Worse Prognosis Research Articles

CircMETTL6 Suppresses Ovarian Cancer Cell Growth and Metastasis Through Inhibition of GDF15 Transcription by Disrupting the NONO-POLR2A Complex.

Circular RNAs (circRNAs) are a distinctive class of non-coding RNAs with covalent closed-loop structure, lacking 5' caps and 3' poly(A) tails. These molecules are prevalent in eukaryotes and play keyroles in cancer. Here, the function of a new circRNA, circMETTL6, in ovarian cancer is identified and investigated. The prognostic significance of circMETTL6 is assessed using RNA in situ hybridization. Functional studies involving circMETTL6 overexpression are performed both in vitro and in vivo. Mechanistic investigations are performed using RNA-seq, RNA pull-down, RNA immunoprecipitation, co-immunoprecipitation, chromatin immunoprecipitation, protein degradation assay and dual-luciferase reporter assays. circMETTL6 is significantly downregulated in ovarian cancer, and its lower expression correlates with worse prognosis. Overexpression of circMETTL6 significantly inhibited proliferation, migration, and invasion of ovarian cancer cell in vitro, as well as tumor growth and metastasis in vivo. Mechanistically, circMETTL6 recruited the non-POU domain containing octamer binding protein (NONO) by binding to its Coiled-coil domain and disrupted its binding with RNA polymerase II subunit A (POLR2A), and consequently inhibiting growth differentiation factor 15 (GDF15) transcription, thereby suppressing ovarian cancer progression. These findings establish circMETTL6 as a novel tumor suppressor in ovarian cancer. Targeting the circMETTL6/NONO/GDF15 axis presents a potential therapeutic avenue for ovarian cancer treatment.

VEGFA Gene Expression in Breast Cancer Is Associated With Worse Prognosis, but Better Response to Chemotherapy and Immunotherapy.

Vascular endothelial growth factor-A (VEGFA) is a key inducer of angiogenesis, responsible for generating new blood vessels in the tumor microenvironment (TME) and facilitating metastasis. Notably, Avastin, which targets VEGFA, failed to demonstrate any significant benefit in clinical trials for breast cancer (BC). This study aimed to investigate the clinical relevance of VEGFA gene expression in BC. A total of 7,336 BC patients across eight independent cohorts: ISPY2 (GSE173839), Sweden Cancerome Analysis Network-Breast (SCAN-B) (GSE96058), Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), GSE25066, GSE163882, GSE34138, GSE20194, and The Cancer Genome Atlas (TCGA), were analyzed. The calculated median VEGFA expression level was used to stratify these cohorts into high and low groups. High VEGFA was associated with worse disease-free, disease-specific, and overall survival in the METABRIC cohort, with findings supported by the SCAN-B cohort, which also showed worse overall survival (all P < 0.02). High VEGFA expression was seen in triple-negative breast cancer (TNBC) but not in BC with lymph node metastasis. Additionally, there was a significant correlation between high VEGFA expression and higher silent and non-silent mutations, single-nucleotide variant (SNV) neoantigens, homologous recombination defect, intratumoral heterogeneity, in the TCGA cohort. In the TCGA, METABRIC, and SCAN-B cohorts, high VEGFA BC was also associated with higher cell proliferation: higher Ki67 gene expression, higher Nottingham histological grade, and consistent enrichment of all the Hallmark cell proliferation-related gene sets. Unexpectedly, the angiogenesis gene set was not enriched in any of the cohorts and showed no association with infiltrations of lymphatic or blood vascular endothelial cells besides pericytes. High VEGFA BC had significantly less infiltration of anti-cancer immune cells but higher infiltration of pro-cancer immune cells in TCGA, METABRIC, and SCAN-B cohorts. Interestingly, BC, which had a pathological complete response (pCR) after anthracycline- and taxane-based neoadjuvant therapy, was associated with significantly heightened VEGFA expression in both estrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2)- and TNBC subtypes in the GSE25066 cohort and after immunotherapy in ER+/ HER2- subtype, but not TNBC in the ISPY2 cohort. Our research indicates that high VEGFA BC confers high cell proliferation, reduced immune cell infiltration, and poorer survival, but allows better response to anthracycline- and taxane-based chemotherapy, and immunotherapy.

Abstract TMP108: Incidence and Characteristics of Acute Ischemic Stroke after Cardiac Arrest

Introduction: Brain injury is the main cause of death and disability post-cardiac arrest, and hypoxic-ischemic brain injury (HIBI) severity is associated with poor outcomes. There is limited information about the co-occurrence of acute ischemic stroke with HIBI post-cardiac arrest and its impact on outcome. Methods: We performed a retrospective analysis of brain MRI reports from patients with cardiac arrest in a multicenter cohort to evaluate the incidence of acute ischemic stroke and HIBI. Patients with MRI in the first 7 days after cardiac arrest were included. Patients with traumatic brain injury, intracranial hemorrhage, recent neurosurgical procedures, or ischemic stroke at admission were excluded. A secondary manual review by a board-certified vascular neurologist was pursued if the MRI report did not specify the absence of ischemic stroke. Univariate and multivariable analysis was performed to explore the characteristics of the ischemic lesions and to evaluate if it was related to poor functional outcomes (i.e., Cerebral Performance Category of 4-5). Results: Among 396 patients who met the inclusion criteria, 91 had cerebral infarction based on MRI (22.9%). The most common pattern of stroke was multifocal small embolic (51.6%), followed by single embolic (25.3%), watershed (12.1%), territorial (7%), and lacunar (5%). The patients with acute ischemic stroke were older (p&lt;0.01). In the logistic regression, older age, non-witnessed cardiac arrest, and non-shockable rhythm were associated with worse prognosis (p&lt;0.05). The presence of acute ischemic stroke was not significantly associated with the cause of arrest, percutaneous coronary intervention (PCI), or the use of targeted temperature management (TTM). Individuals with acute ischemic stroke had lower rates of HIBI (odds ratio [OR] 0,55 [0.34-0.87], p&lt;0.01). In univariate and multivariate analysis, the presence of acute ischemic stroke was not associated with outcome, as opposed to the presence of HIBI (p&lt;0.01). Conclusion: More than one-fifth of the comatose patients after cardiac arrest present acute ischemic stroke on MRI. The most common pattern is multifocal embolic, which may be related to cardiac embolism and hypercoagulable state after the arrest and not from PCI or cardiac arrest rhythm. The detection of acute ischemic stroke is higher among individuals without HIBI and is not associated with worse outcomes.

