Mean Tumor Mutational Burden Research Articles

Clinical and molecular features of early onset pancreatic adenocarcinoma.

Pancreatic adenocarcinoma (PDAC) is a major health burden and may become the second cause of death by cancer in developed countries. The incidence of early-onset pancreatic cancer (EOPC, defined by an age at diagnosis <50 years old) is increasing. Here, we conducted a study of all PDAC patients followed at our institution. Patients were classified as EOPC or non-early onset (nEOPC, >50). Eight hundred and seventy eight patients were included, of which 113 EOPC, exhibiting a comparable performance status. EOPC were more often diagnosed at the metastatic stage (70.0% vs 58.3%) and liver metastases were more prevalent at diagnosis (60.2% vs. 43.9%). The median overall survival (OS) from diagnosis was 18.1 months, similar between EOPC and nEOPC. Among patients who underwent surgery, recurrence-free survival was similar between age groups. Among metastatic patients, first line progression free survival was similar but EOPC received more treatment lines (72.3% vs. 58.1% received ≥2 lines). Regarding molecular alterations, the mean tumor mutational burden (TMB) was lower in EOPC (1.42 vs. 2.95 mut/Mb). The prevalence of KRAS and BRCA1/2 mutations was similar, but EOPC displayed fewer alterations in CNKN2A/B. Fifty eight patients (18.6%) had actionable alterations (ESCAT I-III) and 31 of them received molecularly matched treatments. On the transcriptomic level, despite its clinical aggressiveness, EOPC was less likely to display a basal-like phenotype. To conclude, EOPC were diagnosed more frequently at the metastatic stage. OS and 1st line PFS were similar to nEOPC. EOPC displayed specific molecular features, such as a lower TMB and fewer alterations in CDKN2A/B.

Characterization of DNA damage repair mutations in lung cancer in an underserved urban patient population.

e20058 Background: DNA-damage repair (DDR) mutations in lung cancer have shown potential for use as therapeutic targets and predictive biomarkers. However, the relationship between DDR mutations and socioeconomic factors remains largely unknown. In this study, we characterize the distribution of DDR gene mutations in lung cancer patients at a single academic medical center serving a unique population consisting of primarily underserved, underinsured patients. Methods: All lung cancer patients seen at the University of Illinois Chicago (UIC) between 11/2/2015 and 9/11/2023 with TEMPUS genetic data available were included in the study (N = 235). DDR mutations of interest were ARID1A, ATM, ATR, ATRX, BAP1, BRCA1, BRCA2, BRIP1, CHEK2, ERCC3, FANCA, FANCC, MLH3, MRE11, MSH6, MUTYH, NBN, PALB2, and RAD50. The population was subdivided into a DDR mutation positive group and a DDR mutation negative group. Each group was compared with respect to lung cancer type, tumor mutational burden (TMB), and socioeconomic factors including sex, race, insurance category, and zip code. Results: The overall frequency of DDR mutations in the population was 28.5% (n = 67). The most common DDR mutations were ARID1A (20.7%), CHEK2 (12.8%), ATM (9.9%), BRCA2 (9.9%), ATRX (7.9%), and MUTYH (7.9%). The histological distribution of the DDR mutation positive group was adenocarcinoma (76.1%), squamous cell carcinoma (4.4%), adenosquamous carcinoma (2.9%), neuroendocrine carcinoma (5.9%), and other (10.4%). The histological distribution of the DDR negative group was adenocarcinoma (60.1%), squamous cell carcinoma (22.0%), adenosquamous carcinoma (1.1%), neuroendocrine carcinoma (4.1%), and other (12.5%). There was a significant effect in TMB, t(55) = 2.97, p = 0.004, with a higher mean TMB in the DDR positive group (M = 14.4, SD = 11.1) compared to the DDR negative group (M = 9.4, SD = 5.1). The most common zip codes in the DDR positive groupwere 60608 (9.0%), 60629 (9.0%), and 60616 (7.5%) compared to 60616 (8.3%), 60609 (5.3%), and 60624 (4.7%) in the DDR negative group. Demographic factors of the two groups are compared below. Conclusions: The frequency and distribution of DDR mutations in lung cancer at UIC appears similar to what has been previously reported in the literature. There is a higher tumor mutational burden in lung cancers with DDR mutations, which may suggest greater susceptibility to immunotherapy. There may be a correlation between the presence of DDR mutations and lung cancer type, insurance category, and patient geographic distribution. Future work will include obtaining further geographic data for the study population such as average income, pollution exposure, and smoking rate by neighborhood. [Table: see text]

Histologic and Genomic Analysis of Conjunctival SCC in African and American Cohorts Reveal UV Light and HPV Signatures and High Tumor Mutation Burden.

Conjunctival squamous cell carcinoma (conjSCC) is more prevalent and aggressive in sub-Saharan African countries compared with the rest of the world. This study aims to compare the genomic, immunophenotypic, and histologic features between patients from the United States and Ethiopia, to identify etiopathogenic mechanisms and unveil potential treatment strategies. We compared histologic features and mutational profiles using whole exome sequencing, high-risk human papillomavirus (HPV) status, PD-L1 expression, and tumor-infiltrating lymphocytes in conjSCC tumors of patients from Ethiopia (ETH; n = 25) and the United States (from MD Anderson [the MDA cohort]; n = 29). Genomic alterations were compared with SCCs from other anatomic sites using data from The Cancer Genome Atlas. Solar elastosis was seen in 78% of ETH and 10% of MDA samples. Thicker tumors had higher density of CD8+ and CD3+ cells. HPV status was similar between the cohorts (ETH = 21% and MDA = 28%). The mean tumor mutation burden (TMB) was significantly higher in conjSCC (3.01/Mb, log10) and cutaneous SCC compared other SCC subtypes. ETH samples had higher TMB compared to the MDA cohort (3.34 vs. 2.73). Mutations in genes associated with ultraviolet light (UV) signature were most frequently encountered (SBS7b = 74% and SBS7a = 72%), with higher prevalence in the ETH cohort, whereas SBS2 and SBS13 signatures were more common among MDA HPV+ conjSCCs. Our findings suggest that UV exposure may play a major role in conjSCC, with a higher prevalence in the ETH cohort compared with the MDA cohort, where HPV also contributes.

