KRAS Subtypes Research Articles

PDAC heterogeneity resolved spatially at the single-cell level: new biological answers, new questions on optimal translation†.

Pancreatic cancer is a highly aggressive disease. Developing new strategies and using powerful methodologies for its early detection, coupled with in-depth comprehension of the mechanisms governing subtype evolution, will not only help to stratify PDAC patients' prognosis but also prevent unfavourable subtype plasticity upon treatment with chemotherapy. Michiels et al have developed a new approach to better capture PDAC heterogeneity at the single tumour duct spatial resolution level, leveraging detection of transcripts for mutant KRAS and multiple subtype markers. Their study sheds light on the association of mutant KRAS and PDAC phenotypic heterogeneity. The findings support functional cooperation of plastic tumour cells and opens new challenges towards PDAC patient stratification and therapeutic intervention. Pathology-based tools will be of prime importance to address these issues in a clinically meaningful manner. © 2024 The Pathological Society of Great Britain and Ireland.

Molecular and clinical characteristics of patients with non-small-cell lung cancer (NSCLC) harboring KRAS G12V mutations.

8618 Background: KRAS G12V is one of the most common drivers of non-small cell lung cancer (NSCLC), accounting for around 3 percent of cases. Recently, there have been promising approaches in early clinical research to therapeutically target this mutation. However, this subset of patients is poorly characterized both molecularly and clinically, and data on therapy-dependent outcome are lacking. We performed this real world analysis to gain insight into the genomic and clinical characteristics of a large cohort of NSCLC patients with KRAS G12V mutations. Methods: Molecular data of 662 UICC stage I-IV lung cancer patients diagnosed between 2018 and 2023 and harbouring a KRAS G12V mutation in their tumor tissue were linked to the medical record data in the Network Genomic Medicine (NGM) database. The mutational status was determined by next-generation sequencing (NGS) and further immunohistochemistry (IHC) for PD-L1 status was performed. Results: 662 patients with a KRAS G12V mutation were diagnosed between 01/2018 and 03/2023 (stage I: 33 (6.0%), II: 29 (5.3%), III: 89 (16.3%), IV: 396 (72.4%)), which is a proportion of 15.3% among all registered KRAS-mutated lung cancer patients in this period (n=4332). Among the KRASG12V positive primary lung carcinomas, 605 (94.3%) showed an adenocarcinoma and 17 (2.6%) a squamous cell carcinoma. The median age at diagnosis was 67 years (range: 33-91), of which 338 were men (52.6%) and 304 women (47.4%). The majority of the cohort were active or former smokers (active: 289 (54.9%); former: 208 (39.2%)). In the group of never smokers (n=33, 6.2%), there were 5 men (15.2% of never smokers) and 28 women (84.8% of never smokers). The most common mutation site at initial diagnosis in patients with metastatic disease was brain and bone metastases with 41.5% and 37.4%, respectively. The most common co-mutations with a frequency of ≥ 5% were TP53 (40.2%), STK11 (28.3%), KEAP1 (22.6%) and NTRK1-3 (8.7%). Preliminary median overall survival at UICC stage IV was 525 (95% CI: 427 – 579) days. The first PD-L1-independent analysis showed a response rate of 40.9% (18/44) to initial chemotherapy (CTX)/immune-checkpoint blockade (ICB) combination, 66.7% (8/13) to ICB alone and 18.8% (6/32) to CTX alone. Conclusions: The cohort is characterized by heavy tobacco consumption. Among the never-smokers, the high proportion of women is noteworthy and will be analyzed further. Metastases at first diagnosis and concurrent mutations show clear differences to other KRAS subtypes, which highlights the heterogeneity of KRAS subtypes. We will continue to analyze the overall prognosis as well as the first indications of a PD-L1-independent benefit of immunotherapy compared to chemotherapy alone.

Characteristics and clinical outcomes of US veterans with advanced non–small cell lung cancer (NSCLC) by KRAS subtype: A National Veterans Health Administration analysis.

Characteristics and clinical outcomes of US veterans with advanced non–small cell lung cancer (NSCLC) by KRAS subtype: A National Veterans Health Administration analysis.

The Clinical Implications of KRAS Mutations and Variant Allele Frequencies in Pancreatic Ductal Adenocarcinoma.