Genomic landscape study of esophago-gastric adenocarcinoma (EGAC) in young patients under the age of 30 years.

480 Background: Despite recent advances in treatment of EGAC, prognosis continues to be poor with reported 5-year survival of less than 30%. EGAC is more frequently diagnosed at an old age with the median age at diagnosis around 65 years. However, approximately 10% of EGAC are diagnosed at a younger age of less than 50 years and those patients present with more advanced stages resulting in worse prognosis. Our study investigated the genomic landscape of EGAC diagnosed under the age of 30 years to better understand the characteristics of EGAC occurring in very young population. Methods: 8,001 cases of clinically advanced EGAC who underwent comprehensive genomic profiling (CGP) from 2012 to 2024 were included in the study. Patients aged less than 30 years were classified as ‘EGAC-young’ and patients aged 50 and older were classified as ‘EGAC-old’. All classes of genomic alterations (GA), microsatellite instability high (MSI-high) status, tumor mutation burden (TMB), genomic ancestry, genomic signature, and homologous recombination defect signature (HRDSig) were determined from the sequencing data. PD-L1 was measured by IHC using the Dako 22C3 tumor proportional score (TPS) system. Comparisons utilized the Fisher Exact method with the Benjamini-Hochberg adjustment to reduce the false discovery rate. Results: Out of 8,001 cases, 7389 (92.4%) were classified as ‘EGAC-old’ and 26 (0.3%) as ‘EGAC-young’. Both groups had a higher frequency of male patients but there was no significant difference between the two groups (86.4% vs 76.9%; NS). Median GA per tumor was 6 in both groups. The ‘EGAC-old’ featured a significantly higher frequency of EUR ancestry (92.0% vs 73.1%; P=0.026). There were no significant differences in clinically important GA between both groups, including similar ERBB2 GA (21.2% vs 30.8%; NS) and FGFR3 GA (1.2% vs 7.7%; NS). There was a trend of more frequent GA of AKT2, CCNE1, and KEAP1 noted in ‘EGAC-young’ (0.9% vs 11.5%, 8.5% vs 26.9%, 1.3% vs 11.5%, respectively; P=0.071). MSI-high status was 3.1% in the ‘EGAC-old’ but not detected in the ‘EGAC-young’ (NS). The median TMB was higher in the ‘EGAC-old’ vs ‘EGAC young’ (3.8 mutations/Mb vs 1.9 mutations/Mb; P=.003). The frequencies of a positive HRDSig were similar in both groups (5.6% vs 8.0%; NS). There were no significant differences in COSMIC trinucleotide signatures. PD-L1 expression was identified in greater than 20% of the ‘EGAC-old’ but was not measured in the ‘EGAC-young’. Conclusions: Clinically advanced EGAC in young patients under the age of 30 years features a genomic landscape that differs from EGAC identified in older patients, including lower TMB and a trend of increased GA frequency of genes related to poor prognosis in other types of cancer. Further studies are warranted to utilize CGP findings in identifying potential implications for treatment and prognostication in these rare cases of EGAC occurring in very young patients.

Loss of tumor cell surface hepatocyte growth factor activator inhibitor-1 predicts worse prognosis in esophageal squamous cell carcinoma.

Hepatocyte growth factor activator inhibitor-1 (HAI-1) is an epithelial type-1 transmembrane protease inhibitor that regulates the pericellular activities of hepatocyte growth factor activator and type-2 transmembrane serine proteases. It is strongly expressed in the stratified squamous epithelium and functions on the cell surface. We previously reported that the cell surface immunoreactivity of HAI-1 was reduced at the invasion front of oral squamous cell carcinoma. In this study, we investigate the relationship between cell surface HAI-1 (csHAI-1) and prognosis of esophageal squamous cell carcinoma (ESCC) after surgery. The effect of HAI-1 knockdown on cultured ESCC cells was also analyzed in vitro. HAI-1 exhibited distinct cell surface immunoreactivity in normal esophageal epithelium. In contrast, alterations in HAI-1 immunoreactivity were frequent in cancer cells, which exhibited aberrant intracytoplasmic localization and decreased cell surface immunoreactivity. The preservation of csHAI-1 immunoreactivity was a sign of a well-differentiated phenotype of ESCC cells. The decreased csHAI-1 was associated with shorter overall survival (OS) and disease-free survival (DFS) in the patients. In 55 cases of early (T1) ESCC cases, decreased csHAI-1 also predicted poor OS and DFS. The loss of HAI-1 enhanced migration and invasion of ESCC cells in vitro. These results suggest that the decreased cell surface immunoreactivity of HAI-1 is associated with a less differentiated phenotype and worse prognosis in ESCC. The cell surface-localized HAI-1 may serve as a promising marker for predicting recurrence and prognosis of ESCC.

