Project Genomics Evidence Neoplasia Information Research Articles

Treatment Patterns and Clinical Outcomes Among Patients With Metastatic Prostate Cancer Harboring Homologous Recombination Repair Mutations

BackgroundThere is currently limited literature assessing the real-world treatment patterns and clinical outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) mutations. MethodsMedical charts were abstracted for mCRPC patients with ≥ 1 of 12 HRR somatic gene alterations treated at US oncology centers participating in the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange. Treatment patterns and clinical outcomes were assessed from the initiation of first-line or later (1L+) mCRPC therapy received on or after July 1, 2014. ResultsAmong 138 patients included in the study, the most common somatic HRR mutations were CDK12 (47.8%), BRCA2 (22.5%), and ATM (21.0%). Novel hormonal therapy and taxane chemotherapy were most commonly used in 1L; taxane use increased in later lines. Median overall survival (95% confidence interval [CI]) was 36.3 (30.7-47.8) months from initiation of 1L therapy and decreased for subsequent lines. Similarly, there was a trend of decreasing progression-free survival and prostate-specific antigen response from 1L to 4L+ therapy. ConclusionsTreatment patterns identified in this study were similar to those among patients with mCRPC regardless of tumor HRR mutation status in the literature.

Abstract 4977: The prevalence of key oncogenic driver mutations in stage I-III non-small cell lung cancer: Results from the AACR GENIE BPC dataset

Abstract Background: While there is growing interest in targeted therapy for non-small cell lung cancer (NSCLC) in perioperative settings, data on key oncogenic driver mutations is limited in early-stage NSCLC. This real-world database study aims to evaluate the prevalence of select genomic alterations in stage I-III NSCLC. Methods: From the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) Biopharma Collaborative (BPC) V2.1-consortium dataset, we included adult patients with a confirmed diagnosis of NSCLC who had genomic testing using stage I-III NSCLC tissue samples. Descriptive statistics were used to summarize baseline characteristics and the prevalence of select genomic alterations. Results: A total of 465 patients were included in this study, of whom 61% were female, 85% were white, 19% were never smokers, and 77% had adenocarcinoma. Less than 2% of the study population had BRAF V600E, HER2 activating mutations, HER2 amplification, MET amplification, HER3 amplification, RET fusion, ALK fusion, or ROS1 fusion. Among genomic alterations with a prevalence of 2% or higher, such as EGFR sensitizing mutations, KRAS G12C, MET exon 14 skipping, STK11, KEAP1, and TP53, some variations in prevalence were observed across baseline patient and disease characteristics such as race, smoking status, and histology (Table 1). Conclusion: The prevalence of key oncogenic drivers and its relationship to select baseline disease characteristics among patients with early-stage NSCLC are similar to those of advanced NSCLC observed in other real-world clinico-genomic databases. Table 1. Prevalence of Select Genomic Alterations in Stage I-III NSCLC (N=465) Prevalence of Positive Biomarker Status (%) EGFR KRAS G12C MET Exon 14 Skipping STK11* KEAP1* TP53 Overall 17.6 12.7 4.5 16.0 11.0 52.7 Gender Male 7.1 9.3 5.5 18.5 18.5 59.6 Female 24.5 15.9 3.9 14.3 6.3 48.2 Race White 15.6 14.1 4.5 16.5 12.0 53.7 Black 15.0 5.0 5.0 22.2 11.1 60.0 Asian 44.0 4.0 8.0 8.3 4.2 44.0 Smoking Status Never smoker 41.4 1.2 6.9 4.7 1.2 36.8 Former smoker 13.7 16.0 4.6 17.4 12.9 52.4 Current smoker 5.7 12.9 1.4 23.9 15.4 72.9 Histology Adenocarcinoma 20.1 14.3 4.6 18.1 10.4 46.0 Squamous cell carcinoma 0 2.9 4.4 4.6 14.1 86.8 *The numbers of patients tested for STK11 and KEAP1 were 457 and 445, respectively. Citation Format: Ke Zu, Jiemin Ma, Cai Chen, Christine Pierce. The prevalence of key oncogenic driver mutations in stage I-III non-small cell lung cancer: Results from the AACR GENIE BPC dataset [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 4977.

Abstract 802: Molecular profile of gastric cancer in Hispanics living in Puerto Rico

Abstract Gastric cancer (GC) is the 4th leading cause of cancer death globally. The incidence and mortality rates of GC differ dramatically between racial/ethnic groupings. In the United States (U.S.), Hispanics, non-Hispanic Blacks, and Asian or Pacific Islanders are more likely to be diagnosed with GC and have a higher mortality rate than non-Hispanic Whites. Among the Hispanic population living in Puerto Rico (PRH), GC ranks among the top ten leading causes of cancer death, whereas this malignancy is not a major cause of cancer mortality in the mainland U.S. Tumor profiling approaches have resulted in the discovery of actionable gene alterations, which serve as a guide for treatment strategies and ultimately enhance the overall survival rates of individuals diagnosed with cancer. However, descriptive information regarding the genetic mutational landscape of GC tumors from PRH is limited. This study aims to describe the genomic profile of GC tumors in PRH and to identify the most prevalent genetic mutations. We retrospectively examined GC tumor mutational profiles from 106 PRH that underwent NGS testing from 2015 to 2022 (provided by CARIS Life Sciences and the Precision Oncology Alliance). We compared PRH GC tumor somatic mutation prevalence to TCGA and the AACR Project Genomics Evidence Neoplasia Information Exchange (GENIE), both available through the cBioPortal for Cancer Genomics. Descriptive statistics were performed to characterize the database. Among the top mutated genes for GC tumors in PRH were TP53 (54.1%, n=85), ARID1A (34.2%, n=73), KMT2D (30.5%, n=82), CDH1 (29.4%, n=85) and ZFHX3 (27.3%, n=55). The most frequent gene amplifications were ERBB2 (7.1%, n=84), KRAS (6.0%, n=84), and CCNE1 (4.9%, n=81). Compared to other datasets, PRH had significantly different mutational frequencies of GC driver genes like TP53, ARID1A, CDH1, and KMT2D. This study is the first to report PRH GC tumor mutational profiles and compare the mutational frequencies to other non-Hispanic and U.S. mainland Hispanic populations using TCGA and GENIE data sets. Furthermore, our study provides data on the specific mutational landscape for Hispanics with GC and the implications on therapeutic options and clinical outcomes. Developing new treatments for genomically diverse populations requires understanding the most common carcinogenic molecular pathways that affect Hispanics with GC. Citation Format: Ingrid Montes-Rodriguez, Hilmaris Centeno-Girona, Noridza Rivera, Marcia Cruz-Correa. Molecular profile of gastric cancer in Hispanics living in Puerto Rico [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 802.