The KRAS proto-oncogene is a major driver of pancreatic tumorigenesis and is nearly ubiquitously mutated in pancreatic ductal adenocarcinoma (PDAC). KRAS point mutations are detected in over 90% of PDAC cases, and these mutations have been shown to be associated with worse therapy response and overall survival. Pathogenic KRAS mutations are mostly limited to codons 12, 13 and 61, with G12D, G12V, G12R, Q61H, and G13D accounting for approximately 95% of the mutant cases. Emerging data have shown the importance of specific mutant subtypes, as well as KRAS variant allele frequency on clinical prognosis. Furthermore, novel technologies and therapies are being developed to target specific mutant subtypes, with encouraging early results. In this paper, we aim to review the recent studies regarding the relative impact of specific mutant KRAS subtypes on oncologic outcomes, the application of variant allele frequency in next generation sequencing analyses, and the ongoing research into therapies targeting specific mutant KRAS subtypes.

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.

Abstract 2093: Co-treatment with KRAS G12D inhibitor MRTX1133 plus TTFields against human pancreatic and Colorectal cancer cell lines results in synergistic up-regulation of cleaved PARP in KRAS G12D & unexpectedly in KRAS G12V as well

Abstract Background: Both colorectal and pancreatic cancers are major global health issues and among deadliest cancers with great disease burden. The most commonly mutated oncogenic alteration in human cancers is KRAS, which is prevalent in pancreatic malignancies. The KRAS G12D mutation subtype is present in more than 40% of pancreatic ductal adenocarcinoma (PDAC). To this date there is no available targeted therapy options for patients with KRAS subtype mutations. MRTX1133 has been identified as a non-covalent, potent, and selective inhibitor of KRASG12D. This small molecule inhibitor has been shown to suppress KRASG12D signaling in cells and in vivo. Tumor Treating Fields (TTFields) therapy is a novel approach to treating cancer, the electric fields alter the behavior of cancer cells and prevent them from growing and dividing. We hypothesize that the co-application of MRTX1133 with TTFields will enhance the effects of MRTX1133 in PDAC and colorectal cancer (CRC). Martials and Methods: PDAC cell line CFPAC1 with KRAS G12 V mutation and LS513 CRC cell line with KRAS G12D Mutation were treated with same dose of MRTX1133 (500 nM) and were co-treated with 150kHz TTFields. After 48 hours western blot was used to probe for cleaved PARP, cleaved C3, phosphor-ERK and DUSP6. Results: In both KRAS G12D & KRAS G12V cell lines, synergistic upregulation of cPARP was observed following 48-hour co-treatment. Synergistic inhibition of pERK happened in KRAS G12D cell line but no change in pERK level following TTFields or MRTX1133 treatment was seen. Upregulation of cC3 in KRAS G12D happened in only co-treatment conditions. DUSP6 levels increased following MRTX1133 treatment in KRAS G12V cell line. Conclusions: The surprising synergistic upregulation of cPARP in both KRAS G12V and G12D cells following co-treatment of KRAS G12D inhibitor MRTX1133 and TTFields can bring hope for other KRAS mutation subtypes as well as G12D. the increase in cPARP in KRAS G12V with no effect on pERK is particularly interesting and demonstrates the need of more studies to investigate the mechanisms of this synergy. Citation Format: Vida Tajiknia, Praveen Srinivasan, Maximilian PInho-Schwermann, William MacDonald, Connor Purcell, Wafik El-Deiry. Co-treatment with KRAS G12D inhibitor MRTX1133 plus TTFields against human pancreatic and Colorectal cancer cell lines results in synergistic up-regulation of cleaved PARP in KRAS G12D & unexpectedly in KRAS G12V as well [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 2093.

Extrahepatic cholangiocarcinoma: Genomic variables associated with anatomical location and outcome.

