Differences In Genomic Alterations Research Articles

Ancestry-, Sex-, and Age-Based Differences of Gene Alterations in NSCLC: From the Real-World Data of Cancer Genomic Profiling Tests.

Some genomic alterations in non-small cell lung cancer (NSCLC) are known to differ according to race, sex, or age. These studies have been limited in sample size and thus they cannot detect the differences precisely and comprehensively. Tissue-based comprehensive genomic profiling was performed on 75,362 patients with NSCLC from the United States during routine clinical care. Additionally, we examined data of a Japanese NSCLC cohort with 1,019 patients. In the US cohort, 296 genes were examined for pathogenic alterations. Predominant genetic ancestry was inferred using a SNP-based approach, and patients were categorized into European (EUR), African (AFR), East Asian (EAS), Admixed American (AMR), and South Asian (SAS) ancestry groups. Patients were additionally stratified by histologic type, age (<40/≥40 years, <75/≥75 years), and sex. The prevalence of high tumor mutational burden (TMB-High) and microsatellite instability status was also calculated. Stratified by ancestry, EGFR alterations were significantly enriched in EAS versus other ancestry groups. The prevalence of ALK was significantly higher in the AMR, EAS, and SAS patients than in AFR and EUR patients. KRAS and STK11 were enriched in EUR and AFR patients versus other groups. TMB-High was significantly enriched in AFR patients versus all other groups. An analysis based on sex revealed differences in prevalence of alterations in 80 genes and TMB-High status. For example, EGFR, ALK, BRAF, and KRAS alterations were significantly enriched in females, whereas TP53, STK11, KEAP1, and TMB-High were significantly enriched in males. With respect to age, the prevalence of alterations in 41 genes, including ALK, RET, MET, EGFR, STK11, KEAP1, BRAF, and KRAS, as well as TMB-High, were significantly different between patients aged <40 years and those aged ≥40 years. Comprehensive analysis from a large real-world dataset revealed ancestry-associated differences in genomic alterations in NSCLC. Age- and sex-related differences in prevalence of genomic alterations and TMB-High status were also observed.

Urachal and Nonurachal Adenocarcinomas of the Urinary Bladder: A Comprehensive Genomic Profiling Study.

Although both urachal (U) and nonurachal (NU) bladder adenocarcinomas (adenoCas) share several histologic similarities, they differ in location and sometimes in therapeutic options. We analyzed the differences in genomic alterations (GAs) between these tumor entities, with the aim of identifying potential therapeutic targets for clinical trials. Overall, 133 U and 328 NU adenoCas were analyzed. Hybrid capture-based comprehensive genomic profiling (CGP) was performed to evaluate all classes of GA. Germline status of GA was predicted using a validated somatic-germline computational method. CGP was performed using the FoundationOne and FoundationOne CDx assays (Foundation Medicine, Inc). The most frequent GA in both U and NU cohorts included TP53 (86.5% v 81.1%) and KRAS (34.6% v 27.7%). GAs characteristic of colorectal adenoCa, such as SMAD4 (P = .069) and GNAS (P = .071), were more common in U versus NU. Conversely, TERT (P < .01) and RB1 (P = .071) were more prevalent in NU adenoCa. Notably, both U and NU adenoCas exhibited possibly targetable GA in PIK3CA (7.5% v 7.9%) and ERBB2 (6.8% v 7.6%). Biomarkers associated with potential benefit from anti-PD-1/L1 were infrequent. Median tumor mutational burden was 2.6 and 3.5 mutations per megabase for U and NU, respectively, and PD-L1 expression >1% was rare. Genomic ancestry and genomic signature distribution were similar in both tumor types. GAs were most commonly of somatic nature. Limitations include lack of clinical data, tumor heterogeneity, and retrospective nature. U and NU adenoCAs revealed differences in GA, with PIK3CA and ERBB2 being identified as putative therapeutic targets. Biomarkers of response to anti-PD-(L)1 were uncommon. Results highlight the potential of CGP to personalize treatment options of bladder adenoCa and inform clinical trial designs.

Sex- and Age-Associated Differences in Genomic Alterations among Patients with Advanced Non-Small Cell Lung Cancer (NSCLC).

Genomic mutations impact non-small cell lung cancer (NSCLC) biology. The influence of sex and age on the distribution of these alterations is unclear. We analyzed circulating-tumor DNA from individuals with advanced NSCLC from March 2018 to October 2020. EGFR, KRAS, ALK, ROS1, BRAF, NTRK, ERBB2, RET, MET, PIK3CA, STK11, and TP53 alterations were assessed. We evaluated the differences by sex and age (<70 and ≥70) using Fisher's exact test. Of the 34,277 samples, 30,790 (89.83%) had a detectable mutation and 19,923 (58.12%) had an alteration of interest. The median age of the ctDNA positive population was 69 (18-102), 16,756 (54.42%) were female, and 28,835 (93.65%) had adenocarcinoma. Females had more alterations in all the assessed EGFR mutations, KRAS G12C, and ERBB2 ex20 ins. Males had higher numbers of MET amp and alterations in STK11 and TP53. Patients <70 years were more likely to have alterations in EGFR exon 19 del/exon 20 ins/T790M, KRAS G12C/D, ALK, ROS1, BRAF V600E, ERBB2 Ex20ins, MET amp, STK11, and TP53. Individuals ≥70 years were more likely to have alterations in EGFR L861Q, MET exon 14 skipping, and PIK3CA. We provided evidence of sex- and age-associated differences in the distribution of genomic alterations in individuals with advanced NSCLC.