Genomic drivers in craniopharyngiomas: Analysis of the AACR project GENIE database.

Craniopharyngiomas are rare tumors originating in the sellar region, with limited information on their somatic mutational landscape. In this study, we utilized a publicly available genomic database to profile the somatic mutational landscape of craniopharyngioma patients and interrogate differences based on histologic subtype. We utilized the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE)® database accessed from cBioPortal (v13.1-public) to query all patients with craniopharyngiomas. Of the 336 patients with sellar tumors, 51 (15.2%) had craniopharyngiomas. Of these 51 patients, 42 (82.4%) were adamantinomatous subtype and 9 (17.6%) were papillary subtype. In this cohort, 32 (62.7%) patients were pediatric, while 19 (37.3%) were adult. The top mutations in the cohort were: CTNNB1 (n = 37; 73%), BRAF (n = 7; 14%), ARID1B (n = 5; 10%), KMT2D (n = 4; 8%), FANCA (n = 4; 8%), ATM (n = 4; 8%), and TERT (n = 3; 8%). Of the 37 patients with CTNNB1 mutations, 8 (21.6%) had S33X, 9 (24.3%) had S37X, 7 (18.9%) had T41X, and 5 (13.5%) had D32X. In this cohort, CTNNB1 mutations tended to co-occur with ATM (n = 4; 10.8%), KMT2C (n = 4; 10.8%), TERT (n = 3; 8.1%), BLM (n = 3; 8.1%), and ERBB2/3 (n = 3; 8.1%), suggesting CTNNB1 mutations tended to co-occur with mutations in genes important in cell growth and survival, chromatin accessibility, and DNA damage response pathways. CTNNB1 mutations account for a large proportion of somatic mutations in craniopharyngiomas. Identification of specific point mutations and secondary drivers may advance development of novel craniopharyngioma preclinical models for targeted therapy testing.

Real-world prevalence of homologous recombination repair mutations in advanced prostate cancer: an analysis of two clinico-genomic databases.

Homologous recombination repair mutation (HRRm) status may guide risk-stratification and treatment decisions, including polyadenosine diphosphate-ribose polymerase inhibitor use, in advanced prostate cancer. Although HRRm prevalence has been reported in single-institution studies or clinical trials, real-world HRRm prevalence in diverse populations is unknown. We describe HRRm in the clinical setting using two real-world clinicogenomic databases: the Flatiron Health and Foundation Medicine, Inc. Clinico-Genomic Database (CGDB), a national electronic health record-derived database, and the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (GENIE). This cross-sectional analysis included 3757 individuals diagnosed with prostate cancer who had next generation sequencing (NGS) as standard of care. The CGDB included men with advanced/metastatic prostate cancer and genetic data included both germline and somatic pathogenic mutations. The GENIE analysis included men with prostate cancer whose received NGS as standard of care, but the data were filtered to include somatic mutations only. Due to key differences among databases, direct comparisons were not possible. Overall prevalence of HRRm was calculated and stratified by demographic and clinical characteristics. HRRm prevalence (combined germline and somatic) in CGDB (n = 487) was 24.6% (95% CI 20.9-28.7%), with no major differences across demographic and disease characteristic subgroups. HRRm prevalence (somatic) in GENIE (n = 3270) was 11.0% (95% CI 10.0-12.1%), which varied between 9.5% and 18.4% across treatment centers. Approximately one-quarter of patients with advanced/metastatic prostate cancer in the CGDB had germline and/or somatic HRRm, which is consistent with clinical trials such as the PROfound study that used a similar NGS platform and algorithm to define HRRm. In the GENIE database, HRRm prevalence varied by treatment center or NGS platform. More research is needed to understand real-world HRRm prevalence variations.

Metastatic prostate cancer is associated with distinct higher frequency of genetic mutations at diagnosis

Introduction and ObjectivesWe explored characteristic genetic mutations associated with metastatic prostate cancer (PCa) by comparing next generation sequencing (NGS) data between men with or without metastatic disease at diagnosis. MethodsWe queried the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (GENIE) registry for men diagnosed with PCa. Patients were categorized into with (M1) or without metastatic disease (M0) groups. The difference in the frequency of genetic mutations between the two groups and the prognostic significance of the mutations were analyzed using SPSS V28. We included frequency rate of > 5% and P values < 0.05 were considered statistically significant to maintain over 95% true positive detection rate. ResultsOf a total of 10,580 patients with diagnosis of PCa in the dataset, we selected a study cohort of 1268 patients without missing data; 700 (55.2%) had nonmetastatic PCa, 421 (33.2%) and 147 (11.6%) patients had metastatic castration sensitive and resistant PCa respectively. The median age at diagnosis and serum prostate specific antigen (PSA) level for the entire cohort was 62.8 years (IQR 56.3–68.4) and 8.0 ng/ml (IQR 4.9–20.9) respectively. A vast majority of the cohort were of Caucasian ancestry (89.1%). Of a total of 561 genes sequenced, there were mutations in 79 genes (14.1%). The mutation frequency was significantly higher in M1PCa compared to M0PCa, 35.7% and 23.3%, respectively (P = <0.001). The median tumor mutational burden was also significantly higher in the samples from M1PCa (2.59 mut/MB) compared to M0PCa (1.96 mut/MB) (P < 0.001). Compared to M0PCa patients, M1PCa patients demonstrated significantly higher rate of genetic mutations; TP53 (38.73% vs. 17.71% P < 0.001), PTEN (25.70% vs. 11.71% P < 0.001), AR (17.25% vs. 1.43% P < 0.001), APC (11.8% vs. 4.43% P < 0.001), TMPRSS2 (31.5% vs. 11.14% P < 0.001), ERG (23.59% vs. 13.13% P < 0.001), FOXA1 (17.43% vs. 6.33% P < 0.001), MYC (8.45% vs. 2.29% P < 0.001), RB1 (10.39% vs. 2.43% P < 0.001) and CDK12 (8.45% vs. 1.31% P < 0.001). Of the various cellular signaling pathways, the androgen receptor signaling pathway was most often impacted. In the cohort with M1 disease, compared to men without genetic mutations the men with genetic mutations demonstrated worse survival (P = <0.001, log rank test). Compared to castration sensitive M1 patients, AR (57% vs. 4% P < 0.001), TP53 (50.7% vs. 34% P < 0.001), PTEN (35.2% vs. 22.1% P < 0.001), RB1(23.9% vs. 4.75% P < 0.001) were significantly more frequently mutated in castration resistant M1 patients. In contrast, mutations of SPOP (13.3% vs. 7.9% P < 0.001), FOXA1 (17.6% vs. 5.3% P < 0.001) and CDK12 (12% vs. 6.45% P < 0.001) were significantly more frequently found in castration sensitive M1 patients compared to castration resistant patients. ConclusionPatients with M1PCa demonstrated characteristic genetic mutations compared to M0PCa, which most often influenced androgen receptor signaling and is associated with worse survival. In addition, we identified distinct genetic mutations between castration sensitive and resistant M1PCa. These findings may be used to further our understanding and management of men with PCa.