554 Background: Genomic determinants of outcome in intrahepatic cholangiocarcinoma have become clear but remain ill-defined in extrahepatic cholangiocarcinoma (ECA). We aimed to clarify the genomic alterations that define ECA, analyze differences between perihilar (PCA) and distal (DCA) disease, and determine clinicopathologic and genomic factors associated with survival. Methods: Patients with EHC with tissue available for targeted next-generation sequencing at Memorial Sloan Kettering Cancer Center were identified. Differences between PCA and DCA were compared, stratified by disease extent and treatment. Associations between genomic alterations and clinicopathologic features and outcomes were analyzed. Univariable and then multivariable cox proportional hazards regression were used to compare survival, which was reported from operation in resected patients and from diagnosis in non-resected patients. Results: Two-hundred-twenty-four patients (n=127 PCA, n=97 DCA, 2006-2022) met inclusion criteria. Median survival was 29 months (IQR [25, 35]; 43 months [35, 48] resection, 17 months [13, 19] without). Compared to PCA, DCA was enriched in TP53mut (67 [69%] vs. 42 [33%]), Q<0.01) and epigenetic pathway alterations (44 [45%] vs. 37 [29%], Q=0.041) and had more altered pathways (3 vs. 2, Q<0.01). KRASmut was similar between PCA (46 [36%]) and DCA (36 [37%]); however, PCA was enriched in KRAS G12V (16 [13%] vs. 4 [4%]) and Q61H (11 [9%] vs. 3 [3%], P=0.002). No other clinicopathologic or genomic variables distinguished PCA from DCA (Table). MDM2mut occurred in 19/141 (13%) patients with nodal/metastatic disease compared to 1/83 (1%) patients with local disease ( Q=0.03), but conferred no survival disadvantage. In resected patients, survival was similar between PCA and DCA and no genomic alterations were associated with outcome. By contrast, in patients without surgery, CDKN2Adel (HR 2.59, 95% CI [1.48, 4.52]) and APCmut (HR 5.11, 95% CI [1.96, 13.3]) were associated with survival disadvantages. Lack of resection (HR 3.13, 95% CI [2.25, 4.36]), CDKN2Amut (HR 1.80 [95% CI 1.80, 2.68), and APCmut (HR 2.00 [95% CI 1.04, 3.87]) were associated with poor survival in the entire cohort. Conclusions: In this study, aside from a higher incidence of TP53mut in DCA and some differences in KRAS subtype alteration patterns, genomic alterations were comparable between PCA and DCA. CDKN2Amut and APCmut were associated with poor survival in all patients but no biomarkers provided significant prognostic information when tumors were resected. [Table: see text]

P1.22-05 Prevalence of KRAS Subtype Alterations in Non-Small Cell Lung Cancer (NSCLC) with Brain Metastases

P1.22-05 Prevalence of KRAS Subtype Alterations in Non-Small Cell Lung Cancer (NSCLC) with Brain Metastases

Evaluating distinct KRAS subtypes as potential biomarkers for immune checkpoint inhibitor efficacy in lung adenocarcinoma.

Despite the acknowledged predictive value of KRAS in immune checkpoint inhibitor (ICI) responses, the heterogeneous behavior of its mutations in this sphere remains largely unexplored. As of now, no studies have definitively categorized KRAS subtype variations as independent prognostic indicators for ICI responses in lung cancer patients. We analyzed a cohort of 103 patients, all harboring different KRAS mutation subtypes, and complemented this data with information from TCGA and GEO databases. Our research focused on delineating the relationships between KRAS mutation subtypes and factors like immunotherapy markers and immune cell composition, in addition to examining survival rates, drug sensitivity, and PD-L1 responses corresponding to distinct KRAS subtypes. We found that the G12V and G12D subtypes demonstrated elevated expressions of immunotherapy markers, implying a potentially enhanced benefit from immunotherapy. Significant variations were identified in the distribution of naive B cells, activated CD4+ memory T cells, and regulatory T cells (Tregs) across different KRAS mutant subtypes. A notable difference was observed in the Tumor Mutation Burden (TMB) levels across the four KRAS subtypes, with the G12D subtype displaying the lowest TMB level. Furthermore, G12C subtype showcased the worst prognosis in terms of progression-free intervals (PFI), in stark contrast to the more favorable outcomes associated with the G12A subtype. Our study reveals that KRAS mutations exhibit considerable variability in predicting outcomes for LUAD patients undergoing ICI treatment. Thus, the evaluation of KRAS as a biomarker for ICIs necessitates recognizing the potential diversity inherent in KRAS mutations.

Prognostic Implication of KRAS G12C Mutation in a Real-World KRAS-Mutated Stage IV NSCLC Cohort Treated With Immunotherapy in The Netherlands