Molecular characteristics and prognostic impact of GNAS mutations in colorectal cancer: An international collaborative study between United States and Japan.

48 Background: GNAS (Guanine nucleotide-binding protein, alpha stimulating) encodes the alpha subunit of the stimulatory G protein, and gain of function mutations in this gene have been previously identified, especially those located at the R201 codon. Although GNAS R201C/H has been associated with mucinous histology and poor response to chemotherapy in appendiceal cancer, the impact of GNAS mutations in colorectal cancer (CRC) remains unclear. Methods: We conducted a comparative, integrative analysis of GNAS mutations in CRC using two cohorts: MD Anderson Cancer Center (MDA) across all stages (N=5,249) and the GALAXY study involving only resectable disease (UMIN000039205, N=2,599). We assessed the correlation between GNAS pathogenic mutations and microsatellite stability, CRC sidedness, co-mutations, and survival outcomes. The Chi-squared test was used for categorical variables, and the log-rank test for overall survival (OS) and disease-free survival (DFS). Results: In the MDA and GALAXY cohorts, GNAS mutations were identified in 107 (2.0%) and 61 (2.4%) patients, respectively. Prevalence of GNAS mutations was higher in right sided tumors (MDA: 3.8% vs. 1.3%, GALAXY: 6.2% vs 2.8%, p&lt;0.01 for both cohorts) and microsatellite instability-high (MSI-H) tumors (MDA: 6.5% vs. 1.8%, GALAXY: 16.5% vs. 1.4%, p&lt;0.01 for both cohorts). There was not an association of GNAS mutations with stage in either cohort. GNAS was significantly enriched for co-mutation with KRAS in the MDA cohort (OR=3.26, P&lt;0.01), similar to prior observations in appendix cancer, but was not significantly associated with KRAS mutations in the GALAXY cohort (OR=1.35, P=0.3). GNAS mutations were mutually exclusive with TP53 in both cohorts (MDA: OR=0.58, P=0.026; GALAXY: OR=0.21, P&lt;0.01). With regards to survival, in the MDA cohort, GNAS mutant tumors had a trend towards worse OS in the overall population (20 mo vs. 33 mo, HR=1.27, 95% CI=0.61-1, P=0.085). The survival impact of GNAS mutations was greatest in metastatic patients (Stage IV: 19 mo vs. 38 mo, HR=1.49, 95% CI=0.47-0.94, P=0.021 vs. Stage I-III: HR=1.35, 95% CI=0.46-1.2, P=0.22). The GALAXY cohort showed no significant association between GNAS mutations and DFS (HR=1.05, 95% CI=0.6-1.8, P=0.9). In both cohorts, GNAS mutations had a worse prognosis in left-sided CRC (MDA: HR for OS = 1.45, P = 0.091; GALAXY: HR for DFS=2.15, P=0.09) with no significant effect observed in right-sided CRC (MDA: HR for OS=0.91, P=0.68; GALAXY: HR for DFS=0.65, P=0.3). Conclusions: Our findings highlighted the intricate role of GNAS mutations in CRC, demonstrating its higher prevalence in MSI-H and right-sided colon, significant association with KRAS mutations, and divergent prognostic impacts based on tumor sidedness. Further research is needed to elucidate the mechanisms behind the worsened survival in left-sided GNAS- mutated CRC.

Proteomic profiling identifies muscle-invasive bladder cancers with distinct biology and responses to platinum-based chemotherapy

Platinum-based neoadjuvant chemotherapy prior to radical cystectomy is the preferred treatment for muscle-invasive bladder cancer despite modest survival benefit and significant associated toxicities. Here, we profile the global proteome of muscle-invasive bladder cancers pre- and post-neoadjuvant chemotherapy treatment using archival formalin-fixed paraffin-embedded tissue. We identify four pre-neoadjuvant chemotherapy proteomic clusters with distinct biology and response to therapy and integrate these with transcriptomic subtypes and immunohistochemistry. We observe proteomic plasticity post-neoadjuvant chemotherapy that is associated with increased extracellular matrix and reduced keratinisation compared to pre-neoadjuvant chemotherapy. Post-neoadjuvant chemotherapy clusters appear to be differentially enriched for druggable proteins. For example, MTOR and PARP are over-expressed at the protein level in tumours identified as neuronal-like. In addition, we determine that high intra-tumoural proteome heterogeneity in pre-neoadjuvant chemotherapy tissue is associated with worse prognosis. Our work highlights aspects of muscle-invasive bladder cancer biology associated with clinical outcomes and suggests biomarkers and therapeutic targets based on proteomic clusters.

AGX101: A TM4SF1-directed tubulin inhibitor conjugate in ongoing first-in-human trial including GI cancers.