A Cost-Effective, Machine Learning-Based New Unified Risk-Classification Score (NU-CATS) for Patients with Endometrial Cancer

Treatment for endometrial cancer (EC) with radiotherapy is increasingly guided by molecular risk classifications. Derived from genomic profiling of The Cancer Genome Atlas (TCGA) project, several EC risk classification systems, including ProMisE and Leiden/TransPORTEC, have been developed. However, the current systems were developed on a relatively homogeneous population. Black or African American (BOAA) patients have consistently been demonstrated to have worse stage-adjusted prognosis than Caucasians. Given this, we intended to develop a new unified risk classification system (NU-CATS) for EC patients using machine learning (ML) utilizing datasets with demographically diverse populations. TCGA-Uterine Corpus Endometrial Carcinoma (n = 596), Memorial Sloan Kettering-Metastatic Events and Tropisms (MSK-MET, n = 1,315) and the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (AACR-GENIE, n = 4,561) were used to identify genetic alterations and clinicopathological features, including age, race, stage, histologic grade and features, and distribution of metastatic disease. Software packages including Keras, Pytorch, and Scikit Learn were tested to build artificial neural networks (ANNs) with a binary output as either intra-abdominal metastatic lesions vs. non-metastatic. A 5-layered ANN (5-6-4-2-1) using 5 inputs ('age at surgery', 'histology', 'race', 'mismatch repair status' and 'TP53'). The optimal performing ANN was selected and cross validated. The weights and biases of the trained ANN were used to reconstruct the algorithm. BOAA patients with EC have worse prognosis than Caucasians, adjusting for TP53 or POLE mutation status. TP53 is the most common gene differentially altered by race in EC. Over 75% of BOAA patients carry TP53 mutations as compared to approximately 40% of Caucasians. Older age is associated with an increasing likelihood of TP53 mutations, high risk histology, and distant metastasis. For patients above age 70, 91% of BOAA and 60% of Caucasian EC patients carry TP53 mutations. The NU-CATS that incorporates age, race, histology, mismatch repair (MMR) status, and TP53 mutation status showed 75% accuracy in prognosticating intra-abdominal metastasis. A higher NU-CATS (>50) is associated with about 2-fold increased risk of having positive pelvic or para-aortic lymph nodes (LNs) and distant. NU-CATS was shown to outperformed TransPORTEC model for estimating risk of FIGO Stage I/II disease progression and survival in BOAA EC patients. Despite adjusting for molecular classification, race and age retain prognostic importance in EC. NU-CATS, a ML-based, cost-effective algorithm, incorporates diverse clinicopathologic and molecular variables of EC, and yields superior prognostication of the risk of nodal involvement, distant metastasis, disease progression, and overall survival as compared to other classification systems.

Distinct genetic variants of early and late-onset prostate cancer

Background: The incidence of early-onset Prostate Cancer (PCa) has increased in the last two decades. Men diagnosed with PCa before age 55 have lower 5-year relative survival rates compared to patients diagnosed later in life. Given the enhanced lethality of early-onset PCa, our aim is to evaluate somatic differences between early and late-onset PCa. Methods: Patients with PCa were dichotomized into early (&lt; 55 years old) and late-onset PCa (≥ 55 years old). Data is derived from the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (GENIE) registry. The GENIE registry contains sequenced tumor samples and clinical data across many cancers a total of 4,546 Patients and 5,740 samples were included with pathologically confirmed prostate adenocarcinoma. The data is derived from 17 cancer centers from 2011 to 2021. Patterns in somatic gene tumor profiles were compared between early-onset and late-onset PCa using a chi-square test and logistic regression. Results: A total of 452 (11.0%) patients had early-onset PCa while 3640 (89.0%) patients had late-onset PCa. Patients with early-onset PCa were more likely to be Black (12.2% vs. 7.7%) and less likely to have metastatic disease (32.0% vs. 45.0%). After logistic regression, early-onset PCa patients had higher odds of having a mutation in CDK12 [1.51 (95% CI: 1.04-2.22)] and ERF [1.81 (95% CI: 1.02-3.24)]. Patients with a CDK12 mutation were more likely to be Black [1.92 (95% CI: 1.28-2.86); p = 0.002) and to have metastatic disease [1.53 (95% CI: 1.16-2.01); p = 0.003). Conclusion: Patients with early-onset PCa had distinct somatic gene tumor mutations in ERF and CDK12. Therapeutic targeting of genes associated with early-onset PCa can be potentially useful in future clinical studies.