Abstract 2524: Molecular and clinicopathologic landscape of HER2 positive breast cancer: A single institution study

Abstract Background: Human epidermal growth factor receptor 2 (HER2) is a transmembrane tyrosine kinase that is encoded by the ERBB2 gene, located on chromosome 17. Expression levels of HER2 are a key pathogenic and treatment-associated factor in breast carcinomas, with HER2 expression reported as per the ASCO/CAP scoring guidelines. Outside the intense focus on the HER2 overexpression few studies currently exist that look at the comprehensive molecular profile of these aggressive tumors. Design: Our institutional pathology database was searched for patients with breast carcinoma diagnosed between 2009 and 2013 and with HER2 scored as 3+ based on immunohistochemistry, or HER2 2+ with confirmatory positive FISH results. Comprehensive next-generation sequencing (NGS) was performed using the Illumina TruSight Oncology 523 gene panel, and clinicopathologic data were gathered from the institutional electronic health record system. A CoMutation plot was made using the CoMut python library. Results: The mean age of the patients at time of diagnosis was 56.1±12.7 years. The tumors were overwhelmingly high-grade, with 26/30 being grade 3 and the remaining 4/30 being grade 2 and a mean size of 2.6 cm. All were histologically invasive ductal carcinoma, and 26/30 were scored as HER2 3+ on IHC while 4/30 were HER2 2+ with positive FISH. ER was positive in 30% of cases (9/30), PR was positive in 23.3% (7/30), p53 was positive by IHC in 53.3% (16/30), and the mean Ki-67 proliferative index was 47.1%. 20 of the 30 (66%) cases meeting the inclusion criteria had pathogenic mutations detected by NGS testing. Several distinct molecular subgroups were seen on the CoMutation plot (figure 1). The mean tumor mutational burden (TMB) was 14.1 mutations per megabase. A significant subset of the tumors 70% (14/20) showed TP53 mutations, and 30% (6/20) show PIK3CA mutations. Of interest, only 1/14 tumors showed a co-occurring homologous recombination repair gene mutation and one tumor (1/20) showed mutations in 2 homologous recombination pathway genes (FANCA and BRCA1) as well as numerous additional mutations (tumor mutational burden of 65.3 mutations per megabase). Conclusion: Overall the mean TMB was 14.1 mutations/megabase in this HER2-positive breast cancer study set. Over 2/3 of our HER2-positive breast cancer cases also had TP53 mutations. In addition, 1/3 had PIK3CA mutations, suggesting that a subset of HER2-positive carcinomas also harbor other potentially actionable mutations which may increase the effectiveness of our existing interventions. Additional studies are needed to further subclassify genetically distinct subsets of HER2-positive breast cancers and to further understand clinical, pathologic and treatment-related differences in this aggressive breast cancer subset. Citation Format: Gokce Deniz Ardor, Zachary M. Coty-Fattal, Luis Z. Blanco, Kalliopi Siziopikou. Molecular and clinicopathologic landscape of HER2 positive breast cancer: A single institution study [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 2524.

Identification of Somatic Mutations in Thai Patients with Renal Cell Carcinoma Using Whole Exome Sequencing Analysis

Background: Whole exome sequencing (WES) is increasingly used to identify genetic alterations of renal cell carcinoma (RCC). However, in Thailand, there is no report that clarifies the common somatic mutations and tumor mutational burden (TMB) in RCC. Therefore, the understanding of the tumor somatic mutational landscape could improve RCC management in the authors’ country. Objective: To perform a descriptive study to identify common somatic mutated genes and TMB in clear cell renal cell carcinoma (ccRCC), papillary renal cell carcinoma (pRCC), and clear cell papillary renal cell carcinoma (ccpRCC). Materials and Methods: The authors enrolled 13 patients, which consisted of 10 cases of ccRCC, two cases of pRCC, and one case of ccpRCC. DNA was isolated from peripheral blood mononuclear cells and tumor tissues for WES to identify tumor somatic mutations. The results were analyzed for correlations with tumor-aggressive features and compared with the public database. Results: The authors identified common somatic mutations in VHL, SVIL, MUC16, CSMD3, CSMD1, and BAP1 in the study patients. In ccRCC cases, VHL mutation was detected in 90% of the cases corresponding to its high frequency in the TCGA’s ccRCC database. In pRCC cases, KDM6A was the only common mutated gene that overlapped with the top-ten most common genes in the TCGA’s pRCC database. Somatic mutations in BAP1, SETD2, and PBRM1 were significantly associated with tumor-aggressive features in the present study. The mean TMB of ccRCC, pRCC, and ccpRCC were 2.017, 2.143, and 6.61 mutations per megabase, respectively. Conclusion: Identification of common somatic mutations and TMB in all subtypes of RCC from the present study showed the diversity of genetic alterations between Thai patients and the public database. This leads to specific therapeutic approaches for Thai patients. Moreover, the authors also detected similar associations between significant mutations reported in prior studies with the tumor-aggressive features in the present cases. Keywords: Renal cell carcinoma; Somatic mutation; Tumor mutational burden; Whole exome sequencing

Pan-tumor survey of ROS1 fusions detected by next-generation RNA and whole transcriptome sequencing

BackgroundTwo ROS1 tyrosine kinase inhibitors have been approved for ROS1 fusion positive (ROS1+) non-small cell lung cancer (NSCLC) tumors. We performed a pan-tumor analysis of the incidence of ROS1 fusions to assess if more ROS1+ patients who could benefit from ROS1 TKIs could be identified.MethodsA retrospective analysis of ROS1 positive solid malignancies identified by targeted RNA sequencing and whole transcriptome sequencing of clinical tumor samples performed at Caris Life Science (Phoenix, AZ).ResultsA total of 259 ROS1+ solid malignancies were identified from approximately 175,350 tumors that underwent next-generation sequencing (12% from targeted RNA sequencing [Archer]; 88% from whole transcriptome sequencing). ROS1+ NSCLC constituted 78.8% of the ROS1+ solid malignancies, follow by glioblastoma (GBM) (6.9%), and breast cancer (2.7%). The frequency of ROS1 fusion was approximately 0.47% among NSCLC, 0.29% for GBM, 0.04% of breast cancer. The mean tumor mutation burden for all ROS1+ tumors was 4.8 mutations/megabase. The distribution of PD-L1 (22C3) expression among all ROS1+ malignancies were 0% (18.6%), 1%-49% (29.4%), and ≥ 50% (60.3%) [for NSCLC: 0% (17.8%); 1–49% (27.7%); ≥ 50% (53.9%).The most common genetic co-alterations of ROS1+ NSCLC were TP53 (29.1%), SETD2 (7.3%), ARIAD1A (6.3%), and U2AF1 (5.6%).ConclusionsROS1+ NSCLC tumors constituted the majority of ROS1+ solid malignancies with four major fusion partners. Given that > 20% of ROS1+ solid tumors may benefit from ROS1 TKIs treatment, comprehensive genomic profiling should be performed on all solid tumors.

MRI radiomics for predicting poor disease-free survival in muscle invasive bladder cancer: the results of the retrospective cohort study.