829 Background: TM4SF1 (Transmembrane-4 L-Six-Family-Member-1) is an endothelial marker with critical roles in angiogenesis, as well as a tumor cell antigen that contributes significantly to invasion and metastasis. TM4SF1 is upregulated 20-fold in angiogenic tumor vascular endothelium compared to normal vasculature endothelium and exhibits a unique nuclear internalization pathway. AGX101 is a novel tubulin inhibitor conjugate specifically directed against TM4SF1, delivering a potent maytansinoid payload directly to the nucleus of cells within the tumor microenvironment. Delivery to both the vascular and tumor cell compartments of the tumor results in three mechanisms of action (MoAs): (1) activation of tumor immune surveillance, (2) tumor blood supply deprivation, and (3) direct tumor cell killing. Methods: TM4SF1 expression was assessed using immunohistochemistry. Safety and pharmacokinetics of AGX101 were evaluated in non-human primates (NHP), with escalating doses to determine the highest non-severely toxic dose (HNSTD). Efficacy studies were also conducted in mouse models, enabling assessment of the minimum effective dose (MED) needed to engage each of the three MoAs. The combination of HNSTD and MED enables calculation of a therapeutic index (TI). The potential for synergy with immune checkpoint inhibitors (ICIs) was also investigated. A first-in-human study of AGX101 in patients with advanced solid tumors with the primary objective of safety and dose-limiting toxicities (DLTs) has initiated. Results: Notable cancers with high TM4SF1 scoring intensity include pancreatic adenocarcinoma, hepatocellular carcinoma, cholangiocarcinoma, and gastric cancer. In esophageal cancer, 20% of patients have a TM4SF1 copy number amplification, and these have worse prognosis. In NHP, AGX101 exhibited a favorable safety profile. In preclinical efficacy studies, monotherapy demonstrated robust efficacy through each of the three MoAs in syngeneic models in mice including CT26 colon carcinoma, and human tumor xenograft models including MIA PaCa-2 pancreatic cancer. Measured by exposure, TI was large. In syngeneic mouse models including CT26, the effects of ICIs were potentiated, suggesting a potential synergistic approach in cancer therapy. The first two dose levels of AGX101 monotherapy in humans has cleared without DLTs. Three patients with pancreatic adenocarcinoma have been treated thus far. Conclusions: AGX101, targeting the TM4SF1 antigen, represents a promising new approach in cancer therapy. The preclinical data suggest that AGX101 could provide a significant therapeutic benefit by novel and differentiated mechanisms of action, namely selectively targeting the tumor vasculature and potentiating immune-based therapies. Further clinical development of AGX101 is ongoing and initial outcome data will become available by the conference. Clinical trial information: NCT06440005 .

Impact of homologous recombination deficiency on survival and chemotherapy response in small bowel adenocarcinoma.

800 Background: Small bowel adenocarcinoma (SBA) is a rare malignancy, and its genomic profile is distinct from that of gastric and colorectal cancers. However, the role of homologous recombination repair (HRR) gene mutations in SBA remains unexplored. This study aims to investigate the clinical significance of HRR gene mutations in SBA. Methods: We retrospectively analyzed data from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) utilization portal, in accordance with its policy. Between June 2019 and February 2024, patients with SBA who underwent comprehensive genomic profiling (Foundation One CDx, Foundation One Liquid, OncoGuide NCC Oncopanel, Guardant 360 CDx, and GenMineTOP) were included. The frequency of HRR variants ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CHEK2, PALB2, RAD51C, RAD51D, RAD51, ATRX, ARID1A, BAP1, CDK12, MRE11, NBN, PTEN, FANCA, FANCC ) was analyzed. Homologous recombination deficiency (HRD) was defined as the presence of one or more alterations in HRR variants. Clinicopathological features, treatment outcomes, and survival were compared between HRD-positive and HRD-negative groups. Results: A total of 628 cases were analyzed, with a median age of 65 years, including 238 males and 390 females. The primary tumor sites were the duodenum in 332 cases and the jejunum in 296 cases. HRD was observed in 165 cases (26.5%) overall. The incidence of microsatellite instability-high (MSI-H) was significantly higher in the HRD-positive group compared to the HRD-negative group (15% vs. 1.1%, P &lt; 0.001). Similarly, the median tumor mutational burden (TMB) values were significantly higher in the HRD-positive group compared to the HRD-negative group (5 Mut/Mb vs. 3.8 Mut/Mb, P &lt; 0.001). The median overall survival (OS) was similar between HRD-positive and HRD-negative groups (1,243 days vs. 1,055 days, P = 0.22). However, in duodenal primary cases, the median OS was significantly longer in the HRD-positive group compared to the HRD-negative group (1,243 days vs. 702 days, P = 0.025). No significant difference in median OS was observed between HRD-positive and HRD-negative groups in jejunal primary cases (1,145 days vs. not reached, P = 0.51). The overall response rate (ORR) to platinum-based chemotherapy in first-line treatment was significantly higher in the HRD-positive group compared to the HRD-negative group in duodenal primary cases (34% vs. 18%, P &lt; 0.05). Conversely, there was no significant difference in ORR between HRD-positive and HRD-negative groups in jejunal primary cases (23% vs. 20%, P = 0.70). Conclusions: Duodenal primary SBA with HRD showed better response rates to platinum-based chemotherapy and had a more favorable prognosis compared to non-HRD cases. In duodenal cancer, which typically has a worse prognosis than jejunal cancer, HRD may represent a novel prognostic and predictive marker for treatment efficacy.

Multicenter, retrospective, observational study of outcomes of treatment for unresectable neuroendocrine tumors G3 of gastroenteropancreatic or unknown primary origin.