IntroductionWith the approval of G12C inhibitors as the second line of treatment for KRAS G12C-mutated NSCLC, and the expanding research regarding targeting KRAS, it is key to understand the prognostic implication of KRAS G12C in the current first line of treatment. We compared overall survival (OS) of patients with stage IV KRAS G12C-mutated NSCLC to those with a KRAS non-G12C mutation in a first-line setting of (chemo)immunotherapy. MethodsThis nationwide population-based study used real-world data from The Netherlands Cancer Registry. We selected patients with stage IV KRAS-mutated lung adenocarcinoma diagnosed in 2019 to 2020 who received first-line (chemo-)immunotherapy. Primary outcome was OS. ResultsFrom 28,120 registered patients with lung cancer, 1185 were selected with a KRAS mutation, of which 494 had a KRAS G12C mutation. Median OS was 15.5 months (95% confidence interval [CI]: 13.6–18.4) for KRAS G12C versus 14.0 months (95% CI:11.2–15.7) for KRAS non-G12C (p = 0.67). In multivariable analysis, KRAS subtype was not associated with OS (hazard ratio = 0.95, 95% CI: 0.82–1.10). For the subgroup with programmed death-ligand 1 at 0% to 49% who received chemoimmunotherapy, median OS was 13.3 months (95% CI: 10.5–15.2) for G12C and 9.8 months (95% CI: 8.6–11.3) for non-G12C (p = 0.48). For the subgroup with programmed death-ligand 1 more than or equal to 50% who received monoimmunotherapy, the median OS was 22.0 months (95% CI: 18.4–27.3) for G12C and 18.9 months (95% CI: 14.9–25.2) for non-G12C (p = 0.36). ConclusionsThere was no influence of KRAS subtype (G12C versus non-G12C) on OS in patients with KRAS-mutated stage IV NSCLC treated with first-line (chemo)immunotherapy.

Relations between mutant KRAS and TP53 subtypes and other co-mutations in pancreatic cancer.

e16294 Background: The most common mutations in pancreatic cancer are found in the KRAS, TP53, CDKN2A, or SMAD4 genes. Mutations in genes involved in the DNA damage repair (DDR) pathway are also frequently seen. Despite extensive research on the patho-genomic features of pancreatic cancer, the clinical significance of these recurring mutations remains poorly understood. Methods: We identified patients with pancreatic cancer treated at Yale Cancer Center between 2016 and 2021 who underwent Oncomine tumor profiling. The incidence and subtypes of KRAS and TP53, and their association with other genomic alterations and clinicopathological variables were measured. We compared the overall survival (OS) after the diagnosis of recurrent or metastatic disease using the Kaplan-Meier method and long-rank tests. Results: One hundred fifty-nine patients were identified and KRAS mutations were seen in 144 (90.6%) patients, including 64 G12D (44.4%), 48 G12V (33.3%), 19 G12R (13.2%), 6 Q61H (4.2%), and 7 others (4.9%). TP53 mutations were identified in 117 (73.6%) patients, including 80 loss-of-function (LOF) (68.4%), 24 gain-of-function (GOF) (20.5%), and 13 variants of unclear significance (VUS) (11.1%). TP53 LOF mutations were more common in tumors with KRAS WT (40.0%), G12D (56.3%), and G12V (56.3%), than in G12R (31.6%) and others KRAS mutation (30.1%). Conversely, TP53 GOF mutations were more common in tumors with G12R (26.3%) and other KRAS mutations (23.1%), than in KRAS WT (6.7%), G12D (14.1%), and G12V (12.5%). There was no difference in OS between KRAS subtypes (p=0.48) or TP53 subtypes (p=0.52). Patients with TP53 WT had a numerically longer but not statistically significant survival (median 1.65 years versus 1.16 years in patients with TP53 mutations, p=0.20). When each KRAS subtype was examined, patients with tumors with G12V but no TP53 mutation had longer OS (median 2.42 years) than those with WT KRAS or non-G12V mutation (median 1.38 years, p=0.02). Mutations in DDR genes were more frequently seen in the KRAS WT (33.3%) and G12D groups (15.6%), compared to that in the G12V (10.4%), G12R (10.5%) groups. Unique co-mutations were observed in certain KRAS subtypes but not others. Conclusions: In this retrospective study of comprehensive genomic and clinical data of pancreatic cancers, we found that KRAS or TP53 mutation subtypes had no significant impact on OS. Different KRAS subtypes have unique co-occurring genomic alterations, which may be clinically relevant as novel KRAS inhibitors continue clinical development.[Table: see text]

Co-mutational status and PD-L1 expression in KRAS mutant non-small cell lung cancer (NSCLC): Role in treatment selection and association with clinical outcomes.