Genomic characterization and immunotherapy for microsatellite instability-high in cholangiocarcinoma

BackgroundMicrosatellite instability-high (MSI-H) is a unique genomic status in many cancers. However, its role in the genomic features and immunotherapy in cholangiocarcinoma (CCA) is unclear. This study aimed to systematically investigate the genomic characterization and immunotherapy efficacy of MSI-H patients with CCA.MethodsWe enrolled 887 patients with CCA in this study. Tumor samples were collected for next-generation sequencing. Differences in genomic alterations between the MSI-H and microsatellite stability (MSS) groups were analyzed. We also investigated the survival of PD-1 inhibitor-based immunotherapy between two groups of 139 patients with advanced CCA.ResultsDifferential genetic alterations between the MSI-H and MSS groups included mutations in ARID1A, ACVR2A, TGFBR2, KMT2D, RNF43, and PBRM1 which were enriched in MSI-H groups. Patients with an MSI-H status have a significantly higher tumor mutation burden (TMB) (median 41.7 vs. 3.1 muts/Mb, P < 0.001) and more positive programmed death ligand 1 (PD-L1) expression (37.5% vs. 11.9%, P < 0.001) than those with an MSS status. Among patients receiving PD-1 inhibitor-based therapy, those with MSI-H had a longer median overall survival (OS, hazard ratio (HR) = 0.17, P = 0.001) and progression-free survival (PFS, HR = 0.14, P < 0.001) than patients with MSS. Integrating MSI-H and PD-L1 expression status (combined positive score ≥ 5) could distinguish the efficacy of immunotherapy.ConclusionsMSI-H status was associated with a higher TMB value and more positive PD-L1 expression in CCA tumors. Moreover, in patients with advanced CCA who received PD-1 inhibitor-based immunotherapy, MSI-H and positive PD-L1 expression were associated with improved both OS and PFS.Trial registrationThis study was registered on ClinicalTrials.gov on 07/01/2017 (NCT03892577).

Differences in Genomic Alterations and Accumulations of Heavy Metals Between Advanced Non-small Cell Lung Cancer Patients with and without Bone Metastasis.

Purpose: Bone metastasis (BoM) has been closely associated with increased morbidity and poor survival outcomes in patients with non-small cell lung cancer (NSCLC). Given its significant implications, this study aimed to systematically compare the biological characteristics between advanced NSCLC patients with and without BoM. Methods: In this study, the genomic alterations from the tumor tissue DNA of 42 advanced NSCLC patients without BoM and 67 patients with BoM and were analyzed by a next-generation sequencing (NGS) panel. The serum concentrations of 18 heavy metals were detected by inductively coupled plasma emission spectrometry (ICP-MS). Results: A total of 157 somatic mutations across 18 mutated genes and 105 somatic mutations spanning 16 mutant genes were identified in 61 out of 67 (91.05%) patients with BoM and 37 of 42 (88.10%) patients without BoM, respectively. Among these mutated genes, NTRK1, FGFR1, ERBB4, NTRK3, and FGFR2 stood out exclusively in patients with BoM, whereas BRAF, GNAS, and AKT1 manifested solely in those without BoM. Moreover, both co-occurring sets of genes and mutually exclusive sets of genes in patients with BoM were different from those in patients without BoM. In addition, the serum concentrations of Cu and Sr in patients with BoM were significantly higher than in patients without BoM. One of our aims was to explore how these heavy metals associated with BoM interacted with other heavy metals, and significant positive correlations were observed between Cu and Co, between Cu and Cr, between Sr and Ba, and between Sr and Ni in patients with BoM. Given the significant impacts of molecular characteristics on patients' prognosis, we also observed a noteworthy negative correlation between EGFR mutations and Co, alongside a significant positive correlation between TP53 mutations and Cd. Conclusions: The genomic alterations, somatic interactions, key signaling pathways, functional biological information, and accumulations of serum heavy metals were markedly different between advanced NSCLC patients with and without BoM, and certain heavy metals (e.g., Cu, Sr) might have potentials to identify high-risk patients with BoM.

