocarcinoma from Black/African American and White/European patients [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C063.

Prevalence of KRAS G12C Mutation and Co-mutations and Associated Clinical Outcomes in Patients With Colorectal Cancer: A Systematic Literature Review.

A systematic literature review was conducted to estimate the global prevalence of Kirsten rat sarcoma virus gene (KRAS) mutations, with an emphasis on the clinically significant KRAS G12C mutation, and to estimate the prognostic significance of these mutations in patients with colorectal cancer (CRC). Relevant English-language publications in the Embase, MEDLINE, and the Cochrane Library databases (from 2009 to 2021) and congress presentations (from 2016 to 2021) were reviewed. Eligible studies were those that reported the prevalence and clinical outcomes of the KRAS G12C mutation in patients with CRC. A total of 137 studies (interventional [n = 8], post hoc analyses of randomized clinical trials [n = 6], observational [n = 122], and longitudinal [n =1]) were reviewed. Sixty-eight studies reported the prevalence of KRAS mutations (KRASm) in 42 810 patients with CRC. The median global prevalence of KRASm was 38% (range, 13.3%-58.9%) and that of the KRAS G12C mutation (KRAS G12C) 3.1% (range, 0.7%-14%). Available evidence suggests that KRASm are possibly more common in tumors that develop on the right side of the colon. Limited evidence suggests a lower objective response rate and inferior disease-free/relapse-free survival in patients with KRAS G12C compared with patients with KRASwt or other KRASm. Our analysis reveals that KRAS G12C is prevalent in 3% of patients with CRC. Available evidence suggests a poor prognosis for patients with KRAS G12C. Right-sided tumors were more likely to harbor KRASm; however, their role in determining clinical outcomes needs to be investigated further.

P-373 Insights of the prevalence of KRAS mutations in a real life population cohort of colorectal cancer based in north of Portugal

P-373 Insights of the prevalence of KRAS mutations in a real life population cohort of colorectal cancer based in north of Portugal

Tumor mutational burden (TMB) in real-world patients with pancreatic ductal adenocarcinoma (PDAC): Differences in genomic alterations (GA) and predictive value for immune checkpoint inhibitor (ICI) effectiveness.

4146 Background: Currently, ICI therapy is recommended for patients with metastatic PDAC whose tumors exhibit dMMR, MSI-H, or high TMB (≥10 mutations/Mb). However, due to the low prevalence of high TMB in PDAC (~1%), few studies have evaluated the role of ICI therapy in this subpopulation. This study aimed to compare GA between PDAC patients with high TMB and low TMB ( &lt; 10 mutations/Mb) and to evaluate the effectiveness of ICIs in real-world PDAC patients by TMB status. Methods: This study included PDAC patients who underwent genomic testing using Foundation Medicine tissue comprehensive genomic profiling (CGP) assays. GA were compared between tissue specimens with high and low TMB by chi-squared, adjusted for multiple comparisons. Patient clinical data was obtained by the US-wide de-identified Flatiron Health and Foundation Medicine real-world clinicogenomic pancreatic database (CGDB), originated from ~280 US cancer clinics between 01/2011 and 09/2022. Real-world overall survival (OS) and time to treatment discontinuation (TTD) were compared between patients receiving an ICI (high TMB versus low TMB) and between patients with high TMB (ICI versus other therapies) by Cox models. Results: We included 21,932 patients with PDAC with tissue CGP data available; 98.7% with low TMB and 1.3% with high TMB. Among actionable alterations, patients with high TMB had higher prevalence of mutations in BRCA2 (p &lt; 0.0001), BRAF (p &lt; 0.0001), PALB2 (p &lt; 0.0001), and genes of the mismatch repair pathway ( MSH2, MSH6, MLH1, and PMS2, p &lt; 0.0001), but lower prevalence of KRAS mutations (p &lt; 0.0001). The most common KRAS mutation in both groups of patients was G12D. In CGDB, 51 patients received an ICI (10 with high TMB and 41 with low TMB) and 17 patients with high TMB received other therapies. Among patients receiving an ICI, those with high TMB had more favorable median OS compared to those with low TMB (25.7 versus 5.2 months, hazard ratio (HR) 0.27, 95% confidence interval (CI) 0.09 - 0.76, p = 0.01) and median TTD (20.7 versus 3.0 months, HR 0.33, 95% CI 0.13 - 0.82, p = 0.02). Among patients with high TMB, those receiving an ICI had more favorable OS compared to those receiving other therapies (25.7 versus 6.6 months, HR 0.31, 95% CI 0.10-0.96, p = 0.043), nominally favoring ICI use in this small cohort (n = 10 versus 17). Conclusions: There is no randomized clinical trial evaluating ICI versus other therapies in PDAC. To our knowledge, this is the largest cohort to date comparing ICI effectiveness in PDAC. We observed more favorable OS among PDAC patients with high TMB receiving ICI versus those with low TMB who received an ICI and more favorable to those with high TMB receiving other therapies. This study supports the FDA-approved use of ICIs in patients with PDAC and high TMB and demonstrates the importance of TMB assessment for patients with PDAC.