To develop an MRI radiomic nomogram capable of identifying muscle invasive bladder cancer (MIBC) patients with high-risk molecular characteristics related to poor 2-year disease-free survival (DFS). We performed a retrospective analysis of DNA sequencing data, prognostic information, and radiomics features from 91 MIBC patients at stages T2-T4aN0M0 without history of immunotherapy. To identify risk stratification, we employed Cox regression based on TP53 mutation status and tumor mutational burden (TMB) level. Radiomics signatures were selected using the least absolute shrinkage and selection operator (LASSO) to construct a nomogram based on logistic regression for predicting the stratification in the training cohort. The predictive performance of the nomogram was assessed in the testing cohort using receiver operator curve (ROC), Hosmer-Lemeshow (HL) test, clinical impact curve (CIC), and decision curve analysis (DCA). Among 91 participants, the mean TMB value was 3.3 mut/Mb, with 60 participants having TP53 mutations. Patients with TP53 mutations and a below-average TMB value were identified as high risk and had a significantly poor 2-year DFS (hazard ratio = 4.36, 95% CI 1.82-10.44, P < 0.001). LASSO identified five radiomics signatures that correlated with the risk stratification. In the testing cohort, the nomogram achieved an area under the ROC curve of 0.909 (95% CI 0.789-0.991) and an accuracy of 0.889 (95% CI 0.708-0.977). The molecular risk stratification based on TP53 mutation status combined with TMB level is strongly associated with DFS in MIBC. Radiomics signatures can effectively predict this stratification and provide valuable information to clinical decision-making.

Circulating Tumor DNA in Colorectal Cancer Liver Metastasis: Analysis of Patients Receiving Liver Resection and Transplant.

Liver metastases occur in about 50% of colorectal cancer cases and drive patient outcomes. Circulating tumor DNA (ctDNA) is emerging as a diagnostic, surveillance, and tumor mutational information tool. Patients with colorectal cancer liver metastasis (CCLM) seen in a multidisciplinary liver tumor clinic from January to August 2022 received ctDNA testing on each visit. ctDNA was obtained using the Guardant360 platform. Tumor mutational burden (TMB) is defined as the number of identified mutations per megabase of genome analyzed. Fifty-two patients had available ctDNA, with 34 (65%) tested preoperatively and 18 (35%) postoperatively; nine patients had sequential pre- and postoperative testing. The median time to test result was 12 days (IQR, 10-13.5). There were a greater number of somatic mutations identified preoperatively (n = 29 v n = 11) and a greater genomic heterogeneity (P = .0069). The mean TMB score was 12.77 in those without pathologic response to cytotoxic therapy and 6.0 in those with pathologic response (P = .10). All nine patients with sequential testing were positive preoperatively, compared with just three (33.3%) postoperatively (P = .0090). Positive postoperative ctDNA was associated with the increased likelihood of disease recurrence after resection (57%) versus negative ctDNA (0%, P = .0419). Routine ctDNA screening in patients with CCLM is logistically feasible. Liver resection and/or transplant may be associated with clearance of detectable ctDNA and a reduction in TMB or genomic heterogeneity. Persistence of ctDNA alterations postresection appears predictive of disease recurrence. Further studies are necessary to confirm these findings, and longitudinal ctDNA testing is needed to monitor changing tumor biology.

SDPS-25 COMPARISON OF MOLECULAR ALTERATIONS BETWEEN SYSTEMIC AND CNS METASTATIC SITES REVEALSMUTATIONAL DISCORDANCES

Abstract INTRODUCTION Central nervous system (CNS) metastases occur in 10-30% of patients with systemic malignancies and can be genomically distinct from systemic metastases. NGS has revolutionized cancer therapies, providing rapid molecular data to identify therapeutic targets. In this study we compare the genomic profile of matched systemic and CNS tumor samples. METHODS Between January 2022 and January 2023, we identified 19 patients who underwent a craniotomy for symptomatic brain metastases (BM) or CSF sampling for leptomeningeal disease (LMD) diagnosis. Results from ten patients are presented (four were excluded due to lack of NGS data or material, sequencing for 5 patients is pending). If systemic tumor NGS was not available, blood-based NGS was used as a surrogate. RESULTS 9/10 patients had lung adenocarcinoma (LUAD), 1/10 breast adenocarcinoma. 8/10 CNS samples were collected from BM, 2/10 from CSF in patients with LMD. 4/10 patients had received prior systemic therapy. Blood-based NGS was used in 60% (6/10). The mean tumor mutational burden (TMB) in body samples was 3.39 mutations/megabase (SD 3.79, SEM 1.34) compared to CNS samples with mean TMB of 10.94 mutations/megabase (SD 7.08, SEM 2.50), 3.23 times higher. In CNS samples, the driver alterations EGFR Ex19del and KRAS G12D and G12F were retained, however all ten CNS samples had additional mutations (mean of differences 8.9). Interestingly, a patient with previously known osimertinib resistance mutation EGFR C797S, acquired a MET amplification and lost the EGFR C797S mutation in the CNS. A breast cancer patient acquired a HER2 amplification in the CSF. CONCLUSIONS With matched NGS of systemic and CNS metastases, we observe substantially higher CNS tumor mutational burden, retention of primary driver alterations, and acquisition of targetable resistance mutations. Our results suggest that sequencing of CNS disease can alter treatment by identifying new therapeutic targets, although larger scale studies are needed.

A comprehensive survey of tumor mutation burden (TMB) using the AACR GENIE cbioportal database: Pathogenesis of NTRK and RET fusion (NTRK+/RET+) positive colorectal (CRC).