660 Background: The 2017 edition of the WHO classification categorized neuroendocrine neoplasms (NEN) as neuroendocrine tumors (NET) G1, G2, G3, and neuroendocrine carcinoma (NEC). Prior to 2017, NET G3 was categorized as NEC in the WHO 2010 classification. Platinum-based chemotherapy, commonly used as first-line treatment for these tumors, shows suboptimal efficacy for NET G3. Additionally, large-scale studies and robust evidence on chemotherapy outcomes for NET G3 are lacking. We investigated chemotherapy regimens for NET G3 and evaluated their outcomes. Methods: We included 73 patients (pts) who were clinically and pathologically diagnosed with unresectable NET G3 of gastroenteropancreatic or unknown primary origin and who started chemotherapy between Jan 2011 and Dec 2019. Clinical data were collected retrospectively and analyzed for regimen selected, treatment efficacy, and prognostic factors. A central pathological review was conducted if tissue samples were available. Results: The median age of pts was 65 years (range 27-85 years), with 45 being male. Among the pts, 49 had pancreatic NETs, 10 had gastrointestinal NETs, and 14 had NETs of unknown primary origin. The median Ki-67 index was 30% (range 20-70%). Twenty-seven patients (37%) had received prior treatment, such as surgery or local therapy. A central pathological diagnosis was confirmed NET G3 in 42 out of 44 patients (95%). Primary treatment regimens were NET-based (somatostatin analogues, everolimus, sunitinib, streptozocin-based chemotherapy, and capecitabine and temozolomide [CAPTEM]) and NEC-based (platinum-based chemotherapy) in 54% and 44% of patients, respectively. NET-based regimens were selected in 36% and 78% of pts, respectively, before and after publication of the WHO 2017 classification. The overall response rate (ORR) was 16% for NEC-based regimens and 19% for NET-based regimens. However, when focusing on NET-based chemotherapy (streptozocin-based and CAPTEM), the ORR was 54%. Median progression-free survival (PFS) was 118 days (95% confidence interval [CI]: 60-337 days) for NET-based regimens and 229 days (95%CI: 133-426 days) for NEC-based regimens. Median overall survival (OS) was 841 days for NET-based regimens (95%CI: 480-989 days) and 658 days (95%CI: 455-1144 days) for NEC-based regimens. There were no significant differences in PFS or OS between the regimens. In multivariable analysis, hepatic tumor volume &gt;25% was a negative predictor of PFS, and NSE ≥16.3 ng/mL was a negative predictor of OS. Conclusions: Since the introduction of NET G3 in the WHO classification, NET-based regimens have become the preferred treatment choice. Although there were no significant differences in PFS or OS between the regimens, the NEC-based regimens was limited. Pts with high hepatic tumor volume or elevated NSE levels had a worse prognosis.

Obesity and biliary tract cancers: Changing epidemiology.

643 Background: The incidence of biliary tract cancers (BTC) continues to rise (Sung et al. 2024). The reasons remain ill-defined. Over 70% of patients are diagnosed without identifiable predisposing factors. Obesity and overweight have emerged as putative contributors. We examined the epidemiologic and molecular characteristics of patients with BTC, with a focus on body mass index (BMI) at presentation and overall survival (OS). Methods: A retrospective cohort study of patients diagnosed with BTC at Memorial Sloan Kettering was conducted from January 2022 to December 2023. Patients were divided based on BMI into: obese (BMI≥30 kg/m 2 ) and non-obese (BMI&lt;30 kg/m 2 ). We collected patients' baseline demographics, and results of somatic next generation sequencing using the MSK-IMPACT platform and compared between obese and non -obese groups using Fisher’s exact test for categorical and Wilcoxon rank sum test for continuous variables. OS was calculated from date of diagnosis, estimated using Kaplan-Meier methods and compared between groups using log rank test. Results: A total of 142 patients were identified. The table summarizes the baseline characteristics including age, BMI, sex, stage at diagnosis, family history, history of malignancy, and race. Obesity was significantly associated with family history of malignancy and white race. Among surviving patients (n=93), with a median follow-up of 13.8 months, 6-month, 1-year, and 2-year overall survival (OS) rates were 85% [95%CI: 80%-92%], 71% [95%CI: 64%-79%], and 54% [95%CI: 43%-68%] respectively. OS was not statistically different among obese and non-obese patients. However, when stratifying OS by BMI and gender, obese males were noted to have inferior OS compared to obese females (6-mo OS 75% and 90% respectively), though not statistically significant. Genetic sequencing did not reveal a specific molecular pattern in either group. Conclusions: Obesity appears not to be associated with young age, stage, or particular somatic alterations in this limited study. OS was not statistically different among obese and non-obese patients. Males with obesity appeared to have a worse prognosis. This observed gender-based difference needs to be further studied, and if confirmed further research is needed to explore potential factors that may explain the clinical observation. Baseline characteristics. Characteristics Overall n=142 Obese (BMI≥30 kg/m 2 ) n=54 Non-Obese (BMI&lt;30 kg/m 2 )n=88 p-value Age 68 (35-91) 69 (35-87) 67 (36-91) &gt;0.9 BMI (kg/m 2 ) 28.1 (16.6-48.5) 33.5 (30-48.5) 24.7 (16.6-29.6) Sex female/male 79 (56%)/63 (44%) 32 (59%)/22 (41%) 47 (53%)/41 (47%) 0.6 Stage Localized/advanced 21 (15%)/121 (85%) 11 (20%)/ 43 (80%) 10 (11%)/ 78 (89%) 0.3 Family history of cancer 91 (65%) 41 (76%) 50 (57%) 0.030 History of second malignancy 26 (18%) 12 (22%) 14 (16%) 0.4 Race White African Asian Other 99 (70%)12 (8.5%)20 (14%)11 (7.7%) 44 (81%)4 (7.4%)1 (1.9%)5 (9.3%) 55 (63%)8 (9.1%)19 (22%)6 (6.8%) 0.004

Role of Cathepsin K in bone invasion of pituitary adenomas: A dual mechanism involving cell proliferation and osteoclastogenesis.