KRAS G12C Mutant Non–Small Cell Lung Cancer Linked to Female Sex and High Risk of CNS Metastasis: Population-based Demographics and Survival Data From the National Swedish Lung Cancer Registry

BackgroundReal-world data on demographics related to KRAS mutation subtypes are crucial as targeted drugs against the p.G12C variant have been approved. MethodWe identified 6183 NSCLC patients with reported NGS-based KRAS status in the Swedish national lung cancer registry between 2016 and 2019. Following exclusion of other targetable drivers, three cohorts were studied: KRAS-G12C (n = 848), KRAS-other (n = 1161), and driver negative KRAS-wild-type (wt) (n = 3349). ResultsThe prevalence of KRAS mutations and the p.G12C variant respectively was 38%/16% in adenocarcinoma, 28%/13% in NSCLC-NOS and 6%/2% in squamous cell carcinoma. Women were enriched in the KRAS-G12C (65%) and KRAS-other (59%) cohorts versus KRAS-wt (48%). A high proportion of KRAS-G12C patients in stage IV (28%) presented with CNS metastasis (vs. KRAS-other [19%] and KRAS-wt [18%]). No difference in survival between the mutation cohorts was seen in stage I-IIIA. In stage IV, median overall survival (mOS) from date of diagnosis was shorter for KRAS-G12C and KRAS-other (5.8 months/5.2 months) vs. KRAS wt (6.4 months). Women had better outcome in the stage IV cohorts, except in KRAS-G12C subgroup where mOS was similar between men and women. Notably, CNS metastasis did not impact survival in stage IV KRAS-G12C, but was associated with poorer survival, as expected, in KRAS-other and KRAS-wt. ConclusionThe KRAS p.G12C variant is a prevalent targetable driver in Sweden and significantly associated with female sex and presence of CNS metastasis. We show novel survival effects linked to KRAS p.G12C mutations in these subgroups with implications for clinical practice.

Treatment Strategies for KRAS-Mutated Non-Small-Cell Lung Cancer.

Activating mutations in KRAS are highly prevalent in solid tumours and are frequently found in 35% of lung, 45% of colorectal, and up to 90% of pancreatic cancers. Mutated KRAS is a prognostic factor for disease-free survival (DFS) and overall survival (OS) in NSCLC and is associated with a more aggressive clinical phenotype, highlighting the need for KRAS-targeted therapy. Once considered undruggable due to its smooth shallow surface, a breakthrough showed that the activated G12C-mutated KRAS isozyme can be directly inhibited via a newly identified switch II pocket. This discovery led to the development of a new class of selective small-molecule inhibitors against the KRAS G12C isoform. Sotorasib and adagrasib are approved in locally advanced or metastatic NSCLC patients who have received at least one prior systemic therapy. Currently, there are at least twelve KRAS G12C inhibitors being tested in clinical trials, either as a single agent or in combination. In this study, KRAS mutation prevalence, subtypes, rates of occurrence in treatment-resistant invasive mucinous adenocarcinomas (IMAs), and novel drug delivery options are reviewed. Additionally, the current status of KRAS inhibitors, multiple resistance mechanisms that limit efficacy, and their use in combination treatment strategies and novel multitargeted approaches in NSCLC are discussed.