2352P Sex-based differences in genomic alterations and biomarkers in anal squamous cell carcinoma (ASCC)

2352P Sex-based differences in genomic alterations and biomarkers in anal squamous cell carcinoma (ASCC)

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

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

Abstract P2-23-12: The Mutational Landscape of 1172 Patients with Hormone Receptor-Positive, HER2-negative Metastatic Breast Cancer Treated with CDK4/6 Inhibitors

Abstract Background: Recent studies suggest differences in outcomes among patients (pts) with metastatic breast cancer (MBC) treated with abemaciclib, ribociclib, or palbociclib, but whether these differences have a genomic basis is unknown. Here, we utilize a large real-world dataset to compare the mutational landscapes of HR+/HER2- MBC samples in which CDK4/6 inhibitor (CDK4/6i) treatment was initiated ≥6 months prior to biopsy to describe variations in tumor biology associated with exposure to each CDK4/6i. We also compare mutations detected by solid tumor sequencing and liquid biopsy to better understand each assay’s ability to identify relevant alterations in this population. Methods: De-identified data from a cohort of pts with HR+/HER2- MBC (n=1172) sequenced with the Tempus xT (DNA-seq of 595-648 genes, whole exome-capture RNA-seq) solid tumor and xF (105-gene panel focused on detecting oncogenic and resistance mutations from cell-free DNA) liquid biopsy assays were retrospectively analyzed. For pts with multiple samples sequenced, the most recent sample was analyzed. Pts were selected based on receipt of CDK4/6i between metastatic diagnosis date and biopsy collection and excluded if &amp;lt; 6 months elapsed between CDK4/6i initiation and biopsy collection. Demographics, clinical characteristics, and NGS findings were compared between groups by Chi-squared/Fisher’s Exact tests or Kruskal-Wallis tests, as applicable. The prevalence of individual gene alterations (consisting of pathogenic/likely pathogenic SNVs/indels and copy number alterations) were compared similarly with adjustment for false-discovery. Results: We compared the immune biomarker and DNA mutational landscapes of 1172 samples collected after a period of treatment with abemaciclib, ribociclib, or palbociclib. Across all pts, the most commonly altered genes were TP53, PIK3CA, ESR1, CDH1, and GATA3. Abemaciclib-treated pts had the highest median TMB and MSI-high frequency (Table). Palbociclib-treated pts were less likely to have a high TMB (≥10 mutations/megabase) or RB1 mutations, a known biomarker of resistance to CDK4/6i (Table). We note that the total N for pts positive for TMB high or MSI-high was very low across all groups. We also compared DNA mutational landscapes between pts tested with solid tumor sequencing and liquid biopsy; the lower prevalence of RB1 mutations in palbociclib-treated pts trended towards significance in both groups (Table). Conclusions: Results from our real-world dataset suggest that treatment with the different CDK4/6i drugs results in unique immune biomarkers and DNA mutational profiles. Detection of relevant alterations such as RB1 by both tissue testing and liquid biopsy supports a role for either assay in identifying mutations associated with CDK4/6i. Our findings raise the possibility that unique targeted treatment strategies and combination therapies may be warranted after progression on the different CDK4/6i drugs. Additional investigation into the differences in genomic alterations and outcomes among CDK4/6i drugs is necessary to further explore the hypotheses generated by this real-world study. Prevalence of immune biomarkers and DNA mutations in pts treated with each CDK4/6i drug 1Pearson’s Chi-squared test; Fisher’s exact test; Kruskal-Wallis rank sum test 2False discovery rate correction for multiple testing 3,4N=464; 708 pts with missing data 5N=1163; 9 pts with missing data Citation Format: Ami N. Shah, Bora Lim, Monica M. Mita, Elizabeth Mauer, Kayla V. Layng, Calvin Chao, Adam M. Brufsky. The Mutational Landscape of 1172 Patients with Hormone Receptor-Positive, HER2-negative Metastatic Breast Cancer Treated with CDK4/6 Inhibitors [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-23-12.

Impact of clinical and genomic factors on outcomes for pancreatic adeoncarcinoma based on race

Background: African-American patients diagnosed with pancreatic adenocarcinoma (PDAC) traditionally have worse outcomes compared with white patients. It is uncertain what role genomic mutations may have on the differences observed. We present a cohort of PDAC patients who underwent comprehensive genomic profiling (CGP) to assess differences in genomic alterations (GA), treatment patterns, and survival in patients based on race.

EP16.03-016 Targetable Alterations in Non-Small Cell Lung Cancer According to Age and Sex

Lung cancer is the second most common malignancy and the leading cause of cancer-related death worldwide. It is critical to understand lung cancer tumor biology to better predict cancer behavior across various populations. This study aimed to evaluate differences in genomic alterations in patients with advanced non-small cell lung cancer (NSCLC) and is an update to a prior abstract.

Mutational landscape of homologous recombination-related genes in small-cell lung cancer.

Homologous recombination deficiency (HRD) is a well-known biomarker which could predict poly-ADP ribose polymerase 1 (PARP) inhibitor and platinum drug response. As an aggressive cancer, small-cell lung cancer (SCLC) is sensitive to platinum drugs, but relapse occurs rapidly. Herein, we aim to illustrate the genomic alteration patterns of homologous recombination repair (HRR)-related genes in a Chinese SCLC cohort and further analyze the relationship among HRR gene mutations and known biomarkers of immune checkpoint inhibitor (ICI) response, including tumor mutation burden (TMB) and programmed cell death-ligand 1 (PD-L1) expression. Next-generation sequencing (NGS)-based target capture sequencing of 543 cancer-related genes was performed to analyze the genomic profiles of 133 Chinese SCLC patients, and TMB was calculated. PD-L1 expression was evaluated in 90 out of 133 patients using the SP142 PD-L1 immunohistochemistry assay. Among the 133 patients with SCLC, 47 (35.3%) had HRR gene mutations. ATM (8.3%) was the most frequently mutated HRR gene in the cohort, followed by NBN (4.5%). Pathogenic somatic and germline mutations of HRR genes were identified in 11 (23.4%) and 4 (8.5%) patients, respectively. HRR gene mutations cooccurred with KMT2D gene mutations. There were several differences in genomic alterations between patients with HRR gene mutations (HRR-Mut) and without HRR mutations (HRR-WT). The results revealed that TP53 and RB1 were commonly mutated genes in both groups. Mutations in the KMT2D gene and genes in the RTK-RAS pathway occurred more frequently in the HRR-Mut group. Furthermore, we found that mutations in HRR genes were associated with high TMB (Wilcoxon, p=0.048), but there was no correlation of HRR gene mutation status with PD-L1 expression. We exhaustively describe the genomic alteration profile of Chinese SCLC patients and provide further evidence that HRR gene mutations are prevalent in SCLC patients.