9038 Background: In NSCLC, different KRAS mutations (mt) define unique subgroups and certain co-mutations (co-mt) could have prognostic and therapeutic implications. Retrospective studies associate poor prognosis with co-mts in STK11 and KEAP1 with KRAS. It is unclear if PD-L1 expression and co-mt in KRAS mt NSCLC impacts outcomes. Methods: Molecular profiles of 27748 NSCLC tumors were tested with next-generation sequencing (Caris Life Sciences, Phoenix, AZ) and classified by KRAS mt. PD-L1 IHC (22C3) was reported as TPS. Real-world post-immunotherapy (IO) overall survival (OS) was obtained from insurance claims and calculated from start of an immune check-point inhibitor (with or without chemotherapy) to the last day of follow-up. Results: In all, 7634 (28%) samples had a KRAS mt; most common being G12C (11%), G12V (5.3%), G12D (3.9%) and G13X (2.0%). The most frequent co-mt was KRAS-TP53 (KP) (46%), similar in all KRAS subtypes. KRAS-STK11(KL) was in 23% of KRAS mt, enriched in G13X (33%) and lowest in G12D (16%). KRAS-KEAP1(KK) was co-mt in 10% of KRAS mt, highest in G13X (16%) and lowest in G12D (8%). KRASmt/ STK11wt/ KEAP1wt/ TP53wt (K only) was 27% of KRAS mt, highest in G12D (36%) and lowest in G13X (16%). A small subgroup, 5.6% was KRAS-STK11-KEAP1 co-mt (KKL). The majority of pts in the KL (61%), KK (52%) and KKL (62%) cohorts had TPS <1%. In 1723 KRAS mt NSCLC pts treated with IO, KL, KK and KKL had significantly worse post-IO OS than KP and K only (table); KKL had the lowest OS. In the TPS≥1% KRAS mt group, KL, KK and KKL had worse post-IO OS than KP and K-only. In TPS<1% group, KL and KK had poor post-IO OS and K-only had favorable outcomes. However, KP had worse post-IO OS compared to K-only in TPS<1%. In G12C and G12V, similar trend with worse post-IO OS in KL, KK and KKL, compared to KP and K only was noted. Conclusions: We report a large real-world dataset evaluating outcomes with check-point inhibitors in NSCLCs with KRAS and specific co-mts. KL, KK and KKL subgroups demonstrate universally poor outcomes in all KRAS subtypes irrespective of PD-L1. Pts with KP co-mts have adverse post-IO outcomes in TPS<1% but favorable in TPS≥1%. TPS score remains a predictive marker of IO outcomes in KP, but not in KL, KK and KKL. These observations emphasize that both PD-L1 and co-mts have a clear association with clinical outcomes in KRAS-mt NSCLC, and must be used in predictive models for individualized therapy. [Table: see text]

Prognostic value of KRAS subtype in patients with PDAC undergoing radical resection.

To explore the frequency distribution of KRAS mutant subtypes in patients with resectable PDAC in China and then evaluate the prognostic value of different KRAS subtypes in patients with PDAC undergoing radical resection. The clinicopathological data and gene test reports of 227 patients undergoing PDAC radical surgery at Hunan Provincial People's Hospital from 1 January 2016 to 1 January 1 2020 were retrospectively evaluated. There were 118 men (52%) and 109 women (48%). The mean age was 58.8 ± 10.3 years. After univariate analysis of the clinicopathological factors (sex, age, presence or absence of underlying disease, location of the primary tumour, tumour TNM stage, T stage, N stage, presence or absence of vascular invasion, presence or absence of nerve invasion, surgical margin, KRAS mutation subtype), variables with P < 0.1 were included in the multivariate Cox regression model analysis, and the log-rank sum test and Kaplan-Meier curves were used to assess the correlation of the KRAS mutation subtype with the overall survival time. KRAS mutations were detected in 184 of 227 patients (81.1%) (G12D: 66; G12V: 65; G12R: 27; Q61:26) and were not detected in 43 patients (18.9%). KRAS mutations were associated with tumour differentiation (P = 0.001), TNM stage (P = 0.013), and T stage (P < 0.001). Multivariate Cox regression model analysis showed that N stage, surgical margin, tumour differentiation, and KRAS-G12D mutation were independent prognostic factors for DFS and OS. Patients with the KRAS-G12D subtype had shorter OS with a median OS of 12 months (HR: 0.55, CI: 0.39-0.77, P < 0.001), and patients with KRAS wild-type had longer OS with a median OS of 19 months (HR: 0.57, CI: 0.42-0.76, P < 0.001). KRAS wild-type individuals are more prevalent in the Chinese population than in European or American populations. Patients undergoing surgery had a reduced percentage of tumors with KRAS-G12D. When determining the prognosis of individuals with radically resected PDAC, reference markers for KRAS mutation subtypes can be employed.