This study aimed to investigate the regulation and underlying mechanism of Cathepsin K (CTSK) in bone-invasive pituitary adenomas (BIPAs). A total of 1437 patients with pituitary adenomas were included and followed up. RNA sequencing, immunohistochemistry, and qRT-PCR were used to analyze CTSK expression. The effects of CTSK on cellular proliferation, bone matrix degradation, and osteoclast differentiation were determined by gain/loss of function experiments in vitro and in vivo. The exploration of signaling pathways was determined through molecular biology experiments. Here, we reported a significant fraction (∼10%) of pituitary adenoma patients developed bone invasion, which was correlated with tumor recurrence. Patients with BIPAs had shorter recurrence-free survival. CTSK expression was increased in BIPA patients and was strongly associated with a worse prognosis. Increased CTSK expression enhanced pituitary adenoma cell proliferation through the activation of the mammalian target of rapamycin (mTOR) signaling pathway and promoted bone invasion by increasing osteoclast differentiation both in vitro and in vivo. Treatment with the CTSK inhibitor odanacatib effectively inhibited pituitary adenoma cell proliferation and bone invasion in these models. Additionally, CTSK facilitated osteoclast differentiation by promoting RANKL expression in MC3T3-E1 cells via interaction with TLR4. Based on these findings, we conclude that CTSK has the potential to become a novel predictive biomarker and therapeutic target for BIPAs.

Genetic differences in colorectal cancer across race and ethnicity.

28 Background: Colorectal cancer (CRC) is the fourth most common cause of cancer death and cancer-related mortality is expected to increase exponentially. Ethnic minorities, in particular African Americans, have increased mortality from CRC. Although multifactorial, differences in somatic gene mutations could contribute to these racial discrepancies. Mutations in the critical oncogene KRAS are associated with worse prognosis in CRC. Recent literature suggests that in CRC patients, KRAS mutations are more frequently found in African Americans compared to Caucasians. This finding led to our hypothesis that molecular alterations across multiple races/ethnicities could explain differences in patient outcomes. This project will also inform a larger analysis using artificial intelligence learning models to predict race from tumor-specific genetic variants, as a tool to identify genetic drivers of race-specific patient outcome. Methods: We examined the molecular alterations in 304 patients diagnosed with CRC who had genetic testing between June 2021 and April 2023 at NYP Queens, NYP Brooklyn, and NYP Cornell. Race and ethnicity, genetic mutations, mortality, tumor location, and age, stage, and the presence of metastasis at diagnosis was collected. Patients self-identified as Non-Hispanic Black (NHB), White (NHW), Asian (NHA), American Indian (NHAI), or Hispanic, Other, or Declined. Median and interquartile range were used to summarize continuous variables, and frequency and proportion were used to summarize categorical variables. The significance of difference across ethnicity groups was tested using Kruskal-Wallis rank sum test for continuous variables and Fisher’s exact test for categorical variables. Mutational correlates of race using a multiple-instance learning artificial intelligence approach (i.e. Anaya et al., Nature Biomedical Engineering, 2023), will be presented. This method will predict race from patients' tumor-specific genetic variants, allowing us to identify specific variants and patterns predictive of race, and potential drivers of patient outcome. Results: Amongst the 304 CRC patients, we identified 116 NHW, 51 NHA, 40 NHB, 35 Hispanic and 1 NHAI, for a total population of 243. BRAF mutations were almost absent in NHB (2.5%) and NHA (3.9%), compared to NHW (13.8%; p=0.02). KRAS mutations were also more prevalent in underserved populations; 65.7% Hispanic, 57.5% NHB, compared with 44.8% NHW (p=0.14). We further identified substantial differences in KRAS mutations when dividing the Asian population into East Asian (62.9%) and South Asian (37.5%). Conclusions: We identified significant differences in key molecular drivers between ethnicities. Our findings suggest that genomic and tumor specific differences across ethnicities could in part explain differences in patient survival across these groups. Mutational correlates of race and survival using natural language processing will be presented.

Organoids, tissue slices and organotypic cultures: advancing our understanding of pancreatic ductal adenocarcinoma through in vitro and ex vivo models.

Pancreatic ductal adenocarcinoma (PDAC) has one of the worst prognoses of all common solid cancers. For the large majority of PDAC patients, only systemic therapies with very limited efficacy are indicated. In addition, immunotherapies have not brought the advances seen in other cancer types. Several key characteristics of PDAC contribute to poor treatment outcomes, and in this review, we will discuss how these characteristics are best captured in currently available ex vivo or in vitro model systems. For instance, PDAC is hallmarked by a highly desmoplastic and immune-suppressed tumor microenvironment that impacts disease progression and therapy resistance. Also, large differences in tumor biology exist between and within tumors, complicating treatment decisions. Furthermore, PDAC has a very high propensity for locally invasive and metastatic growth. The use of animal models is often not desirable or feasible and several in vitro and ex vivo model systems have been developed, such as organotypic cocultures and tissue slices, among others. However, the absence of a full host organism impacts the ability of these models to accurately capture the characteristics that contribute to poor outcomes in PDAC. We will discuss the caveats and advantages of these model systems in the context of PDAC's key characteristics and provide recommendations on model choice and the possibilities for optimization. These considerations should be of use to researchers aiming to study PDAC in the in vitro setting.

The prevalence and prognostic significance of KRAS G12C mutation in metastatic colorectal cancer.