Genetic mutations in smoking-associated prostate cancer.

Tobacco smoking is known to cause cancers potentially predisposed by genetic risks. We compared the frequency of gene mutations using a next generation sequencing database of smokers and nonsmokers with prostate cancer (PCa) to identify subsets of patients with potential genetic risks. Data from the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (GENIE) registry was analyzed. The GENIE registry contains clinically annotated sequenced tumor samples. We included 1832 men with PCa in our cohort, categorized as smokers and nonsmokers, and compared the frequency of mutations (point mutations, copy number variations, and structural variants) of 47 genes with more than 5% mutation rate between the two categories and correlated with overall survival using logistic regression analysis. Overall, 1007 (55%) patients were nonsmokers, and 825 (45%) were smokers. The mutation frequency was significantly higher in smokers compared to nonsmokers, 47.6% and 41.3%, respectively (p = 0.02). The median tumor mutational burden was also significantly higher in the samples from smokers (3.59 mut/MB) compared to nonsmokers (1.87 mut/MB) (p < 0.001). Patients with a smoking history had a significantly higher frequency of PREX2, PTEN, AGO2, KMT2C, and a lower frequency of adenomatous polyposis coli (APC) and KMT2A mutations than compared to nonsmokers. The overall mortality rate (28.5% vs. 22.8%) was significantly higher among smokers (p = 0.006). On a multivariate logistic regression analysis, the presence of metastatic disease at the time of diagnosis (OR: 2.26, 95% CI: 1.78-2.89, p < 0.001), smoking history (OR: 1.32, 95% CI: 1.05-1.65, p = 0.02), and higher frequency of PTEN somatic gene mutation (OR: 1.89, 95% CI: 1.46-2.45, p < 0.001) were independent predictors of increased overall mortality among patients with PCa. Patients with PTEN mutation had poorer overall survival compared to men without PTEN mutations: 96.00 (95% CI: 65.36-113.98) and 120.00 (95% CI: 115.05-160.00) months, respectively (p < 0.001) irrespective of smoking history although the G129R PTEN mutation was characteristically detected in smokers. PCa patients with a tobacco smoking history demonstrated a significantly higher frequency of somatic genetic mutations. Whereas mutations of PREX2, KMT2C, AGO2, and PTEN genes were higher in smokers, the APC and KMT2A mutations were higher in nonsmokers. The PTEN somatic gene mutation was associated with increased overall mortality among patients with PCa irrespective of smoking history. We found that G129R PTEN mutation known to reduce the PTEN phosphatase activity and K267Rfs*9 a frameshift deletion mutation in the C2 domain of PTEN associated with membrane binding exclusively detected in smokers and nonsmokers, respectively. These findings may be used to further our understanding of PCa associated with smoking.

Evaluation and Comparison of Real-World Databases for Conducting Research in Patients With Colorectal Cancer.

Evaluating whether patient populations in clinico-genomic oncology databases are comparable with whom in other databases without genomic component is important. Four databases were compared for colorectal cancer (CRC) cases and stage IV CRC cases: American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange Biopharma Collaborative (GENIE-BPC), The Cancer Genome Atlas (TCGA), SEER-Medicare, and MarketScan Commercial and Medicare Supplemental claims databases. These databases were also compared with the SEER registry database which serves as national benchmarks. Demographics, clinical characteristics, and overall survival were compared in patients with newly diagnosed CRC and patients with stage IV CRC across databases. Treatment patterns were further compared in patients with stage IV CRC. A total of 65,976 patients with CRC and 13,985 patients with stage IV CRC were identified. GENIE-BPC had the youngest patient population (mean age [years]: CRC, 54.1; stage IV CRC, 52.7). SEER-Medicare had the oldest patient population (CRC, 77.7; stage IV CRC, 77.3). Most patients were male and of White race across databases. GENIE-BPC had the highest proportion of patients with stage IV CRC (48.4% v other databases 13.8%-25.4%) and patients receiving treatments (95.7% v 37.6%-59.1%). Infusional fluorouracil, leucovorin, and oxaliplatin with or without bevacizumab was the most common regimen across databases accounting for 47.3%-78.5% of patients receiving first line of therapy. The median survival from diagnosis was 36, 94, 44 months (CRC) and 23, 36, 15 months (stage IV CRC) for patients in GENIE-BPC after left truncation, TCGA, and SEER-Medicare databases, respectively. Compared with other databases, GENIE-BPC had the youngest patients with CRC with the most advanced disease and the largest proportion of patients receiving treatment. Investigators should consider adjustments when extrapolating results from clinico-genomic databases to the general CRC population.

A cost-effective, machine learning-based new unified risk-classification score (NU-CATS) for patients with endometrial cancer

IntroductionTreatment for endometrial cancer (EC) is increasingly guided by molecular risk classifications. Here, we aimed at using machine learning (ML) to incorporate clinical and molecular risk factors to optimize risk assessment. MethodsThe Cancer Genome Atlas-Uterine Corpus Endometrial Carcinoma (n = 596), Memorial Sloan Kettering-Metastatic Events and Tropisms (n = 1315) and the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (n = 4561) datasets were used to identify genetic alterations and clinicopathological features. Software packages including Keras, Pytorch, and Scikit Learn were tested to build artificial neural networks (ANNs) with a binary output as either intra-abdominal metastatic progression (‘1’) vs. non-metastatic (‘0’). ResultsBlack patients with EC have worse prognosis than White patients, adjusting for TP53 or POLE mutation status. Over 75% of Black patients carry TP53 mutations as compared to approximately 40% of White patients. Older age is associated with an increasing likelihood of TP53 mutation, high risk histology, and distant metastasis. For patients above age 70, 91% of Black and 60% of White EC patients carry TP53 mutations. A ML-based New Unified classifiCATion Score (NU-CATS) that incorporates age, race, histology, mismatch repair status, and TP53 mutation status showed 75% accuracy in prognosticating intra-abdominal progression. A higher NU-CATS is associated with an increasing risk of having positive pelvic or para-aortic lymph nodes and distant metastasis. NU-CATS was shown to outperform Leiden/TransPORTEC model for estimating risk of FIGO Stage I/II disease progression and survival in Black EC patients. ConclusionThe NU-CATS, a ML-based, cost-effective algorithm, incorporates diverse clinicopathologic and molecular variables of EC and yields superior prognostication of the risk of nodal involvement, distant metastasis, disease progression, and overall survival.