Extensive genomic analysis in patients with KRAS-mutated solid tumors shows high frequencies of concurrent alterations and potential targets but has limited clinical impact

Background This study aimed to investigate the distribution and frequency of concurrent alterations in different cancers across KRAS subtypes and in different KRAS subtypes across cancers, and to identify potentially actionable targets and patients who received targeted treatment matched to their genomic profile (GP). Materials and Methods In this descriptive and single-center study, we included 188 patients with solid tumors harboring KRAS mutations in codon 12, 13, 61, 117, or 146, referred to the Phase 1 Unit, Rigshospitalet, Copenhagen, Denmark from mid-2016 to 2020. Genomic co-alterations were detected with whole-exome sequencing, RNA sequencing, SNP array, and mRNA expression array on fresh biopsies. The study is part of the Copenhagen Prospective Personalized Oncology study (NCT02290522). Results The majority of patients had colorectal cancer (60.1%), non-small cell lung cancer (11.2%), or pancreatic cancer (10.6%). Most tumors were KRAS-mutated in codon 12 or 13 (93.7%) including G12D (27.1%), G12V (26.6%), G12C (11.7%), and G13D (11.2%). A total of 175 different co-alterations were found, most frequently pathogenic APC and TP53 mutations (55.9% and 46.4%, respectively) and high expression of CEACAM5 (73.4%). Different cancers and KRAS subtypes showed different patterns of co-alterations, and 157 tumors (83.5%) had potentially actionable targets with varying evidence of targetability (assessed using ESMO Scale for Clinical Actionability of molecular Targets). Of the 188 patients included in the study, 15 (7.4%) received treatment matched to their GP (e.g., immunotherapy and synthetic lethality drugs), of whom one had objective partial response according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Conclusion Performing extensive genomic analysis in patients with known KRAS-mutated solid tumors may contribute with information to the genomic landscape of cancers and identify targets for immunotherapy or synthetic lethality drugs, but currently appears to have overall limited clinical impact, as few patients received targeted therapy matched to their GP.

Impact of KRAS Mutation Subtypes and Co-Occurring Mutations on Response and Outcome in Advanced NSCLC Patients following First-Line Treatment.

(1) Background: The purpose was to systematically assess the impact of KRAS subtypes and co-mutations on responses of first-line treatment and outcomes by genetic classification in advanced KRAS mutant NSCLC. (2) Methods: Molecular pathology was confirmed with NGS; Kaplan–Meier analysis and Cox multivariate model were used to analyze the efficacy of first-line treatment and prognosis in KRAS subgroups. (3) Results: Advanced KRAS mutant NSCLC was confirmed among 183 patients, who received first-line therapy. The most common KRAS subtype and co-mutation were G12C (29.5%) and TP53 (59.6%). ICIs/CHE group prolonged PFS to 16.9 m, vs. (CHE)4.6 m vs. (CHE/BEV)7.0 m (p < 0.0001); mOS (ICIs/CHE)37.1 m vs. (CHE)19.8 m vs. [CHE/BEV] 20.7 m (p = 0.024). PFS benefited to different degrees after first-line ICI-based treatment in each genetic classification. KRAS G12D even benefited from OS (p = 0.045). CHE/BEV prolonged mPFS of KRAS/STK11 co-mutation (p = 0.043), but decreased mPFS in G12A subtype (p = 0.026). Multivariate analysis indicated that heavy smoking history (≥20 pack-years) (HR = 0.45, p = 0.039) predicts optimistic prognosis; PS score 1 (HR = 3.604, p = 0.002) and KRAS/SMAD4 co-mutation (HR = 4.293, p = 0.027) remained as independent predictors of shorter OS. (4) Conclusions: First-line treatment with ICI benefited KRAS-mutant-NSCLC patients and resulted in non-negative predictive value for any genetic classification. Bevacizumab should be cautiously chosen for patients with KRAS G12A subtype but is recommended for KRAS/STK11 patients. KRAS/SMAD4 is a new co-mutation genotype that displayed independent risk prognostic factors in patients with advanced KRAS-mutant NSCLC.