Genomic Features of Organ-Specific Metastases in Lung Adenocarcinoma.

BackgroundThe genomic features of cancer cells may confer the metastatic ability of lung adenocarcinoma (LUAD) to metastasize to specific organs. We aimed to identify the differences in genomic alterations between patients with primary LUAD with and without metastases and to elucidate the metastatic biology that may help developing biomarker-directed therapies for advanced or metastatic disease.MethodsA retrospective cohort of 497 patients with LUAD including 388 primary tumors (PR), 53 bone metastases (MT-bone), 30 liver metastases (MT-liver), and 26 brain metastases (MT-brain) was tested for genomic alterations by a next-generation sequencing assay.ResultsThe EGFR, TP53, TERT, LRP1B, CDKN2A, ERBB2, ALK, and KMT2C genes had a high frequency of mutations, and the mutations were shared by PR and metastases groups. TP53 and EGFR were the most common mutated genes. In comparison with PR, KRAS, STK11, ATM, NPM1, and ROS1 were significantly mutated in MT-brain, and TP53, MYC, RSPO2, CDKN2a, and CDKN2B were significantly mutated in MT-liver. The frequencies of TP53, CDKN2A, MTAP, PRKCI, and APC mutations were higher in MT-bone than that in PR. The ERBB, phosphoinositide-3-kinase/protein kinase B (PI3K-AKT), cell cycle, Fibroblast growth factor (FGF), and homologous recombination deficiency signaling pathways were affected in both PR and metastases, and there is higher frequency of mutations in metastases. Moreover, the co-mutations in patients with PR and metastasis were respectively analyzed. In addition, the programmed death ligand 1 (PD-L1) level was obviously related to tumor stage and tumor metastases, and the tumor mutational burden was correlated to clinicopathological features including age, gender, pathological stages, and tumor metastases. FGFR1, KAT6A, MYC, RAD21, TP53, and DAXX were also dramatically correlated to the tumor mutational burden.ConclusionMetastases are the most devastating stage of tumors and the main cause of cancer-related deaths. Our results provided a clinically relevant view of the tumor-intrinsic mutational landscape of patients with metastatic LUAD.

Identification of epithelial and mesenchymal circulating tumor cells in clonal lineage of an aggressive prostate cancer case

Little is known about the complexity and plasticity of circulating tumor cell (CTC) biology in different compartments of the fluid microenvironment during tumor metastasis. Here we integrated phenomics, genomics, and targeted proteomics to characterize CTC phenotypic and genotypic heterogeneity in paired peripheral blood (PB) and bone marrow aspirate (BMA) from a metastatic prostate cancer patient following the rapid disease progression, using the High-Definition Single Cell Assay 3.0 (HDSCA3.0). Uniquely, we identified a subgroup of genetically clonal CTCs that acquired a mesenchymal-like state and its presence was significantly associated with one subclone that emerged along the clonal lineage. Higher CTC abundance and phenotypic diversity were observed in the BMA than PB and differences in genomic alterations were also identified between the two compartments demonstrating spatial heterogeneity. Single cell copy number profiling further detected clonal heterogeneity within clusters of CTCs (also known as microemboli or aggregates) as well as phenotypic variations by targeted proteomics. Overall, these results identify epithelial and mesenchymal CTCs in the clonal lineage of an aggressive prostate cancer case and also demonstrate a single cell multi-omic approach to deconvolute the heterogeneity and association of CTC phenotype and genotype in multi-medium liquid biopsies of metastatic prostate cancer.

Ancestry-based differences in gene alterations in non–small cell lung cancer: Real-world data using genetic ancestry analysis.