289 Background: Kristen rat sarcoma virus ( KRAS ) mutations are reported in 40-45% of colorectal cancer (CRC), and they are associated with poor prognosis. KRAS G12C mutation is reported in 3-4% of CRC patients and may be associated with worse prognosis compared to RAS non-G12C mutations. Here, we explored the prevalence and prognostic significance of KRAS G12C mutation compared to RAS non-G12C and BRAF V600E in a cohort of CRC patients from a tertiary cancer center in the United States (US). Methods: The cBioCancer Genomics Portal was used to obtain genomic data. The prevalence of KRAS G12C mutation, RAS non-G12C ( KRAS G12D, KRAS G13D, KRAS G12V, KRAS A146T, KRAS G12A, KRAS G12S, KRAS G13C, KRAS V14I, KRAS Q61H, KRAS G12R, KRAS Q61R, KRAS K117N, NRAS Q61K , NRAS Q61R , NRAS Q61L , NRAS Q61H , NRAS G13D , NRAS G13C NRAS G13R NRAS G12D , NRAS G12C , NRAS G12V, NRAS G12V and NRAS G60V ) mutations and BRAF V600E mutations was calculated. The median overall survival (mOS) was explored in CRC (MSK, Cancer Cell 2018 cohort). Patients in this cohort were not treated with KRAS G12C targeted therapy. Survival analysis was performed using the Kaplan-Meier method with log-rank test comparisons. Results: In this cohort of patients with stage IV CRC (N=1134), the prevalence of KRAS G12C mutation in patients with stage IV CRC was 3.1%. In patients with RAS non-G12C mutations, BRAF V600E mutation, and RAS/BRAF V600E wild-type (WT), the prevalence was 41.7%, 7.5%, and 47.7% respectively. The mOS in KRAS G12C mutation, RAS non-G12C mutations, BRAF V600E mutation, and RAS/BRAF V600E WT was 65 months (m), 55m, 19m and 105m respectively. Compared to RAS non-G12C , the mOS of CRC patients with KRAS G12C was (65m vs 55m, p=0.54) . Compared to patients with BRAF V600E mutation, the mOS was better in patients with KRAS G12C (65m vs. 19m, p &lt;0.0001) and in patients with RAS non-G12C (55m vs. 19m, p &lt;0.0001). Conclusions: The prevalence of KRAS G12C mutation in this cohort was relatively similar to other reports at 3.1%. Consistent with several other reports, there was no statistically significant difference in the mOS between patients with KRAS G12C mutation and patients with RAS non-G12C mutations. Patients with BRAF V600E mutations had worse mOS compared to patients with KRAS G12C mutation and RAS non-G12C mutations. The reported high mOS in this cohort is possibly due to selection bias (patients able to afford and receive treatment at this tertiary center).

Patients outcomes in lung adenocarcinoma transforming to small-cell lung cancer after tyrosine kinase inhibitor therapy

BackgroundNon-small cell lung cancer (NSCLC) transforming to small cell lung cancer (SCLC) is one of the mechanisms of resistance to tyrosine kinase inhibitors (TKIs). Cases of NSCLC transforming into SCLC have been discovered. However, we lack concentrated data on the characteristics of this population and the transformed SCLC to aid our insight of the biology and clinical value of NSCLC transforming with positive.MethodsWe systematically reviewed the published literatures and summarized the pathological and clinical characteristics, and the prognosis, of published cases.Results140 patients with lung adenocarcinoma (LUAD) were included in this study, with a median age of 56.8 years. The median time from the first diagnosis of LUAD transforming to SCLC (ttSCLC) was 20.0 months. The median overall survival (mOS) after the diagnosis of SCLC was 11.0 months (95% CI, 7.41 to 14.59 months). In the univariate analysis, ever smoking (either former or current) was a promising predictor of a shorter ttSCLC (HR, 1.73; 95% CI, 1.14 to 2.62; P = 0.010). TKIs therapy administered as a second line and beyond treatment was related to a significant delay in SCLC onset compared to first-line therapy (HR, 0.62; 95% CI, 0.40 to 0.96; P = 0.031). The median progression-free survival (mPFS) on first-line platinum plus etoposide after the conversion to SCLC was 3.0 months. Female appeared to be related to worse outcomes after transformation of SCLC.ConclusionTransformed SCLC exhibited poor response to primary SCLC classic chemotherapy and immunotherapy. It carries a worse prognosis. Exploring novel therapeutic strategies for transformed SCLC is imperative.

Dissecting the cellular reprogramming and tumor microenvironment in left- and right-sided Colorectal Cancer by single cell RNA sequencing.

Sidedness and staging are major sources of tumor microenvironment (TME) differences in colorectal cancer (CRC). Subpopulation compositions of stromal cells and immune cells, and interactions between cells collectively constitute the immunosuppressive microenvironment of CRC. In this study, we comprehensively collected single-cell RNA sequencing data from public databases. We filtered out 126,279 cells from 55 CRC samples to characterize the differences in cellular composition, and to elucidate the transcriptional features and potential functions of cell types, temporally and positionally. We observed an increased degree of hypoxia in right side-specific cancer cells compared to left-sided cancer. Cancer-associated fibroblasts (CAFs) illustrated molecular signatures tremendously tended to be associated with functions that orchestrate extracellular matrix remodeling and angiogenesis, and right-sided CAFs characterized the stronger cancer invasion signals. Crosstalk between side-specific cancer cells and stromal together with immune cells characterized CRC via different sample groups, and was pertinent to worse prognosis. Our study captured immunosuppressive pattern exhibiting more intricate intercellular interactions in right-sided CRC. Additionally, during malignant progression of CRC, the transformation of CD8+ T cell cytotoxic and exhausted properties and macrophage pro-inflammatory and anti-inflammatory properties epitomized the cellular reprogramming phenomenon that the function of TME shifted from promoting immunity to suppressive immunity. Our study shed lights on refining personalized therapeutic regimens during malignant progression in left- and right-sided CRCs.

A study of the homologous recombination deficiency signature (HRDSig) status of advanced esophageal squamous cell carcinoma (AESCC) by utilizing comprehensive genomic profiling (CGP).