Clinical significance of circulating-tumour DNA analysis by metastatic sites in pancreatic cancer.

Liquid biopsy is an alternative to tissue specimens for tumour genotyping. However, the frequency of genomic alterations with low circulating-tumour DNA (ctDNA) shedding is shown in pancreatic ductal adenocarcinoma (PDAC). We, therefore, investigated the prevalence of KRAS mutations and ctDNA fraction by the metastatic site in patients with PDAC. This study enrolled previously treated PDAC patients from a plasma genomic profiling study; ctDNA analysis was performed using Guardant360 at disease progression before initiating subsequent treatment. In 512 patients with PDAC, KRAS mutations were detected in 57%. The frequency of KRAS mutation in ctDNA differed depending on the metastatic organ; among patients with single-organ metastasis (n = 296), KRAS mutation detection rate was significantly higher in patients with metastasis to the liver (78%). In addition, the median maximum variant allele frequency (VAF) was higher with metastasis to the liver (1.9%) than with metastasis to the lungs, lymph nodes, peritoneum or with locally advanced disease (0.2%, 0.4%, 0.2% and 0.3%, respectively). The prevalence of KRAS mutations and maximum VAF were higher in patients with metastasis to the liver than in those with metastasis to other sites. This study indicated the clinical utility of ctDNA analysis, especially in PDAC with liver metastases.

High level of ANO1 promotes pancreatic cancer growth in concert with oncogenic KRAS.

Anoctamin-1 (ANO1) was identified as an unfavorable prognostic marker in pancreatic cancer. However, the exact implication of ANO1 in pancreatic cancer is still poorly understood. Here we investigated the effect of ANO1 in pancreatic cancer progression under the context of oncogenic KRAS, aiming at finding a new therapeutic target. Knockdown and overexpression of oncogenic KRAS as well as ANO1 in PDAC cell lines were performed by lentivirus infection. Cell proliferation and migration assay, RNA seq analysis were performed in PDAC cells bearing different status of ANO1 and KRAS. In vivo mice model was used to investigate the xenograft tumor growth with different status of KRAS and ANO1. Our results showed that ANO1 expression level is elevated in poorly differentiated cancer cells. Overexpression of ANO1 in PDAC cancer cells was found to promote cancer cell proliferation in vitro and in vivo, which synergized with the introduction of oncogenic KRAS. Consistently, knockdown of ANO1 expression was found to suppress cancer growth in vitro and in vivo. RNA seq analysis revealed that the observed synergistic cancer-promoting effect from ANO1 and oncogenic KRAS is likely due to concurrent activating key genes involved in lipid metabolism including HMGCS1. The outcome from our study suggests that ANO1 plays an important role in promoting pancreatic cancer development, especially at the presence of oncogenic KRAS. Considering the prevalence of KRAS mutation in pancreatic cancer patients, suppression ANO1 may represent a potential effective therapeutic measure in pancreatic cancer treatment.