9125 Background: Racial differences in morbidity and mortality of non-small cell lung cancer (NSCLC) have been demonstrated and some genomic alterations (e.g. EGFR) in NSCLC are known to differ according to race. However, studies have been limited in sample size and hence, limited in their capacity to detect discrepancies in less frequently altered genes. Here, we investigated alteration prevalence in a large real-world NSCLC cohort, stratified by genetic ancestry. Methods: 75,362 NSCLC patients from the United States, were profiled with comprehensive genomic profiling (CGP) of tissue biopsy, as part of routine clinical care (Foundation Medicine Inc., FMI; Frampton GM, et al. Nat Biotechnol 2013). 296 genes targeted across all assays were examined for known/likely pathogenic alterations of all classes. Predominant genetic ancestry was inferred using a SNP-based approach (Newberg J, et al. AACR 2019), and patients were categorized into European (EUR), African (AFR), East Asian (EAS), Admixed American (AMR), and South Asian (SAS) ancestry groups. Patients were additionally stratified by histological type, age (≥40/ &lt; 40), and sex. The prevalence of high tumor mutational burden (TMB-High), defined as ≥ 10 mutations/mb (Chalmers ZR, et al. Genome Med 2017), and microsatellite instability status (Trabucco, et al. J Mol Diagn 2019) was also calculated. Results: In this NSCLC cohort, ancestry was split 82.2% for EUR, 10.0% for AFR, 4.4% for EAS, 2.7% for AMR, and 0.8% for SAS. 50.4% were female (n = 37,972) and 49.6% male (n = 37,360). The most prevalent alterations in the overall cohort included TP53 (67.5%), KRAS (30.6%), CDKN2A (29.2%), CDKN2B (17.2%), STK11 (16.1%), and EGFR (15.3%). The prevalence of TMB-High status in the overall cohort was 34.6%. Stratified by ancestry, the prevalence of EGFR alterations was significantly enriched in EAS vs. other ancestry groups ( p &lt; 0.001). KRAS and STK11 were enriched in EUR and AFR vs. other groups ( p &lt; 0.001). TMB-High status was significantly enriched in AFR vs. all other groups ( p &lt; 0.001). In EAS and SAS, TMB-High was typically reduced vs. other ancestry groups (TMB-High AFR 41.6%, AMR 20.1%, EAS 14.1%, EUR 35.5%, SAS 11.7%). A similar analysis based on sex revealed differences in prevalence of 80 gene alterations and TMB-High with sex-specific enrichments (e.g., EGFR 19.0% female vs. 11.5% male; KRAS 34.6% vs. 26.6%). With respect to age, the prevalence of 41 gene alterations and TMB-High were significantly different between samples from patients age &lt; 40 and age ≥ 40 (e.g., ALK 21.1% age &lt; 40 vs. 2.7% age ≥ 40; KRAS 13.0% vs. 30.8%; TMB-High 14.4% vs. 34.8%). Conclusions: Comprehensive analysis of this real-world dataset, which includes the largest NSCLC patient cohort, revealed ancestry-associated differences in genomic alterations in NSCLC. Age and sex were also associated with differences in genomic alteration and TMB-High prevalence.

Abstract PS17-27: Molecular evaluation of immunogenicity and genomic alterations in invasive lobular breast cancer

Abstract Background: Invasive lobular carcinoma (ILC) is the second most common type of invasive breast cancer and accounts for 10-15% of all cases. Though ILC has distinct clinical, prognostic and molecular features, studies are limited and include few patients. ILCs show a decreased response to neoadjuvant chemotherapy and an increased resistance to endocrine therapy. Thus, there is a great need to identify alternative therapies, such as immunotherapy, that could improve overall survival. Success of immunotherapy largely depends on tumor immunogenicity which varies with histologic type. Determination of predictive and prognostic biomarkers for ILC will help determine who can benefit the most. Our study investigates canonical markers of immunogenicity - PD-L1 expression and Tumor Mutational Burden (TMB) - in patients with ILC compared to invasive ductal carcinoma (IDC). We further correlate these markers in different subtypes i.e. hormone receptor positive (HR+), HER2 positive (HER2+), and in triple negative breast cancers (TNBC). We also analyze differences in immune cell profiles constituting the tumor microenvironment (TME) and differences in genomic alterations between ILC and IDC. Methods: A retrospective data analysis was performed to identify breast cancer tumors with ILC or IDC histology profiled at Caris Life Sciences (Phoenix, AZ) that were tested for PD-L1 by SP142 assay and had whole transcriptome sequencing data available. ILC and IDC cases were further subtyped as HR+ and HER2+ and TNBC. PD-L1 expression in immune cell was assessed using Ventana PD-L1 (SP142) histochemical assay and PD-L1 expression in tumor cell was assessed by laboratory developed test using SP142 clone with staining higher than 2+ considered positive. TMB was measured by counting somatic non-synonymous missense mutations on the 592 gene panel (Nextseq) next generation sequencing (NGS) assay, and ≥ 10 mutations/megabase (mut/Mb) was considered high. Using the whole transcriptome RNA sequencing (NovaSeq) data we analyzed the difference in immune cell profiles constituting the TME using a computational RNA deconvolution approach. NGS was used to identify significant differences in genomic alterations between ILC and IDC. Results: We identified 1,359 breast cancer patients (ILC: 194 vs IDC: 1,165). Among ILC, 79% were HR +, 11% TNBC, &amp;lt;2% HER2+ and the rest were of unclear subtype, compared to 55% HR +, 31% TNBC, 10% HER2+ in the IDC group. PD-L1 expression in immune cells was lower in ILC (PD-L1≥ 1% ILC: 13% vs. IDC: 35% p &amp;lt;0.0001; PD-L1&amp;gt;10% ILC: 1% vs. IDC: 5% p=0.017). PD-L1 expression in tumor cells was also lower in ILC (ILC 1% vs IDC 5%; p =0.0136). All subtypes of ILC had lower PD-L1 expression in immune and tumor cells when compared to IDC. TMB was similar and comparable in IDC and ILC (median TMB 7 mut/Mb). Assessment of TME showed a significantly increased abundance of cytotoxic lymphocytes and monocytic cells in IDC, and stromal endothelial cells in ILC. Androgen receptor (AR) expression, and mutations in CDH1 (ILC 76% vs IDC 2%) and PIK3CA (ILC 44% vs IDC 30%) were more common in ILC. CDH1 mutation was significantly higher in both TN ILC (ILC 60% vs IDC 1%; p&amp;lt;0.05) and HR+ ILC (77% vs IDC 2%; p&amp;lt;0.05) subtypes of ILC. TP53 mutation was lower in ILC (ILC 26% vs IDC 65%) irrespective of subtype. Conclusion: In summary, PD-L1 expression in immune cells and tumor cells was lower in ILC, however TMB was comparable between ILC and IDC. Immune cell profiling supports a cold or less immunogenic TME for ILC. A composite immune biomarker may be able to better characterize immunogenicity of ILC. Citation Format: Upama Giri, Joanne Xiu, Tatiana Karadimitriou, Sofi Castanon, Foluso Ademuyiwa, Paula Pohlmann, Elias Obeid, Jasgit Sachdev, Elisa Krill-Jackson, Michael Simon, Antoinette Tan, Neelima Denduluri, Lee Schwartzberg, Michael Korn, Evanthia T Roussos Torres. Molecular evaluation of immunogenicity and genomic alterations in invasive lobular breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-27.