Distinguishing primary mucinous ovarian tumors from metastases of non-gynecologic mucinous cancers: Can we leverage next-generation sequencing?

5582 Background: Primary mucinous ovarian cancers (MOC) are histopathologically challenging to differentiate from ovarian metastases of non-gynecologic origin, with this distinction being critical for appropriate management and prognosis. We compared the somatic gene variant landscape of MOC to that of non-gynecologic mucinous tumors. Methods: Data were extracted from the American Association for Cancer Research’s (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database version 13.0 via cBioPortal. This publicly available, multi-institutional database provides next generation sequencing (NGS) genomic profiles of tumors. We queried this database for samples of MOC, mucinous colorectal cancer (MCRC), mucinous appendiceal cancer (MAC), mucinous breast cancer (MBC) and gastric type mucinous cancer (GMC). Frequencies of somatic gene variants including mutations, copy number alterations and structural variants were compared using Chi-squared or Fischer’s exact tests, using the Benjamini-Hochberg method to control for multiple hypothesis testing with q-values reported. Results: A total of 883 tumors were included for analysis: 358 MCRC, 268 MAC, 157 MOC, 59 MBC and 41 GMC samples. Compared to MAC, MOC samples had higher variant frequencies of CDKN2A (33.3% vs 0.4%, q&lt;0.001), CDKN2B (24.0% vs 0.0%, q&lt;0.001), TP53 (64.3% vs 23.5%, q&lt;0.001), ERBB2 (14.3% vs 1.1%, q&lt;0.001) and CDK12 (13.2% vs 0.0%, q&lt;0.001), whereas GNAS variants were more common in MAC (45.5% vs 5.7%, q&lt;0.001). Compared to MCRC, MOC samples had higher variant frequencies of CDKN2A (33.3% vs 2.3%, q&lt;0.001), CDKN2B (24.0% vs 3.7%, q&lt;0.001), TP53 (64.3% vs 42.9%, q&lt;0.001), KRAS (69.4% vs 51.1%, q&lt;0.001) and ERBB2 (14.3% vs 5.3%, q&lt;0.001), whereas MCRC had higher variant frequencies of 57 genes, with the largest differentials among APC (48.8% vs 2.6%, q&lt;0.001), SMAD4 (25.2% vs 5.8%, q&lt;0.001) and TCF7L2 (19.0% vs 0.0%, q&lt;0.001). Samples of MOC had significantly higher rates of KRAS variants compared to GMC (69.4% vs 31.7%, q&lt;0.001) and lower rates of STK11 variants (1.9% vs 22.0%, q&lt;0.001). Compared to MBC, MOC samples had higher variant rates of CDKN2A (33.3% vs 3.4%, q&lt;0.001), TP53 (64.3% vs 10.2%, q&lt;0.001) and KRAS (69.4% vs 0.0%, q&lt;0.001), whereas MBC samples had higher variant frequencies of 11 genes, with the largest differentials among GATA3 (32.1% vs 0.8%, q&lt;0.001), FGF3 (30.4% vs 2.4%, q&lt;0.05) and CCND1 (28.1% vs 1.6%, q&lt;0.001). Conclusions: NGS demonstrates that MOCs carry a distinct genetic signature compared to mucinous tumors of non-gynecologic origin, most commonly with significantly higher variant frequencies of CDKN2A, CDKN2B and lower variant frequencies of GNAS, APC, STK11 and GATA3. This provides rationale for prospective studies evaluating genetic signatures as an adjunct to histopathology in the diagnosis of primary MOC.

The spectrum of homologous recombination deficiency in cervical cancer: Is it also a cervical issue?

5543 Background: Tumors deficient in homologous recombination DNA damage repair (HR-DDR) demonstrate sensitivity to therapeutic agents targeting the HR-DDR pathway, such as poly-ADP ribose phosphate (PARP) inhibitors. The landscape of homologous recombination deficiency (HRD) is not well-characterized for cervical cancer; thus, we sought to analyze the prevalence of somatic pathogenic gene variants (PGVs) in HRD genes in cervical cancers. Methods: The American Association for Cancer Research’s (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database version 13.0 was queried for all cervical cancer tumors via cBioPortal (http://genie.cbioportal.org). This is a publicly available, multi-institutional database of next-generation sequencing (NGS) genomic profiles of multiple tumors. PGV frequencies of 27 genes involved in HR-DDR were descriptively reported for cervical cancer tumors, with histologic stratification: ATM, ARID1A, ATRX, BRCA1, BRCA2, BARD1, BRIP1, BLM, BAP1, CHEK1, CHEK2, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCL, MRE11, NBN, PALB2, RAD50, RAD51, RAD51B, RAD51C, RAD51D, WRN. Results: A total of 857 cervical tumors from 817 patients were included for analysis. At least one somatic PGV in an HRD gene was found in 16.5% of all tumors (141/857). When stratified by histological subtypes with at least 25 tumors sequenced, highest frequencies of ≥1 PGV in HRD genes were observed in mucinous cervical cancer (13/66, 19.7%), cervical adenocarcinoma (48/262, 18.3%), squamous cell cervical cancer (53/349, 15.2%), adenosquamous cervical cancer (6/43, 14.0%) and neuroendocrine cervical cancers (5/42, 11.9%). Substantial rates of PGVs in HRD genes were also observed in histological subtypes with fewer than 25 sequenced tumors. Across all tumors, HRD genes with the highest frequencies of PGVs were ARID1A (9%), BAP1 (3%), ATM (1.6%) and BRCA1 (1.6%). Conclusions: NGS data demonstrate a substantial rate of somatic PGVs in HRD genes in cervical cancers, including among HPV related subtypes. These data suggest the need to expand routine functional HRD status assessment to cervical cancers in order to further characterize the landscape of HRD in these tumors. Furthermore, genetically driven clinical trials are warranted to evaluate the efficacy of HRD-targeted therapies such as PARP inhibitors, ataxia telangiectasia, and Rad-3 related kinase (ATR) inhibitors. [Table: see text]

Hereditary breast and ovarian cancer syndrome: A misnomer?