Next-generation sequencing of non-small cell lung cancer at a Quebec health care cancer centre

BackgroundLung cancer is the leading cause of cancer death in both men and women. Quebec has the highest lung cancer mortality out of all provinces in Canada, believed to be caused by higher smoking rates. Molecular testing for lung cancer is standard of care due to the discovery of actionable driver mutations that can be targeted with tyrosine kinase inhibitors. To date, no detailed molecular testing characterization of Quebec patients with lung cancer using next generation sequencing (NGS) has been performed. Materials and methodsThe aim of this study was to describe the genomic landscape of patients with lung cancer (n = 997) who underwent NGS molecular testing at a tertiary care center in Quebec and to correlate it with clinical and pathology variables. ResultsCompared to 10 other NGS studies found through a structured search strategy, our cohort had a higher prevalence of KRAS mutations (39.2%) compared to most geographical locations. Additionally, we observed a significant positive association between decreasing age and a higher proportion of KRAS G12C mutations. ConclusionOverall, it remains important to assess institutional rates of actionable driver mutations to help guide governing bodies, fuel clinical trials and create benchmarks for expected rates as quality metrics.

Molecular Characteristics of Early-Onset Colorectal Cancer According to Detailed Anatomical Locations: Comparison With Later-Onset Cases.

Early-onset colorectal cancer diagnosed before the age of 50 years has been increasing. Likely reflecting the pathogenic role of the intestinal microbiome, which gradually changes across the entire colorectal length, the prevalence of certain tumor molecular characteristics gradually changes along colorectal subsites. Understanding how colorectal tumor molecular features differ by age and tumor location is important in personalized patient management. Using 14,004 cases with colorectal cancer including 3,089 early-onset cases, we examined microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF mutations in carcinomas of the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum and compared early-onset cases with later-onset cases. The proportions of MSI-high, CIMP-high, and BRAF -mutated early-onset tumors were lowest in the rectum (8.8%, 3.4%, and 3.5%, respectively) and highest in the ascending colon (46% MSI-high; 15% CIMP-high) or transverse colon (8.6% BRAF -mutated) (all Ptrend <0.001 across the rectum to ascending colon). Compared with later-onset tumors, early-onset tumors showed a higher prevalence of MSI-high status and a lower prevalence of CIMP-high status and BRAF mutations in most subsites. KRAS mutation prevalence was higher in the cecum compared with that in the other subsites in both early-onset and later-onset tumors ( P < 0.001). Notably, later-onset MSI-high tumors showed a continuous decrease in KRAS mutation prevalence from the rectum (36%) to ascending colon (9%; Ptrend <0.001), followed by an increase in the cecum (14%), while early-onset MSI-high cancers showed no such trend. Our findings support biogeographical and pathogenic heterogeneity of colorectal carcinomas in different colorectal subsites and age groups.

Abstract A010: Molecular characteristics and prognosis of early-onset colorectal cancer according to detailed anatomical locations: Comparison to later-onset cases