Abstract IA09: Genomics of common AYA lymphomas: Hodgkin lymphoma and primary mediastinal B-cell lymphoma

Abstract Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBCL) are both B-cell malignancies that commonly arise in the mediastinum and have a peak incidence in the adolescent and young adult (AYA) age range of 15-39y. Advances in sequencing technology with low-input samples have allowed for recent advances in our knowledge of the key molecular alterations in these lymphoma subtypes. In this session, we will discuss the unique genomic features of HL and PMBCL and highlight what is known about differences across the age spectrum. We will also discuss how genomics can inform the use of novel therapies for HL and PMBCL. Hodgkin lymphoma has traditionally been challenging to study by standard genomic platforms given the rarity of the Hodgkin Reed Sternberg (HRS) cell among the extensive inflammatory infiltrate. Recently, our group and others have utilized flow cytometry to sort HRS cells and intratumoral T and B cells for genomic analyses. Optimization of library preparation for ultralow (&amp;lt;5ng) input now allows for whole-exome characterization of classical HL. Sequencing of the first 10 HL exomes revealed inactivating mutations in β-2-microglobulin (B2M) in 7 of 10 cases. B2M alterations resulted in loss of MHC Class I expression, providing a potential mechanism of HRS cell immune escape (Reichel et al., Blood 2015). Other common alterations observed in this cohort were TNFAIP3 (in 6/10 cases) and HISTH1E (5/10 cases). More recently, a larger cohort of 23 cases of cHL was evaluated by whole-exome sequencing (Wienand et al., Blood Advances 2019). Here the most frequent alterations occurred in B2M (39%), NFKNIE (26%), and TNFAIP3 (26%). Further analysis of this cohort integrating genomic mutations, somatic copy number alterations, and structural variants identified key pathways that are altered in cHL including genomic mechanisms of immune evasion, enhanced JAK/STAT signaling, and alterations in NF-κB signaling. It is not known if differences in genomic alterations exist across the age spectrum in cHL and how this might guide therapy. For example, loss of B2M is associated with younger/AYA age range (median age of B2M negative (altered) vs. positive = 30y vs. 47y, p&amp;lt;0.001). Further studies are needed to fully characterize the HL genome and understand the implications of alterations for therapy in both pediatric and adult cohorts. Primary mediastinal B-cell lymphoma is a rare subtype of non-Hodgkin lymphoma, accounting for 2% to 3% of NHL. The disease typically presents as a large mediastinal mass in patients in the AYA age range, with an increased incidence in females. Although previously considered a subtype of diffuse large B-cell lymphoma, PMBCL is now recognized as its own clinical and molecular/pathologic entity that shares many similarities with Hodgkin lymphoma. Recent genomic characterization of PMBCL has been performed using whole-exome sequencing (Mottok et al., Blood 2019; Chapuy et al., Blood 2019). These studies reported recurrent alterations in components of JAK/STAT and NF-κB signaling as well as genetic mechanisms of immune evasion similar to that observed in cHL including alterations in B2M, CD274, and CIITA. In addition, cases were observed to have high tumor mutational burden and an apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) mutation signature, which may confer sensitivity to PD-1 blockade. In summary, recent genomic findings in HL and PMBCL demonstrate molecular similarities between these lymphoma subtypes and define the genetic basis for immune evasion sensitivity to PD-1 blockade. This has translated to national clinical trials for AYAs with HL and PMBCL. A randomized phase III trial of nivolumab + AVD vs. brentuximab + AVD for children and adults with advanced stage HL is currently ongoing (NCT03907488). In PMBCL, a randomized phase III trial evaluating nivolumab in combination with standard therapy for upfront disease is in development and will include pediatric and adult patients across NCTN sites. Citation Format: Lisa G. Giulino-Roth. Genomics of common AYA lymphomas: Hodgkin lymphoma and primary mediastinal B-cell lymphoma [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr IA09.