10594 Background: Germline pathogenic gene variants (PGV) in homologous recombination deficiency (HRD) genes are traditionally associated with breast, ovarian, pancreatic, prostate and melanoma skin cancer. Recent evidence suggests other cancers may also be associated with these genes. We analyzed the prevalence of somatic HRD mutations in common, traditionally non-hereditary breast and ovarian cancer (HBOC) associated incident cancers in the US. Methods: Data were collected from the American Association for Cancer Research’s (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database version 13.0 via cBioPortal (http://genie.cbioportal.org). This is a publicly available, multi-institutional database of next-generation sequencing (NGS) genomic profiles of tumor samples. The database was queried for all cancers with at least 20,000 incident cases in 2022, as reported by the American Cancer Society, excluding well established HBOC associated cancers – breast, ovarian, prostate, pancreatic, melanoma. Frequencies of somatic PGVs were reported for nine HRD genes currently included in National Comprehensive Cancer Network (NCCN) management guidelines for HBOC: ATM , BARD1, BRCA1, BRCA2, BRIP1, CHEK2, PALB2, RAD51C and RAD51D. Results: A total of 78,285 tumor samples across 12 cancer types were included. At least 1 somatic HRD was found in 6.8% of all included tumors. At least 1 HRD PGV was most common in: Uterine Cancer (694/5,760, 12.1%), Non-Melanoma Skin Cancer (127/1,209, 10.5%), Bladder Cancer (462/4,605, 10.0%), Colorectal Cancer (1306/14,625, 8.9%) Non-Hodgkin’s Lymphoma (5/58, 8.6%), Esophagogastric Cancer (356/4,649, 7.7%), Hepatobiliary Cancer (219/3,325, 6.6%), Lung Cancer (1,480/23,621, 6.3%), Kidney Cancer (113/2,564, 4.4%), Brain Cancer (420/10,206, 4.1%), Thyroid Cancer (89/2,246, 4.0%) and Leukemia (80/5,417, 1.5%). The most common PGVs across all cancer types were BRCA1/2 and ATM (Table). Conclusions: A pan-cancer analysis using NGS data demonstrates a substantial rate of somatic HRD PGVs in common, traditionally non-HBOC associated cancers in the US. These data raise the possibility that germline pathogenic variants in HRD genes could be associated with several more cancers than currently known, underscoring the need for studies evaluating risks of the aforementioned cancers in germline PGV carriers. Additionally, these findings present opportunities for trials evaluating the efficacy of HRD-targeting therapies in these cancers. [Table: see text]

The GENIE BPC NSCLC Cohort: A Real-World Repository Integrating Standardized Clinical and Genomic Data for 1,846 Patients with Non-Small Cell Lung Cancer.

We describe the clinical and genomic landscape of the non-small cell lung cancer (NSCLC) cohort of the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) Biopharma Collaborative (BPC). A total of 1,846 patients with NSCLC whose tumors were sequenced from 2014 to 2018 at four institutions participating in AACR GENIE were randomly chosen for curation using the PRISSMM data model. Progression-free survival (PFS) and overall survival (OS) were estimated for patients treated with standard therapies. In this cohort, 44% of tumors harbored a targetable oncogenic alteration, with EGFR (20%), KRAS G12C (13%), and oncogenic fusions (ALK, RET, and ROS1; 5%) as the most frequent. Median OS (mOS) on first-line platinum-based therapy without immunotherapy was 17.4 months [95% confidence interval (CI), 14.9-19.5 months]. For second-line therapies, mOS was 9.2 months (95% CI, 7.5-11.3 months) for immune checkpoint inhibitors (ICI) and 6.4 months (95% CI, 5.1-8.1 months) for docetaxel ± ramucirumab. In a subset of patients treated with ICI in the second-line or later setting, median RECIST PFS (2.5 months; 95% CI, 2.2-2.8) and median real-world PFS based on imaging reports (2.2 months; 95% CI, 1.7-2.6) were similar. In exploratory analysis of the impact of tumor mutational burden (TMB) on survival on ICI treatment in the second-line or higher setting, TMB z-score harmonized across gene panels was associated with improved OS (univariable HR, 0.85; P = 0.03; n = 247 patients). The GENIE BPC cohort provides comprehensive clinicogenomic data for patients with NSCLC, which can improve understanding of real-world patient outcomes.

Molecular profiling of colorectal cancer in a genetically admixed Hispanic population.

Colorectal cancer (CRC) is among the leading causes of cancer-related deaths among Hispanics living in the United States (USH). Understanding the most common carcinogenic molecular pathways that affect Hispanics with CRC is crucial to guide research efforts in developing new therapeutic modalities incorporating genomically diverse populations. Tumor profiling techniques help identify actionable alternatives to recommend treatment and improve survival in cancer patients. We conducted a secondary data analysis to evaluate the mutational profile of 218 CRC tumors in Hispanics living in Puerto Rico (PRH) who underwent next-generation sequencing (NGS) testing from 2015 to 2020. We compared the prevalence of CRC tumor somatic mutations in PRHs with the mutational profiles reported for CRC from The Cancer Genome Atlas (TCGA) Pan-Cancer Clinical Data, the AACR Project Genomics Evidence Neoplasia Information Exchange (GENIE)-Non-Hispanic, and GENIE-Hispanic datasets. Among the top mutated genes in CRC tumors in PRHs were APC, TP53, and KRAS, which had significantly higher mutational frequencies in PRH compared to the examined datasets, including GENIE-Hispanics. The most frequent gene amplifications for PRH were CDX2, CDKN1B, and HNRNPA2B1. Targetable biomarkers for CRC, such as microsatellite instability-high (MSI), wild-type KRAS, wild-type NRAS, V600E BRAF, and ERBB2 gene amplifications were found in 2.0%, 43.8%, 97.8%, 3.9%, and 2.3%, respectively, of PRH patients. This is the first study to report the mutational profile of CRC tumors in PRHs and make comparisons to other non-Hispanic and USH populations.