33 Background: Receptor tyrosine kinase fusion (RTK+) has been identified in colorectal carcinoma (CRC). Tumor agnostic treatment has been approved in NTRK fusion ( NTRK+) and RET fusion ( RET+) positive solid tumor. However, overall response rate (ORR) was the lowest among entrectinib-treated NTRK+ CRC (20%, 2/10) and selpercatinib treated RET+ CRC (20%, 2/10) among all NTRK+ and RET+ solid tumors respectively. Methods: We surveyed all 58 human RTKs to identify RTK fusions in CRC and RET and NTRK fusions in other solid tumors using AACR GENIE cbioportal public version 13.0. We abstracted and compared the tumor mutation burden (TMB) of these fusions from the cbioportal database. Patient and tumor characteristics were also abstracted. Results: Among the 14812 unique CRC patients identified in the AACR GENIE cbioportal, a total of 153 unique RTK fusions were identified (44 with known fusion partners, 109 with intragenic rearrangement) in 27 out of the total 58 human RTKs. The most common RTK fusions in CRC were in FGFR1 (N = 23), EGFR (N = 21), ERBB2, NTRK1, RET, FGFR2 (N = 10 each), FLT1 and FLT3 (N = 9 each), FLT4 and ALK (N = 7 each). Considering only samples with identified fusion partners, the mean TMB was 66.6 +/-15.8 (mt/MB) for NTRK+ CRC (N = 9), and 35 +/-11.5 for RET+ CRC (N = 4), which were significantly higher when compared to mean number of 6.2 +/- 5.4 of TMB for all other RTK+ CRC (ALK, EGFR, FGFR1/2, ERBB4, FLT1/3/4, LMKT2, MET, NTRK2, PDGFR-b, ROS1) (N = 30, P&lt; 0.05). Furthermore, NTRK+ CRC harbored significantly higher TMB than RET+ CRC (P = 0.003). The mean TMB was 4.0 +/- 1.9 for RET+ NSCLC (N = 65), 2.6 +/- 1.6 for RET+ Thyroid cancer (N = 52), which were both significantly lower than RET+ CRC. Mean TMB was 3.1 +/- 1.7 for NTRK+ glioma (N = 21), 3.3 +/- 1.7 for NTRK+ thyroid cancer (N = 21), 6.5+/-5.1 for NTRK+ Melanoma (N = 8), 5.9 +/- 3.4 for NTRK+ NSCLC (N = 7), 5.1 +/- 1.2 for NTRK+ breast cancer (N = 7) all of them were significantly lower than the mean TMB of NTRK+ CRC. 1482 (10.0%) patients with CRC had their MSI status reported. 3 out of 3 NTRK+ CRC patients with known MSI status were all MSI-H (100%). 12 out of 12 non-NTRK/non-RET RTK+ CRC patients were MSI-S. Conclusions: In this comprehensive survey of human RTK fusions in CRC, NRTK+ and RET+ CRC harbor significantly higher TMB compared to other RTK+ CRC or to other NTRK+/RET+ solid tumors. Limited data showed NTRK+ CRC were all MSI-H. NTRK+ and RET+ CRC are distinct molecular subtypes of CRC with unique pathogenesis from all other NTRK+ or RET+ solid tumors. We hypothesize that NTRK+/RET+ CRC may benefit from pembrolizumab that has been approved for histologic agnostic high TMB tumors rather than RET or NTRK tyrosine kinase inhibitors (low ORR in CRC) that also have histological agnostic indications.

Analysis of rare fusions in NSCLC: Genomic architecture and clinical implications

ObjectivesMolecular diagnosis for targeted therapies has been improved significantly in non-small-cell lung cancer (NSCLC) patients in recent years. Here we report on the prevalence of rare fusions in NSCLC and dissect their genomic architecture and potential clinical implications. Materials and MethodsOverall, n = 5554 NSCLC patients underwent next-generation sequencing (NGS) for combined detection of oncogenic mutations and fusions either at primary diagnosis (n = 5246) or after therapy resistance (n = 308). Panels of different sizes were employed with closed amplicon-based, or open assays, i.e. anchored multiplex PCR (AMP) and hybrid capture-based, for detection of translocations, including “rare” fusions, defined as those beyond ALK, ROS1, RET and <0.5 % frequency in NSCLC. ResultsRare fusions involving EGFR, MET, HER2, BRAF and other potentially actionable oncogenes were detected in 0.5% (n = 26) of therapy-naive and 2% (n = 6) TKI-treated tumors. Detection was increased using open assays and/or larger panels, especially those covering >25 genes, by approximately 1–2% (p = 0.001 for both). Patient characteristics (age, gender, smoking, TP53 co-mutations (56%), or mean tumor mutational burden (TMB) (4.8 mut/Mb)) showed no association with presence of rare fusions. Non-functional alterations, i.e. out-of-frame or lacking kinase domains, comprised one-third of detected rare fusions and were significantly associated with simultaneous presence of classical oncogenic drivers, e.g. EGFR or KRAS mutations (p < 0.001), or use of larger panels (frequency of non-functional among the detected rare fusions 57% for 25+ gene- vs. 12% for smaller panels, p < 0.001). As many rare fusions were identified before availability of targeted therapy, mean survival for therapy-naïve patients was 23.8 months, comparable with wild-type tumors. ConclusionApproximately 1–2% of advanced NSCLC harbor rare fusions, which are potentially actionable and may support diagnosis. Routine adoption of broad NGS assays capable to identify exact fusion points and potentially retained protein domains can increase the yield of therapeutically relevant molecular information in advanced NSCLC.

Genomic landscape of clinically advanced KRAS wild-type pancreatic ductal adenocarcinoma.

KRAS mutation is a common occurrence in Pancreatic Ductal Adenocarcinoma (PDA) and is a driver mutation for disease development and progression. KRAS wild-type PDA may constitute a distinct molecular and clinical subtype. We used the Foundation one data to analyze the difference in Genomic Alterations (GAs) that occur in KRAS mutated and wild-type PDA. Comprehensive genomic profiling (CGP) data, tumor mutational burden (TMB), microsatellite instability (MSI) and PD-L1 by Immunohistochemistry (IHC) were analyzed. Our cohort had 9444 cases of advanced PDA. 8723 (92.37%) patients had KRAS mutation. 721 (7.63%) patients were KRAS wild-type. Among potentially targetable mutations, GAs more common in KRAS wild-type included ERBB2 (mutated vs wild-type: 1.7% vs 6.8%, p <0.0001), BRAF (mutated vs wild-type: 0.5% vs 17.9%, p <0.0001), PIK3CA (mutated vs wild-type: 2.3% vs 6.5%, p <0.001), FGFR2 (mutated vs wild-type: 0.1% vs 4.4%, p <0.0001), ATM (mutated vs wild-type: 3.6% vs 6.8%, p <0.0001). On analyzing untargetable GAs, the KRAS mutated group had a significantly higher percentage of TP53 (mutated vs wild-type: 80.2% vs 47.6%, p <0.0001), CDKN2A (mutated vs wild-type: 56.2% vs 34.4%, p <0.0001), CDKN2B (mutated vs wild-type: 28.9% vs 23%, p =0.007), SMAD4 (mutated vs wild-type: 26.8% vs 15.7%, p <0.0001) and MTAP (mutated vs wild-type: 21.7% vs 18%, p =0.02). ARID1A (mutated vs wild-type: 7.7% vs 13.6%, p <0.0001 and RB1(mutated vs wild-type: 2% vs 4%, p =0.01) were more prevalent in the wild-type subgroup. Mean TMB was higher in the KRAS wild-type subgroup (mutated vs wild-type: 2.3 vs 3.6, p <0.0001). High TMB, defined as TMB > 10 mut/mB (mutated vs wild-type: 1% vs 6.3%, p <0.0001) and very-high TMB, defined as TMB >20 mut/mB (mutated vs wild-type: 0.5% vs 2.4%, p <0.0001) favored the wild-type. PD-L1 high expression was similar between the 2 groups (mutated vs wild-type: 5.7% vs 6%,). GA associated with immune checkpoint inhibitors (ICPIs) response including PBRM1 (mutated vs wild-type: 0.7% vs 3.2%, p <0.0001) and MDM2 (mutated vs wild-type: 1.3% vs 4.4%, p <0.0001) were more likely to be seen in KRAS wild-type PDA.