Abstract B20: Characterization of tumor mutational landscape in smokers and nonsmokers with urothelial carcinoma

Abstract Introduction and Objectives: Smoking is a major risk factor for development of bladder cancer. It has been previously shown that smoking-related and non-smoking-related cancers have characteristic mutational signatures. Hypothesizing that somatic alterations differ between smokers and nonsmokers with urothelial carcinoma, we used next-generation sequencing to evaluate for differences in genomic alterations between these two groups of patients. Methods: We identified in our prospectively maintained institutional database all patients with urothelial carcinoma whose tumors underwent next-generation sequencing using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay. A panel of genes previously reported by The Cancer Genome Atlas (TCGA) as being commonly mutated in bladder cancer was chosen for analysis. Results: A total of 1,044 samples from 968 patients were included in the analysis. Seven hundred eighty-five (85%) of the samples represented bladder tumors and 259 (25%) of the samples represented tumors of the upper tract. Patients with smoking history comprised 66% of the cohort. The most frequently altered genes in active or former smokers and never smokers were TERT promoter (55% and 60%), TP53 (43% and 41%), KDM6A (30% and 26%), and FGFR3 (27% and 26%). Conclusions: Mutational profiling of urothelial tumors in this large cohort of patients showed high incidence of genomic alterations consistent with prior studies. The frequency of alterations in these genes was similar between smokers and nonsmokers. To further understand smoking-related mutational process, we are examining mutational signatures and differences in genomic alterations as a function of smoking intensity exposure. Citation Format: Aleksandra Walasek, Nima Almassi, Min Yuen Teo, Samuel Funt, Nikolaus Schultz, Guido Dalbagni, Wenhu Hu, Hikmat Al-Ahmadie, Dean F Bajorin, Jonathan E Rosenberg, Gopakumar Iyer, Bernard H. Bochner, David B. Solit, Eugene J. Pietzak. Characterization of tumor mutational landscape in smokers and nonsmokers with urothelial carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr B20.

Contrasting genomic profiles in post-systemic treatment metastatic sites (MET), pretreatment primary tumors (PT), and liquid biopsies (LB) of clinically advanced prostate cancer (PC).

5534 Background: Comprehensive genomic profiling (CGP) was done on pre-systemic treatment (pre) PT, post-treatment (post) MET sites and LB in PC to uncover differences in genomic alterations (GA) and potential impact on therapy selection. Methods: 1,294 PC tissues and 782 LB underwent hybrid-capture based CGP. PT biopsies and resections were compared with post-treatment MET biopsies from bone (BO), liver (LIV), lung (LU), brain (BN), lymph node (LN) and soft tissue (ST) sites and LB. TMB was determined on up to 1.1 Mbp of sequenced DNA for tumor samples. Tumor cell PD-L1 IHC was measured (Dako 22C3). Results: Differences in alteration frequencies between PT, MET and LB for selected genes are shown in the Table. TMPRSS2:ERG fusion frequencies were similar between PT and MET (35% vs 33%) but varied between MET sites (27% in BO and ST to 40% in LN). GA in AR were lowest in pre PT (2%) and highest in MET (24% in LU to 50% in LIV). BN had the highest GA/tumor (8) and the most PTEN GA. BRCA2 GA frequency varied from 0% in BN to 15% in LI. Potential predictors of IO response included CDK12 GA (16% in LU) and MSI high status (29% in BN). High PD-L1 expression was found in only two cases (LN) and low PD-L1 expression was relatively uncommon. ERBB2 amplifications were increased in MET compared with PT. RB1 GA were increased in LIV cases. LB GA had a similar increase in AR and TP53 GA to MET and appeared to be a blend of MET site biopsies across alteration frequencies. Conclusions: CGP of PT, MET and LB in PC demonstrates differences most likely associated with exposure to systemic therapies. Differences identified in the MET GA landscape suggest that liquid biopsies may capture a broader range of therapeutic opportunities for PC patients. [Table: see text]