The pattern of KRAS mutations in non-small cell lung cancer (NSCLC): A retrospective study from south-eastern Georgia.

e15110 Background: Carcinogenic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation is a common oncogenic mutation found in lung cancer. It is a gain-of-function mutation that is the most commonly mutated oncogene in NSCLC; occurs in about 30% of all lung adenocarcinomas. A lot of progress has been made in targeted therapies against other oncogenic drivers, such as EGFR, HER2, MET, BRAF mutations. However, KRAS mutant lung cancer is still very difficult to manage and options are limited. Most recently, K-ras G12C has a newly approved novel targeted therapy. Different KRAS mutations may also represent different outcomes. Multiple studies have been looking into mutant KRAS and investigating it in the clinical relevance in lung cancer. Here we characterize a cohort of KRAS subtypes in all tumor types of lung cancer from south-eastern Georgia. Methods: This is a retrospective study that evaluated patients with K-ras mutant lung cancer from Augusta, Georgia geographical area. Samples were obtained from May 15th, 2015 to January 4th, 2022 and patients with KRAS mutant lung cancers were identified via Guardant platform. Results: In our cohort of patients, a total of 622 patients were evaluated in which 531 patients had a lung cancer diagnoses. Of those 531 patients, 383 had lung adenocarcinoma, 109 lung squamous cell, 34 NSCLC, 3 small cell, 1 lung carcinoid, and 1 large cell lung carcinoma. Of the 531 lung cancer patients, 14 (2.6%) patients expressed KRAS mutation with 12 (3.1%) patients expressing KRAS with lung adenocarcinoma. NRAS was expressed separately in 2 patients and HRAS was expressed separately in 1 patient. Our cohort of patients with K-ras mutant NSCLC had TP53 co-mutation in 78 (14%), MSI-High mutation in 60 (11%) patients, and EGFR mutation in 23 (4.3%) patients. The most common KRAS subtype in lung adenocarcinoma was G12V (42%), G12C (42%), and Y64D (8.3%). Two patients were unable to identify the type of the K-ras mutation. In addition, 92% of the carriers for KRAS mutation in lung adenocarcinoma were males. Its been noted that G12C mutation is the most common; however, in south-east Georgia, G12V is as common as G12C. Conclusions: KRAS mutation subtypes have distinct genomic landscape which requires further assessment to guide future therapeutic development. In the geographical area of Augusta, Georgia, KRAS subtype G12V is as common as G12C.

Clinical characteristic and outcomes of KRAS G13 mutant non-small cell lung cancers.

e21017 Background: KRAS is the most commonly mutated oncogene in lung adenocarcinoma. Different KRAS mutations (mts) have unique prognostic and therapeutic implications. New drugs to target KRAS G12C have raised interest in studying the unique clinical and molecular characteristics of the different KRAS subtypes. We sought to evaluate the clinical outcomes of KRAS G13C/D (*) mutant (mut) non-small cell lung cancers (NSCLC) patients (pts), compared to those with G12C and other non-G12C mutations. Methods: We identified 255 KRAS mt NSCLC pts at Brown University-Lifespan Cancer Institute that were diagnosed between 06/2016 to 12/2021. Demographics, therapies and outcomes were retrospectively recorded. Progression-free (PFS) and overall survival (OS) was compared using log-rank test. For clinical relevance, we divided pts into G12C, G13*, and other non-G12C groups. Treatments (tt) received were divided into chemotherapy alone and immune-checkpoint inhibitor (IO) containing regimens. Results: Across the KRAS cohort (n = 255), median age was 71 years and 62% were females. Most pts had advanced disease (85%) at diagnosis (dx) and &gt; 90% were smokers. Most common KRAS mt was G12C (42%), and 7% of pts had G13*. Compared to other KRAS mut groups, G13 * had worse PFS counted from dx (median 4 vs 12 m, p = .037). When comparing outcomes of any tt among pts with G13*, G12C and other non-G12C KRAS mut, G13 group had the worst PFS (2.1 vs 10.3 vs 6.4 m, p = .004) and OS (4.1 vs 27.8 vs 18.1 m, p = .027). When treated with IO-based regimens, pts with G13 had also worse outcomes than those with other KRAS mts: PFS 1.8 vs 7.3 m, respectively, (p &lt; 0.001) and OS 1.8 vs 16.5 m, respectively (p = .006). Within the G13 group, pts who received IO-based regimens had worse PFS (1.8 vs 7.9 m, p = .037) and OS (1.8 vs 16.1 m, p = .093), compared to chemotherapy alone. While response to all systemic therapies was poor in G13* group (disease control rate [DCR] 10%, p = .004), DCR was particularly low with IO-based tt in G13* (0%) compared to other groups (p = .023). Conclusions: Pts with KRAS G13C/D had poor survival and response to therapies in comparison with G12C and other non-G12C KRAS mts, particularly with IO-containing regimens. Recently (Judd et al, MCT-21-0201), STK11 and KEAP1 were reported to be frequently co-mutated with KRAS G13* (37.3 and 12.6%) compared to other KRAS mts, and this genotype may confer primary resistance to IO. We hypothesize that the poor outcomes and immune resistance in G13* mut may be secondary to higher prevalence of STK11 and KEAP1 co-mutations. Larger data sets should confirm our observations and correlate them with PD-L1 scores and co-mutations.[Table: see text]

Diagnostic and Prognostic Values of KRAS Mutations on EUS-FNA Specimens and Circulating Tumor DNA in Patients With Pancreatic Cancer.