Comprehensive genomic profiling (CGP) of clinically advanced and metastatic cutaneous adnexal carcinomas (CAs; MCADCA): A genomic landscape study.

9587 Background: Cutaneous adnexal tumors are a large group of malignant neoplasms that exhibit morphologic differentiation towards one of the four primary adnexal structures present in normal skin: hair follicles, sebaceous glands, sweat-apocrine glands, and sweat-eccrine glands. Methods: 276 cases of MCADCA underwent hybrid capture-based CGP to evaluate all classes of genomic alterations (GA). Microsatellite instability (MSI) status, tumor mutational burden (TMB), genomic loss of heterozygosity (gLOH), genomic ancestry prediction and COSMIC genomic signature were determined from sequencing results. PD-L1 was measured by IHC (TPS; Dako 22C3). Fisher exact method was used for statistical analysis with the false discovery rate corrected using Benjamini-Hochberg adjustment. Results: Sequencing was performed on the primary cutaneous tumor in 131 (47.4%) and on a local recurrence or metastatic site biopsy in 145 (52.5%) MCADCA. Male preponderance (64-81%) and age distributions mean (59-63 yrs) were similar in all groups with apocrine (APO) older than eccrine (ECC) (72 vs 62 yrs; p = .001). There were 173 (62.7%) sweat gland (SWT) derived, 55 (19.9%) were sebaceous gland (SEB) derived, 14 (5.1%) were hair follicle (HRF) derived and 34 (12.3%) were unclassified (UNK). 150/173 (86.7%) of SWT were ECC and 23 (13.3%) were APO. The SWT cases included 12 (6.9%) digital papillary ca’s (DPA), 11 (6.3%) mucinous ca’s (MAC), 19 (11.0%) poroca’s (POR), 14 (8.1%) spiradenoca’s (SPR), 10 (5.8%) syringoadenoca’s (SRNG) and 77 (44.5%) unclassified ca’s (UNC). GA/tumor were highest in SEB vs SWT (7.9 vs 4.9; p = .004) and lowest in DPA (2.1 vs 5.0 non-DPA; p = .03). There we no ancestry distribution differences. When compared with the SWT group, the SEB group had higher frequencies of RB1 GA (38.2% vs 8.1%; p &lt; .0001) and TP53 GA (76.4% vs 43.4%; p = .0002) indicating likely neuroendocrine differentiation. The MAC group had significantly higher PTCH1 GA than the non-MAC group (36.4% vs 1.8%; p = .044). MSI-High status was highest in the SEB group vs all other groups (SEB 15.7% vs SWT 1.2%; p = .005). gLOH &gt; 16% was most frequent in SEB when compared with SWT (19.6% vs 7.2%; p = .081). The MMR signature was more frequent in SEB than SWT (32.0% vs 2.1%; p = .005). The mean TMB was high in all MCADCA ranging from 10.4 mut/Mb in HRF to 38.8 mut/Mb in MAC with the exceptions of APO (2.7 mut/Mb; p = .001 and DPA 1.4 mut/Mb; p = .003). PD-L1 expression was not significantly different in all the MCADCA with low positive scores SWT vs SEB (37.0% vs 33.3%; NS). Conclusions: As there is limited evidence on the treatment of MCADCA, we provide a repertoire of common GA found. An increased frequency of GA is observed in SEB MCADCA. Clinical trials are needed to evaluate MCADCA-based biomarkers prognostic of ICI response. Only then can we successfully incorporate novel therapeutic strategies in the evolving landscape of treatment.

Programmed cell death ligand 1 (PD-L1) expression landscape and its relationship with tumor mutational burden (TMB) in a community-based cancer center patient population in rural central Nebraska.

e15141 Background: PD-L1 and TMB are the most widely used immunotherapy biomarkers to identify populations who would benefit from immunotherapy, with the higher values predicting better therapeutic efficacy. We sought to explore the occurrence and correlation of these two biomarkers in a community based cancer center patient population in rural central Nebraska. Methods: One hundred sixty consecutive cancer patients(pts) diagnosed and treated between 2018-2022 at Morrison Cancer Center were evaluated. Malignant tumor tissue specimens were analyzed for PD-L1expression and TMB (Foundation test). PD-L1 expression was classified as low ( &lt; 1%), intermediate (1% ≥ PD-L1 &lt; 50%), high (≥ 50%), and TMB classified as low [1–5 mutations/Megabase (muts/Mb)], intermediate (6–19 muts/Mb), high (≥ 20 muts/Mb)]. PD-L1 and TMB values were treated as continuous variables to calculate a Pearson correlation coefficient and p value. Results: Mean age at diagnosis was 64 years (range 33-89). Malignant histology diagnoses included 55 pts with lung, 18 colorectal, 12 breast, 15 unknown primary, 15 pancreas, 10 renal, 3 melanoma, 1 thyroid, 6 ovary, 5 uterus, 5 head and neck, 5 prostate, 5 biliary, and 1 vulvar. Fifty four percent (86/160) of pts had low, 33% (53/160) had intermediate, and 13% (21/160) had high PD-L1 expression score with a mean PD-L1 value of 13.8% (range 0-100). Sixty six percent (106/160) of pts had low, 30% (48/160) had intermediate, and 4% had high TMB with a mean TMB value of 5.6 muts/Mb (range 0-66). A marginal linear correlation between PD-L1 expression and TMB was observed (Pearson Correlation Coefficient = 0.172, P = 0.0270). Conclusions: PD-L1 and TMB are both important biomarkers for immunotherapy. Increasing availability and use of both PD-L1 and TMB testing in the community oncology practice beseeches the question of frequency of these two biomarkers in various cancers in the community oncology patient population as well as any association between them. The results of our study gives a glimpse of the distribution landscape of these two biomarkers for community oncology patients and suggest that PD-L1 and TMB may be independent markers with a weak association. PD-L1 and TMB may each inform use of immunotherapy by different mechanisms. [Table: see text]

Comparative Genomic Landscape of Urothelial Carcinoma of the Bladder Among Patients of East and South Asian Genomic Ancestry.