EPID-12. IMPACT OF RACE AND GEOGRAPHIC LOCATION ON IDH MUTATIONS AND GLIOBLASTOMA SURVIVAL

Abstract Glioblastoma (GBM) is the most common primary malignant brain tumor of the central nervous system with a 5-year survival of &lt; 5%. Population studies have demonstrated that among all ethnicities, non-Hispanic whites (NHW) have the worst prognosis; however, differences within the oncogenome based on ethnicity have not been assessed. We utilized the Texas Cancer Registry (TCR) for population-based analysis including 4,134 GBM patients between the years of 1995 to 2013 with 75.6% NHW and 16.5% Hispanics. In accordance with previously published findings, within the TCR we detected a 12% relative survival improvement in Hispanics compared to NHW when controlling for known survival mediators including age, resection, chemotherapy, and radiation. In order to assess for oncogenic differences, we utilized a prospectively maintained database of 257 GBM patients within the city of Houston, TX (14.9% Hispanic) and 48 GBM patients from the National Institute of Neurology and Neurosurgery in Mexico City, Mexico (100% Hispanic) to assess for oncogenomic differences attributable to ethnicity. Next generation sequencing of GBM within the Houston cohort, for 315 tumor-related genes, identified no significant differences in genomic alterations owing to ethnicity. However, when we compared the multigenerational, mixed-heritage Hispanics present in the Houston cohort to the Mexico cohort (Sanger sequencing), a significant difference was found in the frequency of IDH1and IDH2mutations (29.8 % Mexico Hispanics, 7.9% Houston Hispanics; p=0.014). In particular, the rate of IDH2mutations is significantly enriched in the Mexico population (19%) when compared to the Houston population (0%) or to previously published rates of IDH2 mutations in GBM (~3%). Ultimately, these findings highlight the need for multiethnic trial enrollment as well as the need for improved testing of IDH2 mutations in patients of distinct ethnicities. Future studies are needed to identify the mechanisms promoting the increased frequency of IDH2 mutations in Mexican Hispanics.

976P - Efficacy of immune checkpoint inhibitors (ICI) and genomic alterations by body mass index (BMI) in advanced renal cell carcinoma (RCC)

BackgroundAn elevated BMI is associated with improved prognosis in certain solid tumors treated with ICI; however, real-world data and genomic analysis has been lacking. We investigated the effect of BMI on RCC patients treated with PD-1/PD-L1 based ICI and explored potential genomic alterations (GA). MethodsUsing the International Metastatic RCC Database Consortium (IMDC) database, we performed a retrospective analysis on patients treated with ICI alone or in combination with other therapies. The association of BMI with overall survival (OS), time to treatment failure (TTF), and objective response rate (ORR) was evaluated using Cox and logistic regressions respectively, adjusted for IMDC risk groups, histology, line and type of therapy, age, gender, and race. In an exploratory analysis of patients with clear cell RCC and available NGS panel data (275-447 genes), GA frequencies and tumor mutational burden (TMB) were compared by BMI status using Fisher’s exact and Mann-Whitney U tests. Results were considered statistically significant if p<0.05 or q<0.10. ResultsOf 1055 eligible patients, 735 had BMI data at start of ICI. Median follow up was 13.5 (<1-78.6) months (mos). Patients were mostly male (76%), had clear cell histology (85%), and were intermediate risk (60%). Overall, 31% received first-line ICI and 31% received combination ICI (19% with VEGF, 12% with CTLA-4/other therapies). At ICI initiation, 274 (37%) patients were considered low BMI (<25kg/m2) and 461 (63%) considered high BMI (≥25kg/m2). Patients with high BMI had better OS compared to those with low BMI, with 1-yr OS 79% vs 66% (adjusted HR=0.75, 0.57-0.97, p=0.03). ORR (30% vs 21%, adjusted p=0.06) and TTF (median 7.4 vs 4.9 mos, adjusted p=0.8) did not statistically differ. In a subset of 319 patients with clear cell RCC and available NGS data, GA and TMB (6.81 vs 6.81 mut/Mb, p=0.9) were found to be similar between those with high BMI compared to low BMI. ConclusionsHigh BMI is associated with improved OS in advanced RCC patients treated with ICI. In an exploratory analysis, there were no differences in genomic alterations on NGS by BMI status. Further correlative work is ongoing. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureS.K. Pal: Advisory / Consultancy: Astellas; Advisory / Consultancy: Aveo; Advisory / Consultancy: BMS; Advisory / Consultancy: Eisai; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Genentech; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Myriad; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Research grant / Funding (institution): Medivation. A.R. Hansen: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): GSK; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: Pfizer. F. Donskov: Research grant / Funding (institution): Ipsen; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer. T. Yuasa: Advisory / Consultancy: BMS; Advisory / Consultancy: Novartis; Advisory / Consultancy: Ono; Advisory / Consultancy: Pfizer. U. Vaishampayan: Advisory / Consultancy, Research grant / Funding (institution): Astellas; Advisory / Consultancy: Bayer; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Advisory / Consultancy: Genentech; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Sanofi. N.S. Basappa: Advisory / Consultancy: Astellas; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy: Eisai; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Janssen; Advisory / Consultancy: Merck; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche. D.Y.C. Heng: Advisory / Consultancy: Astellas; Advisory / Consultancy, Research grant / Funding (institution): BMS; Research grant / Funding (institution): Exelixis; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Janssen. T.K. Choueiri: Advisory / Consultancy: Alexion; Advisory / Consultancy: Alligent; Advisory / Consultancy: Analysis Group; Research grant / Funding (institution): Agensys; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Cerulean; Advisory / Consultancy, Research grant / Funding (institution): Corvus; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Advisory / Consultancy, Research grant / Funding (institution): Foundation Medicine; Advisory / Consultancy, Research grant / Funding (institution): GSK; Advisory / Consultancy, Research grant / Funding (institution): Ipsen; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Peloton; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Prometheus; Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech. All other authors have declared no conflicts of interest.