INTRODUCTION:The ability of carbohydrate antigen 19-9 (CA19-9) to differentiate pancreatic cancer from other benign pancreatic lesions is unsatisfactory. This study explored the diagnostic value of KRAS gene mutations and plasma circulating tumor DNA (ctDNA) in patients with pancreatic cancer.METHODS:The prospective cohort study comprised 149 consecutive patients with solid pancreatic lesions who underwent endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). KRAS subtype mutations were analyzed by digital droplet PCR (ddPCR) in EUS-FNA histopathology tissue samples, and blood samples were sent for plasma ctDNA analysis. The final diagnosis was based on surgical resection pathology or follow-up for at least 2 years.RESULTS:Adding KRAS mutation ddPCR increased the sensitivity and accuracy of EUS-FNA from 71.4% to 91.6% (P < 0.001) and 75.8% to 88.6% (P < 0.001), respectively. By comparison, the sensitivities of circulating biomarkers ctDNA and CA19-9 were only 35.2% and 71.2%. The area under the curve of the receiver operating characteristic curve (AUC) of EUS-FNA and KRAS ddPCR combination was >0.90 for distinguishing pancreatic cancer from benign lesions, whereas the AUC of EUS-FNA and CA19-9 combination was 0.83. The median survival time was significantly shorter in patients with G12D KRAS mutations than that in patients with other mutations (180 vs 240 days, P < 0.001).DISCUSSION:FNA tissue sample KRAS mutation analysis in tissues significantly improves the diagnostic accuracy of cyto/histopathological evaluation in EUS-FNA samples. The combination of EUS-FNA and tissue sample KRAS ddPCR provided a more accurate method for pancreatic cancer diagnosis, superior to the combination of EUS-FNA and CA19-9/ctDNA. G12D KRAS mutations in pancreatic cancer were independently associated with poor overall survival.

55P Potential benefits of extensive genomic analysis in patients with KRAS mutated solid tumors: Concurrent alterations and potential targets

The KRAS gene is mutated in approximately 22% of all tumors. This study aimed to investigate the distribution and frequency of concurrent alterations in different cancers across KRAS subtypes and in different KRAS subtypes across cancers, and to identify potentially actionable targets and patients who received targeted treatment matched to their genomic profile (GP).

Effect of KRAS and BRAF mutations in metastatic colorectal cancer patients: A systematic review and meta-analysis based on tumor sidedness and KRAS subtypes.

Metastatic or recurrent colorectal cancer (MRCRC) has a poor prognosis. The aim of the present meta-analysis was to assess the prevalence of different subtypes of KRAS mutation and BRAF mutation in metastatic CRC patients, and evaluate the relationship between the tumor sidedness and prevalence of KRAS and BRAF mutation. We searched MEDLINE/PubMed, the Cochrane Library, and ClinicalTrials.gov from January 2010 to July 2020. The data were extracted independently according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The statistical analysis was done using STATA and Meta-Disk 1.4 applications. Overall, 6699 colorectal cancer patients were included. KRAS and BRAF mutation was reported in 28% and 6% of patients, respectively. The overall prevalence of right primary and left primary metastatic CRC patients with mutated KRAS was 40% and 60%. However, the prevalence BRAF mutated right primary and left primary metastatic CRC patients was 37% and 63%. The overall HR was 2.38 for patients with metastatic CRC who had a mutated type of KRAS. Our study showed a mean overall survival of 35.4 month for KRAS mutant and a 10.12 month survival for BRAF mutant patients with metastatic colorectal cancer patients. The prevalence of KRAS and BRAF mutations varied significantly according to the location of the tumor. BRAF mutations are more commonly found in metastatic colorectal cancers on the right side. Liver was the most common site of metastases in patients with mutant KRAS and the mortality of patients with mutant KRAS was 2.3 times higher than the patients with wild types. These results help to better describe the population of mCRC patients and can have implications for improving and organizing anti-EGFR therapies. Further research is needed to assess differences in survival through mutation status and primary tumor location.