Despite the low rate of urothelial carcinoma of the bladder (UCB) in patients of South Asian (SAS) and East Asian (EAS) descent, they make up a significant portion of the cases worldwide. Nevertheless, these patients are largely under-represented in clinical trials. We queried whether UCB arising in patients with SAS and EAS ancestry would have unique genomic features compared to the global cohort. Formalin-fixed, paraffin-embedded tissue was obtained for 8728 patients with advanced UCB. DNA was extracted and comprehensive genomic profiling was performed. Ancestry was classified using a proprietary calculation algorithm. Genomic alterations (GAs) were determined using a 324-gene hybrid-capture-based method which also calculates tumor mutational burden (TMB) and determines microsatellite status (MSI). Of the cohort, 7447 (85.3%) were EUR, 541 (6.2%) were AFR, 461 (5.3%) were of AMR, 74 (0.85%) were SAS, and 205 (2.3%) were EAS. When compared with EUR, TERT GAs were less frequent in SAS (58.1% vs. 73.6%; P = .06). When compared with non-SAS, SAS had less frequent GAs in FGFR3 (9.5% vs. 18.5%, P = .25). TERT promoter mutations were significantly less frequent in EAS compared to non-EAS (54.1% vs. 72.9%; P < .001). When compared with the non-EAS, PIK3CA alterations were significantly less common in EAS (12.7% vs. 22.1%, P = .005). The mean TMB was significantly lower in EAS vs. non-EAS (8.53 vs. 10.02; P = .05). The results from this comprehensive genomic analysis of UCB provide important insight into the possible differences in the genomic landscape in a population level. These hypothesis-generating findings require external validation and should support the inclusion of more diverse patient populations in clinical trials.

Abstract 650: A machine learning model accurately predicts response to immune checkpoint inhibitors in colorectal cancer using the gut microbiome

Abstract Background: Immune checkpoint inhibitors (ICI) have shown a long-lasting response in many cancers such as colorectal cancer. However, only patients with microsatellite instability (MSI-High) or mismatch repair deficiency (dMMR) benefit from ICI. One of the many factors that can influence ICI-response is the gut microbiome, however its effect remains elusive. Here we aim to investigate the role of the gut microbiome in ICI-response using machine learning (ML). Methods: Clinical and genomic data of ICI-treated CRC patients were retrieved from the KEYNOTE-177 trial. Microbiome abundances from The Cancer Genome Atlas (TCGA) were downloaded from the cBioportal database. A label propagation semi-supervised ML approach was conducted to label patients’ responses to ICI treatment in the TCGA cohort. Tumor mutational burden (TMB), MSI status, treatment, histological subtype, TNM staging and prior chemotherapy were fitted into the semi-supervised model to predict ICI-response in the combination cohort. The normalized abundance of 1406 microbial signatures were regularized using a LASSO model to avoid multicollinearity. Signatures with a non-zero LASSO coefficients were fitted into a supervised ML Random Forest Classification model (RFC) to evaluate their prediction for ICI-response. Samples were split with 80:20 training-testing ratio, and model’s performance was evaluated on the testing set using mean bootstrap estimate, 10-fold cross-validation (CV), and area under curve (AUC). Results: A total of 538 CRC patients from the TCGA and 29 ICI-treat patients from the KEYNOTE-177 trial were fitted into the semi-supervised model to label ICI-response in the TCGA cohort. A total of 95 patients were labeled as responder (R) while 488 patients were labeled as non-responder (NR). Responders had significantly higher TMB levels than NR (mean TMB: 22.5 vs. 12.2, p-value &amp;lt;0.0001). Of the 95 R, 42 were MSS, and 53 patients were MSI-High. While 417 of the NR were MSS. A total of 25 microbial signatures were screened after LASSO for their ICI prediction and were fitted into the RFC model along with TMB and MSI status (Hereafter called RFC27). The RFC27 model performed on the testing set with mean bootstrap estimate of 0.88 and 95%CI: [0.83-0.94], 10-fold CV of 0.84 and AUC of 0.97. TMB and MSI showed highest feature contribution followed by Actinopolyspora and Bacteroides Eggerthia. The relative abundance of both microbiotas was significantly different between R and NR (mean: 0.99 vs. 0.47, 2.0 vs. 1.6; p-value &amp;lt;0.001 respectively). Conclusions: Our results show that the gut microbiome can accurately predict ICI-response and their higher abundance contributed to a better response. Previous studies also reported a pro-inflammatory response of Bacteroides in addition to their association with ICI-response in melanoma patients, thus providing a potential therapeutic marker for ICI. Citation Format: Ayah N. Al-Bzour. A machine learning model accurately predicts response to immune checkpoint inhibitors in colorectal cancer using the gut microbiome [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 650.

Abstract 2375: Whole exome sequencing and immune profiling of cervical adenocarcinoma reveal a “cold” tumor-immune phenotype

Abstract Purpose: Cervical adenocarcinomas (CAC), a less common cervical cancer histology with poor prognosis as compared to squamous cell carcinoma (CSCC), disproportionally present at advanced stages in young women and incidence is increasing; however, the same chemoradiation (CRT) paradigm is used by clinicians for both histologies. Given the rarity of CAC, little is known about genomic pathways and tumoral immune factors that differentiate CAC from CSCC and could drive differences in patient outcomes. Objective: To identify distinctions in the mutational landscape and immune phenotype of CAC and CSCC tumors in patients undergoing CRT which may be potential therapeutic targets. Methods: 80 patients with FIGO stage IB-IVA cervical cancer who underwent definitive CRT were prospectively enrolled on an IRB approved clinical trial. Cervical tumor DNA (9 CAC patients; 58 CSCC patients) and cervical tumor microenvironment samples (13 CAC patients, 67 CSCC patients) were collected by a noninvasive swab technique at baseline, and after 1, 3, and 5 weeks of CRT. WES and neoantigen prediction were performed and tumor mutation burden (TMB) was calculated as the number of somatic coding mutations per megabase. Lymphocyte immunostaining was performed according to standard protocols and cells were analyzed using a LSRFortessa X-20 Flow Cytometer (BD Biosciences) and FlowJo 10.6.1. Statistical comparison of mean values was performed by t-test. Results: Baseline mean TMB and tumor neoantigen was lower in CAC compared to CSCC (1.1±0.14 vs 5.2±3.5 respectively for TMB, p&amp;lt;0.01; 6.0±8.5 vs 455.3±472.5 respectively for neoantigen, p&amp;lt;0.01) and persisted during CRT. The top 3 most frequently altered genes unique to CAC were GPR98, SLC12A3, and TP53. The baseline mutational profile of CAC tumors was most similar to other adenocarcinomas including prostate and pancreatic cancer in TCGA. There was a significant reduction for CAC in baseline CD4+ T-cell infiltration in CAC compared to CSCC (p=0.01) which persisted through the course of CRT (p=0.02 at week 3). There was a trend toward decreased CD4+ T-cell activation, including co-expressing CD69 (p=0.17) and Ki67 (p=0.06), decreased CD8+ T-cell infiltration (p=0.19), and decreased Ki67+CD8+ T-cells as compared to CSCC (p=0.02). Conclusions: In contrast to CSCC, immune profiling of the CAC tumor microenvironment suggests a reduction in immune cell infiltrate and absence of or failed T-cell activation. Similarly, unique genetic alterations were detected between histologies, and CAC tumors displayed reduced TMB and loss of tumor neoantigen expression. These findings are consistent with an “immune cold” phenotype in CAC. These patients may be less likely to benefit from immunotherapy. Future investigation into molecularly targeted therapies or strategies that help mobilize peritumoral T-cells in response to CRT may better potentiate improved CRT response in CAC. Citation Format: Julianna Bronk, Xiaogang Wu, Rui Wang, Ananta Yanamandra, Tatiana Karpinets, Chike Abana, Molly El Alam, Katarina Tomasic, Daniel Lin, Erica Lynn, David Lo, Timothy Harris, Xingzhi Song, Andrew Futreal, Jianhua Zhang, Jagannadha Sastry, Ann Klopp, Lauren Colbert. Whole exome sequencing and immune profiling of cervical adenocarcinoma reveal a “cold” tumor-immune phenotype [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 2375.