Abstract 930: Treatment patterns and overall survival among men with metastatic castration-resistant prostate cancer harboring DDR mutations

Abstract Background: Limited information is available about treatments and clinical outcomes among men with metastatic castration-resistant prostate cancer (mCRPC) whose tumors harbor DNA damage repair (DDR) mutations. Methods: This retrospective chart review study included men diagnosed with mCRPC with ≥1 DDR mutation detected by tumor comprehensive genomic profiling who began a line of therapy on or after July 1, 2014, at oncology centers in the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) consortium. The index date was the initiation of a new therapy in this period, in patients who developed castration-resistant disease and progressed while receiving androgen deprivation therapy. Data on all available lines of therapy post-index were collected. Outcomes reported include time to treatment discontinuation for any reason (TTTD) and overall survival (OS), which were assessed using Kaplan-Meier analyses. Results for tumor response-related endpoints are forthcoming. Results: A total of 138 patients with mCRPC met the inclusion criteria. The mean age at index was 68 years, and 76% of patients were White. The median follow-up time was 27.1, 15.9, 11.3, and 9.4 months for 1L, 2L, 3L, and 4L+ therapy, respectively. Common sites of metastases included bone (74%), lymph nodes (69%), and lungs (10%). Common tumor DDR mutations included CDK12 (48%), BRCA2 (23%), ATM (21%), and BRCA1 (8%). Assessment of germline mutations was conducted in 114 (83%) patients; the most common was BRCA2 (8%). First-line (1L) treatment information was available for 119 (86%) patients, 2L for 101 (73%), and 3L for 75 (54%) patients. Novel hormonal therapy (NHT; 55%) and taxane chemotherapy (20%) were most common in 1L. Enzalutamide (35%) and abiraterone acetate (14%) were the most frequently used NHTs. Compared to 1L, the proportion of patients receiving NHTs was lower in 2L (33%) and 3L (17%), while the proportion of patients receiving taxanes was higher (36% in 2L and 31% in 3L). In 3L, poly ADP-ribose polymerase (PARP) inhibitors were used in 21% of patients. Median TTTD was 5.6 months (95% CI: 4.2, 7.2) in 1L, 3.9 months (95% CI: 3.0, 4.6) in 2L, and 4.0 months (95% CI: 3.3, 4.7) in 3L. Median OS was 36.3 months (95% CI: 30.7, 47.8) from the start of 1L, 21.1 months (95% CI: 15.6, 29.3) from the start of 2L, and 14.1 months (95% CI: 9.5, 20.5) from the start of 3L. Conclusions: These findings provide real-world insights about treatment patterns and clinical outcomes among patients with mCRPC harboring DDR mutations. Such insight may provide a helpful benchmark for research aimed at improving clinical outcomes, particularly in later lines of therapy. Citation Format: David B. Solit, Niharika B. Mettu, Shannon J. McCall, Mallika Dhawan, Priyanka J. Bobbili, Maral DerSarkissian, Jasmina Ivanova, Bhakti Arondekar, Jane Chang, Alexander Niyazov, Jocelyn Lee, Risha Huq, Michelle Green, Michelle Turski, Aruna Muthukumar, Tracy Guo, Mei Sheng Duh, William K. Oh. Treatment patterns and overall survival among men with metastatic castration-resistant prostate cancer harboring DDR mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 930.

Abstract 4262: Genomic profiling of uveal melanoma patients using the GENIE database

Abstract Uveal melanoma (UM) is the most common primary adult intraocular tumor. Frequently mutated genes in UM include BAP1, EIF1AX, GNA11, GNAQ CHEK2, and SF3B1. This study aims to investigate the genomic characteristics of UM patients using a large cohort of clinicogenomic data. We assessed the frequency of genetic mutations in UM patients obtained from the AACR Project Genomics Evidence Neoplasia Information Exchange (GENIE) cohort v12.1. We excluded patients with samples from a local recurrence, not otherwise specified tumor samples, and data not collected for sampling localization from our cohort. A total of 296 UM patients were included in this study, 164 (55.4%) of which were male and 131 (44.6%) were female. The sample mean age was 59.5 (SD: 14.1), and most patients were of white ethnicity (83.8%). Of 243 patients with known vital status, 32.1% (n = 78) of them were alive, while 67.9% (n = 165) of them were deceased. Sequencing samples were collected from the primary tumor in 141 patients, and from a metastatic nodule in 146 patients. We found that GNAQ and GNA11 were mutated in 43.9% and 43.6% of patients, respectively. BAP1 was mutated in 35.1%, SF3B1 in 22.3%, and EIF1AX in 13.2% of patients. No patients had GNAQ and GNA11 mutations concurrently. All patients had a median mutation count of 3, with no differences between the two genders. No significant differences were found in the frequency of mutations in regard to gender. GNAQ and GNA11 mutations were identified to be the most frequent mutations among UM patients, with a mutual exclusivity relationship between the two genes. New therapeutic modalities should consider the comprehensive genomic profiling of UM patients to improve their overall survival rate and quality of life. Citation Format: Shaden Tashtoush, Ashaar Al-Akhras, Alina Ghazou, Sebawe Syaj. Genomic profiling of uveal melanoma patients using the GENIE database. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4262.