Abstract Background: Evidence suggests that, compared to later-onset colorectal cancer (CRC), early-onset CRC (diagnosed before 50 years of age) occur more frequently in rectal location and less frequently in proximal colon location. Studies also indicate heterogeneity of molecular characteristics within early-onset CRCs and between early-onset and later-onset CRCs. Understanding how tumor molecular features and biological aggressiveness of early-onset CRC differ by detailed tumor location is important in personalized patient management. Methods: Using 14,004 CRC cases including 3,089 early-onset cases from The Cancer Genome Atlas and the Genetics and Epidemiology of CRC Consortium (GECCO), we examined microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF mutations in cancers of the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum. We further conducted CRC-specific survival analyses of detailed tumor location stratified by molecular characteristics using multivariable Cox proportional hazards models. Results: The proportions of MSI-high, CIMP-high, and BRAF-mutated early-onset tumors gradually increased from the rectum (8.8%, 3.4%, and 3.5%, respectively) to the ascending colon (46% MSI-high; 15% CIMP-high) or transverse colon (8.6% BRAF-mutated), followed by declines in the cecum for MSI-high (36%) and BRAF-mutated (4.6%) tumors. Notably, later-onset MSI-high tumors showed a continuous decrease in KRAS mutation prevalence from the rectum (36%) to ascending colon (9%; Ptrend &amp;lt;0.001) followed by an increase in the cecum (14%), while early-onset MSI-high cancer showed no such trend. In survival analyses, there was a trend for better CRC-specific survival from the cecum to sigmoid colon (Ptrend&amp;lt;0.001) (but not to rectum), which did not significantly differ by age of diagnosis (Pinteraction=0.61). Multivariable-adjusted hazard ratios (HRs) for sigmoid vs. cecum were 0.86 (95% CI, 0.64-1.14) for early-onset cases and 0.81 (95% CI, 0.70-0.93) for later-onset cases. Notably, the prognostic association of tumor location differed by MSI status (Pinteraction=0.001). Non-MSI-high tumors exhibited the cecum-to-sigmoid trend for better CRC-specific survival [Ptrend &amp;lt;0.001; multivariable-adjusted HR for the sigmoid colon (vs. cecum), 0.80; 95% CI, 0.70-0.92], whereas MSI-high tumors demonstrated an opposite cecum-to-sigmoid trend for worse survival (Ptrend = 0.020; the corresponding HR, 2.13; 95% CI, 1.15-3.92). Conclusions: Our findings support biogeographical and pathogenic heterogeneity of CRC in different age groups and colorectal subsites. Both detailed colorectal location and tumor molecular features need to be accounted for prognostication of early-onset and later-onset CRCs to advance precision medicine. Citation Format: Tomotaka Ugai, Yin Cao, Koichiro Haruki, Tabitha A. Harrison, Daniel D. Buchanan, Peter T. Campbell, Andrew T. Chan, Steven Gallinger, Marc J. Gunter, Michael Hoffmeister, Mark A. Jenkins, Roger L. Milne, Polly A. Newcomb, Rish K. Pai, Andrew J. Pellatt, Robert E. Schoen, Bethany Van Guelpen, Michael O. Woods, Amanda I. Phipps, Ulrike Peters, Shuji Ogino. Molecular characteristics and prognosis of early-onset colorectal cancer according to detailed anatomical locations: Comparison to later-onset cases [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr A010.

RESEARCH ON KRAS MUTATIONS IN PATIENTS WITH COLORECTAL POLYPS LARGER THAN 10 MM

Objectives: Determine the prevalence of KRAS mutations using RNA samples and the association with endoscopic and histopathological images of colorectal polyps larger than 10mm. Subjects and methods: A cross-sectional study on 84 patients at the Gastroenterology-Hepatobiliary center - Bach Mai Hospital from 01/2017 - 12/2021. Perform a colonoscopy, select the largest polyp over 10mm in size to characterize and perform polypectomy, taking the specimen for histopathology according to WHO criteria 2010. Identification of KRAS gene mutations in tissue samples using RNA samples. Results: 10.7% of the KRAS gene is mutated. KRAS gene mutation rates tended to be higher in villous polyps compared to tubular polyps (33.3% vs. 9.2%) and high-grade dysplastic polyps compared to low-grade dysplastic polyps (23.1% vs. 8.6%), though no correlation between KRAS gene mutations and endoscopic imaging characteristics of polyps has been reported. Conclusion: KRAS gene mutations are not common in polyps larger than 10 mm but are related to the villious component and the degree of dysplasia on the histopathology of the polyp.

EP03.01-011 Prevalence of KRASMutations in Treatment-naïve Non-small Cell Lung Cancer Patients in Hong Kong

There are limited studies on the prevalence of KRAS and KRAS G12C mutations in Chinese NSCLC patients in mainland China, reporting from a range of 7.5% to 9.8% KRAS mutations and 2.1% to 4.3% KRAS G12C mutation in NSCLC patients. In addition to genetic factors, the difference in environmental and lifestyle factors may potentially affect the prevalence of KRAS and KRAS G12C mutations therefore the aim of this study is to examine the prevalence in Hong Kong NSCLC patients.