Abstract 3931: BRD4, BRD3, NSD3, and ZNF532 fusions in histologies beyond NUT carcinomas: Investigation of a large pan-cancer cohort

Abstract Background: NUT rearrangements drive NUT carcinomas (NCs), which are rare, poorly differentiated tumors with a survival from diagnosis of ~6-7 months. Common NUT fusion partners (NCFPs) include BRD4, BRD3, NSD3, and ZNF532, which are associated with epigenetic changes leading to tumor growth. Recent clinical trials have aimed to address NCs, but little is known about fusions involving NCFPs in other histologies. We characterized NCFPs in a large, pan-cancer cohort. Methods: The MSK-IMPACT (DNA sequencing; n=71,423) and MSK-Fusion (RNA sequencing; n=10,897) clinical cohorts were mined to identify patients (pts) with all forms of structural variants (SVs) involving NCFPs, detected between April, 2015 and June, 2022. The targeted NGS panels included BRD4 and NSD3 only; detection of BRD3 and ZNF532 SVs was possible for fusions with a partner present on either panel. SVs were manually reviewed to identify in-frame fusions with oncogenic potential if critical domains present in NC fusions were conserved. Pts were followed through July 2022 and manual chart review enabled assessment of treatment history and clinical outcomes. Results: SVs involving NCFP genes were detected in 182 (BRD4=110, NSD3=61, BRD3=8 and ZNF532=3) pts (0.002%). Putative NCFP fusions not involving any of the NUT gene family members comprised a total of 20 fusions with likely oncogenic potential including 11 with BRD4 (55%), 5 with NSD3 (25%), 3 with ZNF532 (15%), and 1 with BRD3 (5%). BRD4::NOTCH3 and ZNF532::MALT1 were the most enriched fusions, present in 3 samples each. The most common histologies were breast (3 ductal; 1 lobular), lung (2 squamous cell carcinoma, 1 adenocarcinoma and 1 mixed histology), and colon and esophageal adenocarcinoma (2 samples each). Median age at diagnosis was 62. 11 (55%) pts were female and 9 (45%) were male. 13 (65%) pts ultimately were diagnosed with stage IV disease and had a median overall survival from stage IV diagnosis of 2.5 years (95% CI: 1.41, NR). DNA sequencing in 19/20 tumors revealed a mean tumor mutational burden (TMB) of 5.0 mut/Mb including 15 with low TMB (&amp;lt;10) and 3 with high TMB (&amp;gt;10). No tumor showed microsatellite instability (MSI-high). TP53 mutations were the most common co-alteration, found in 11 (58%) cases. 18/20 pts received systemic therapy; 18 (90%) received cytotoxic chemotherapy and/or mAb therapy, including 13 (65%) who received a platinum. 8 pts (40%) received immunotherapy (IO), and 4 (20%) received small molecule inhibitors. No pts received BET inhibitors. Among pts who received IO, median time to treatment discontinuation was 64 days (95% CI: 20, NR). Conclusion: Tumor sequencing from a large cohort reveals potential oncogenic fusions involving BRD4, BRD3, NSD3, and ZNF532 across multiple histologies. Further biological characterization of their oncogenicity and potential targetability is warranted. Citation Format: Ian R. Nykaza, Christopher A. Febres-Aldana, Sabrina T. Lin, Ryma Benayed, Kerry Mullaney, Emiliano Cocco, Alexia Iasonos, Marc Ladanyi, Alexander E. Drilon, Yonina R. Murciano-Goroff. BRD4, BRD3, NSD3, and ZNF532 fusions in histologies beyond NUT carcinomas: Investigation of a large pan-cancer cohort. [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 3931.

MP56-03 A COMPLIMENTARY ANALYSIS OF PLASMACYTOID UROTHELIAL CARCINOMA OF THE BLADDER: GENOMIC LANDSCAPE INDEPENDENT OF SOMATIC CDH1 MUTATIONS AND REAL-WORLD CLINICAL OUTCOME STUDY