PD10-11 DISTINCT CLINICAL GENOMIC VARIATIONS AMONG MEN WITH LOCALIZED VS METASTATIC PROSTATE CANCER

You have accessJournal of UrologyCME1 Apr 2023PD10-11 DISTINCT CLINICAL GENOMIC VARIATIONS AMONG MEN WITH LOCALIZED VS METASTATIC PROSTATE CANCER Ahmed El-shafie, Mohammed Al-Toubat, Allison H. Feibus, SeyedBehzad Jazayeri, Soroush Bazargani, Devon Thomas, Mark Bandyk, and K.C. Balaji Ahmed El-shafieAhmed El-shafie More articles by this author , Mohammed Al-ToubatMohammed Al-Toubat More articles by this author , Allison H. FeibusAllison H. Feibus More articles by this author , SeyedBehzad JazayeriSeyedBehzad Jazayeri More articles by this author , Soroush BazarganiSoroush Bazargani More articles by this author , Devon ThomasDevon Thomas More articles by this author , Mark BandykMark Bandyk More articles by this author , and K.C. BalajiK.C. Balaji More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003250.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Our objective was to identify unique genetic mutations associated with metastatic prostate cancer (PCa) by comparing next generation sequencing (NGS) data between men with localized and metastatic disease METHODS: We queried the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (GENIE) registry for men diagnosed with PCa. Patients were categorized into localized (m0) and metastatic (m1) groups. The difference in the frequency of genetic mutations between the two groups and the prognostic significance of the differentially expressed genes were analysed using SPSS V24. We included frequency rates of >5% and p values <0.05 were considered statistically significant to maintain over 95% true positive detection rate. RESULTS: A total of 1,027 patients, with localized (n=459) and metastatic PCa (n=568) were included in the study. Patients were mostly non-Hispanic White men (89%) with a median age of 61 years (IQR 56-66 years). 421 (41%) of our cohort had Gleason grade group (GG) 2 disease, 277 (27%) had GG3 disease, and 267 (26%) had GG4 or GG5 disease. We identified alterations in 89 genes in our analyses. Patients with M1PCa had significantly higher genomic aberrations in TMPRSS2 (31.51% vs 11.14%, p<0.001); ERG fusion (23.59% vs 13.13%, p<0.001); PTEN loss (25.7% vs 16.16%, p<0.001); TP53 mutation (38.73% vs 12.23%, p<0.001); FOXA1 (17.43% vs 6.33%, p<0.001); KMT2C (9.51% vs 6.11%, p=0.02) (Figure 1). We then isolated the signalling pathways most likely to be affected by these mutations, and found that the androgen receptor was most often impacted (Figure 2). Patients with alterations in all 6 of the genes listed above had the worst progression-free survival (p = <0.01, log rank test) (Figure 1). CONCLUSIONS: In M1PCa, patients had significantly higher frequency of TMPRSS2, ERG, PTEN loss, TP53, FOXA1, and KMT2C somatic gene mutations compared to samples from patients with m0PCa. Additionally, patients who had mutations in all 6 of these genes harboured more aggressive cancer and poorer outcomes. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e330 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ahmed El-shafie More articles by this author Mohammed Al-Toubat More articles by this author Allison H. Feibus More articles by this author SeyedBehzad Jazayeri More articles by this author Soroush Bazargani More articles by this author Devon Thomas More articles by this author Mark Bandyk More articles by this author K.C. Balaji More articles by this author Expand All Advertisement PDF downloadLoading ...

MP46-02 LYMPHOVASCULAR INVASION IN NON-METASTATIC MUSCLE INVASIVE BLADDER CANCER IS ASSOCIATED WITH CHARACTERISTIC GENETIC MUTATIONS

You have accessJournal of UrologyCME1 Apr 2023MP46-02 LYMPHOVASCULAR INVASION IN NON-METASTATIC MUSCLE INVASIVE BLADDER CANCER IS ASSOCIATED WITH CHARACTERISTIC GENETIC MUTATIONS Mohammed Al-Toubat, Ahmed El-Shafie, Allison H. Feibus, Seyedbehzad Jazayeri, Naser Mubarak, Khalid Mohammed, and Mark Bandyk K. C. Balaji Mohammed Al-ToubatMohammed Al-Toubat More articles by this author , Ahmed El-ShafieAhmed El-Shafie More articles by this author , Allison H. FeibusAllison H. Feibus More articles by this author , Seyedbehzad JazayeriSeyedbehzad Jazayeri More articles by this author , Naser MubarakNaser Mubarak More articles by this author , Khalid MohammedKhalid Mohammed More articles by this author , and Mark Bandyk K. C. BalajiMark Bandyk K. C. Balaji More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003292.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Lymphovascular invasion (LVI) in invasive bladder cancer is strongly associated with metastatic disease. We aim to identify the genes that could be the potential drivers of LVI in non-metastatic lymph node negative muscle invasive bladder cancer (M0N0MIBC). METHODS: We queried the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (GENIE) registry. Key genes were identified in respect to LVI status in 316 patients with M0N0MIBC. The relationships among LVI-associated genomic subtypes, clinicopathological features and patient outcomes were explored. All patients had imaging and pathologic evaluation to ensure M0 and N0 status. We included frequency rates of > 5% and p/q values <0.05 were considered statistically significant to maintain >95% true positive detection rate. SPSS V24 was used for analyses. RESULTS: A total of 316 patients were included in our study cohort, all of which had M0N0MIBC disease. Overall, 112 (35.4%) patients had LVI-positive and 204 (64.6%) patients were LVI-negative. Male patients constituted the majority of the cohort [230 (72.8%)]. 248 men (78.5%) in the cohort were Caucasian. Median age was 70 years (65-75 IQR). At the time of the analysis, 312 (98%) patients had not received any systemic treatment. LVI was associated with a higher T stage and more aggressive grade (p=0.02). We identified alterations in 56 genes. Patients with LVI had significantly higher mutation alterations rate in 7 genes (p<0.001) - CDKN2A, CDKN2ADT, CDKN2B, MTAP, HMCN1, DMRTA1, KMT2D. There was downregulation of 3 genes - RB1, SOX4 and CDKAL1 among those with LVI (Figure 1). Patients with LVI had a shorter overall survival (p<0.001) and a shorter 5 year progression-free survival (p<0.001) (Figure 2). CONCLUSIONS: Imbalance between genetic expression of extracellular matrix components (HMCN1) and cell-cycle regulators (CDK family) could initiate LVI in association with disease progression in patients with N0M0MIBC. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e630 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Mohammed Al-Toubat More articles by this author Ahmed El-Shafie More articles by this author Allison H. Feibus More articles by this author Seyedbehzad Jazayeri More articles by this author Naser Mubarak More articles by this author Khalid Mohammed More articles by this author Mark Bandyk K. C. Balaji More articles by this author Expand All Advertisement PDF downloadLoading ...