You have accessJournal of UrologyCME1 Apr 2023MP56-03 A COMPLIMENTARY ANALYSIS OF PLASMACYTOID UROTHELIAL CARCINOMA OF THE BLADDER: GENOMIC LANDSCAPE INDEPENDENT OF SOMATIC CDH1 MUTATIONS AND REAL-WORLD CLINICAL OUTCOME STUDY Kyle Rose, Andrea Necchi, Facundo Davaro, Elizabeth Davaro, Heather Huelster, Joseph Jacob, Grennady Bratslavsky, Dean Pavlick, Douglas Lin, Natalie Danzinger, Petros Grivas, Hikmat Al-Ahmadie, Vamsi Parimi, Philippe Spiess, Bishoy Faltas, Jeffrey Ross, and Roger Li Kyle RoseKyle Rose More articles by this author , Andrea NecchiAndrea Necchi More articles by this author , Facundo DavaroFacundo Davaro More articles by this author , Elizabeth DavaroElizabeth Davaro More articles by this author , Heather HuelsterHeather Huelster More articles by this author , Joseph JacobJoseph Jacob More articles by this author , Grennady BratslavskyGrennady Bratslavsky More articles by this author , Dean PavlickDean Pavlick More articles by this author , Douglas LinDouglas Lin More articles by this author , Natalie DanzingerNatalie Danzinger More articles by this author , Petros GrivasPetros Grivas More articles by this author , Hikmat Al-AhmadieHikmat Al-Ahmadie More articles by this author , Vamsi ParimiVamsi Parimi More articles by this author , Philippe SpiessPhilippe Spiess More articles by this author , Bishoy FaltasBishoy Faltas More articles by this author , Jeffrey RossJeffrey Ross More articles by this author , and Roger LiRoger Li More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003309.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Plasmacytoid urothelial carcinomas of the bladder (PUC) represent an aggressive malignancy with somatic CDH1 mutations, poor survival, and few systemic therapy options. We aimed to analyze the genomic landscape of urothelial carcinomas stratified by CDH1 status and PUC histology, while utilizing real-world clinical outcome data. METHODS: 7,903 clinically advanced patients with UCB underwent hybrid capture based comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GAs) as well as microsatellite instability (MSI), tumor mutational burden (TMB), and genomic loss of heterozygosity (gLOH, high≥16%). Plasmacytoid histology was confirmed by pathologic evaluation. GAs were compared by plasmacytoid histology and CDH1-mutated (CDH1-M) vs. wild-type (WT). The Flatiron Heath-Foundation Medicine Urothelial Clinico-Genomic Database (FH-FMI CGDB) was used to characterize overall survival (OS) and progression-free survival (PFS) in CDH1-M vs. WT, stratified by systemic therapy administered. RESULTS: CDH1 mutations were identified in 158 patients, who demonstrated a higher frequency MSI-high status (2.7% vs. 0.8%, p<0.01), mean TMB (14.8 vs. 9.9%, p<0.01), but lower gLOH (6.8% vs. 20.3%, p<0.01). PUC was identified on pathologic analysis in 103 (65%) patients with CDH1 mutations. Table 1 demonstrates the frequency of GAs between these three groups. There were no differences in genes associated with DNA damage response. In the non-PUC cohort, GAs on chromosome 9p21 were increasingly mutated. From the FH-FMI CGDB, 22 patients (3.7%) featured CDH1 mutations, and shared similar demographics to CDH1-WT. These patients demonstrated worse OS (OS 3.3 vs. 9.5 months, p=0.03) and PFS (2.8 vs 3.5 months; p=0.09) when treated with immune checkpoint inhibitors, but no difference following chemotherapy. CONCLUSIONS: CDH1 mutations are not exclusive to PUC, which possesses a distinct genomic profile and natural history. Real-world clinical outcomes support that CDH1 mutations predict resistance to immune checkpoint inhibition, but not chemotherapy. Taken together, these results further support genomic profiling of advanced bladder tumors and treatment individualization based on genomic signatures. Source of Funding: NA © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e774 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kyle Rose More articles by this author Andrea Necchi More articles by this author Facundo Davaro More articles by this author Elizabeth Davaro More articles by this author Heather Huelster More articles by this author Joseph Jacob More articles by this author Grennady Bratslavsky More articles by this author Dean Pavlick More articles by this author Douglas Lin More articles by this author Natalie Danzinger More articles by this author Petros Grivas More articles by this author Hikmat Al-Ahmadie More articles by this author Vamsi Parimi More articles by this author Philippe Spiess More articles by this author Bishoy Faltas More articles by this author Jeffrey Ross More articles by this author Roger Li More articles by this author Expand All Advertisement PDF downloadLoading ...

Single and multi-hit PIK3CA short variant (SV) genomic alterations (GA) in clinically advanced prostate cancer (CAPC): A genomic landscape study.

258 Background: Tumors harboring 2 or more PIK3CA Short variants (SV) (“Multi-hit”) have been described in breast cancer as linked to enhanced clinical outcome from anti-PIK3CA targeted therapies including alpelisib and investigational agents in clinical trials. The landscape and clinical implications of multi-hit PIK3CA alterations in other tumors, including in CAPC, are underexplored. Methods: 19,978 CAPC samples underwent hybrid capture based comprehensive genomic profiling (CGP) to evaluate all classes of GA and determine tumor mutational burden (TMB), microsatellite instability (MSI), genomic ancestry, signature and loss of heterozygosity (gLOH). Tumor cell PD-L1 expression was determined by IHC (Dako 22C3). Results: 18,741 (93.8%) CAPC were PIK3CA wild type (WT), 1,155 (5.8%) featured a single PIK3CA SV and 82 (0.4%) featured multi-hit PIK3CA SVs. The median ages of CAPC patients with single hit (69.1 yrs) or multi-hit (68.7 yrs) PIK3CA SV were older than the PIK3CA WT (67.6 yrs) CAPC (p&lt;.0001 for both). At 14.0%, African ancestry was more frequent in PIK3CA WT CAPC than in single-hit (10.4%; p=.001) and multi-hit (10.2%; not significant). Single-hit (81.4%; p&lt;.0001) and multi-hit (85.2% p=.05) PIK3CA SV CAPC featured significantly more MMR trinucleotide genomic signatures than PIK3CA WT (64.8%). Single-hit (2.7%; p=.02) and multi-hit (5.8% p=.05) PIK3CA SV CAPC featured significantly more POLE trinucleotide genomic signatures than PIK3CA WT (0.4%). MSI high status was significantly more common in both PIK3CA single-hit (12.4% vs 2.5%; p&lt;.0001) and multi-hit (35.4% vs 2.5%; p&lt;.0001). Mean TMB was also significantly higher in single-hit PIK3CA (11.1 vs 3.5 mut/Mb; p&lt;.0001) and multi-hit (42.9 vs 3.5 mut/Mb; p&lt;.0001). Noteworthy differences in GA of potential importance for CAPC pts included significantly higher frequencies of GA in BRCA2 in multi-hit vs WT (18.3% vs 8.5%; p=.019), ATM in multi-hit vs WT (13.4% vs 5.6%; p=.02) and PTEN in single-hit vs WT (40.2% vs 30.1%; p&lt;.0001) and lower frequencies of GA in CDK12 (3.6% vs 5.6%; p=.009) and SPOP (7.4% vs 9.8%; p=.012) in single-hit vs WT. There were no differences in gLOH or PD-L1 expression among the 3 groups. Conclusions: Although uncommon, the identification of multi-hit PIK3CA GA in CAPC highlights a potentially unique subtype of this disease that may be associated with enhanced responsiveness to anti-PIK3CA targeted therapy strategies.