485 Background: The role of poly-ADP-ribose polymerase (PARP) inhibitors is currently under investigation as a potential therapeutic option for AESCC. Homologous recombination deficiency signature status (HRDSig) positivity has been shown to predict biallelic loss of BRCA1/2 which may simultaneously portend a worse prognosis and a sensitivity to poly-ADP-ribose polymerase (PARP) inhibitors. In this study, we attempt to characterize the genomic alterations present in AESCC based on HRDSig status utilizing comprehensive genomic profiling (CGP) techniques. Methods: 2,029 cases of AESCC underwent comprehensive genomic profiling with an examination of all genomic alterations (GA). MSI high status, tumor mutation burden (TMB) levels, genomic ancestry and genomic trinucleotide signatures were determined from the sequencing data. HRDSig status was calculated using a broad set of genome-wide copy number features (PMID 37769224). Results were compared using the Fisher exact system with the Benjamini-Hochberg adjustment to correct for false discovery. Results: 154 (7.6%) of the 2029 AESCC cases featured a positive HRDSig status (HRDSig+). The age (66-67) and gender (58%-63% male) distribution were similar in the HRDSig+ and HRDSig- AECSS cases as was the frequency of GA/tumor (9 for both). The median TMB was higher in the HRDSig+ (6.3 vs 3.8; P&lt;.0001) as was frequency of TMB &gt; 10 mutations/Mb (19.5% vs 10.0%; P=.004). An APOBEC trinucleotide signature was also more frequent in the HRDSig+ AESCC (11.0% vs 5.4%; P=.05). As anticipated, GA in genes associated with HRD including BRCA1 (10.4% vs 1.4%; P&lt;.0001) and BRCA2 (14.3% vs 2.0%; P&lt;.0001) was present. MTOR pathway activating mutations were also more frequent in the HRDSig+ AESCC group including PTEN (13.0% vs 7.3%; P=.06). Conclusions: With a 7.6% frequency, HRDSig+ status is a relatively rare event in AESCC. CGP with determination of HRDSig status in AESCC may prove useful in tailoring PARP inhibitor-based treatment regimens and may potentially uncover other genomic alterations that can aid in designing targeted therapy combinations in future. Characteristics of comprehensive genomic profiling of clinically advanced esophageal squamous cell carcinoma by HRDSig status. AESCC HRDSig- (n=1875) AESCC HRDSig+ (n=154) P-value Pathogenic genomic alterations BRCA1 1.4% (26) 10.4% (16) 0.00 BRCA2 2.0% (36) 14.3% (22) 0.00 PTEN 7.3% (137) 13.0% (20) 0.06 COSMIC trinucleotide signature APOBEC 5.4% (101) 11.0% (17) 0.05 Tumor mutational burden (TMB) Median TMB (range) (IQR) 3.8 (0-85) (2.5-6.3) 6.3 (0-61) (3.8-8.8) 0.00 TMB≥10 mut/Mb 10.0% (188) 19.5% (30) 0.00

Characterization of the real-world first line (1L) use of single dose tremelimumab regular interval durvalumab (STRIDE), for treatment of unresectable hepatocellular carcinoma (uHCC), using two electronic medical record (EMR) databases.

534 Background: In October 2022, the US FDA approved the STRIDE (Single Dose Tremelimumab Regular Interval Durvalumab) regimen, comprising tremelimumab 300 mg for 1 dose plus durvalumab 1500 mg every 4 weeks, for the 1L treatment of uHCC in adults aged ≥18 years. Thus far there is limited data characterizing STRIDE's 1L use in the real world. This observational study aims to describe patient characteristics, and clinical profiles of a 1L STRIDE cohort. Methods: A retrospective cohort study was conducted using EMR data from two community oncology practice networks, Florida Cancer Specialists and American Oncology Network, from January 1, 2018, to March 31, 2024. Adults with HCC who received ≥1 administration of the STRIDE regimen as 1L treatment following diagnosis were included. Patients with evidence of other cancers or systemic therapies pre-index date were excluded, to establish a cancer-naïve cohort at index. Index date was first administration of STRIDE. The analysis described the patient characteristics and clinical profile at index date. Patient demographics, severity indicators (cancer stage, albumin-bilirubin index (ALBI), alpha fetoprotein (AFP), Eastern Cooperative Oncology Group (ECOG)) and lab data were assessed on or closest to index date. Results: 79 patients initiated the 1L STRIDE regimen. The median (P25, P75) age at index was 70 (63.2-76.4) years. 72.2% were males, 64.6% were white, and 69.6% were overweight or obese patients. 95% had their first HCC diagnosis between 2022-2024 and the mean time from diagnosis to index date was 3.8 months (SD: 10.2). Among patients with reported cancer stage (n=57), most (82.5%, n=47) were diagnosed with stages IIIA to IVB. 18% had ECOG scores ≥2. 86% had ALBI grades between 2-3; 42.1% had AFP level ≥400 ng/ml; 30.4% had cirrhosis (among those that reported comorbidities) and 24.1% received any loco-regional therapy. Conclusions: Our study provides a real-world profile of patients on 1L STRIDE. Compared to the HIMALAYA trial, these findings suggest that patients in this real-world study tend to be older, diagnosed at late-stage, have a poor liver profile, and potentially worse prognosis over time. Further research is required to explore treatment pathways after index date, over a long follow-up, which may provide more insight into the continuity and effectiveness of IL STRIDE in the real-world.

Analysis of Prognostic Factors for Internal Carotid Artery Invasion by Nasopharyngeal Carcinoma

Background: The prognostic impact of internal carotid artery (ICA) invasion in nasopharyngeal cancer (NPC) patients is not well established. Thus, we conducted a retrospective study to analyze the prognostic factors for ICA invasion by NPC. Methods: This retrospective study included consecutive biopsy-proven NPC patients who received CCRT from November 2015 to December 2022 at E-Da Hospital. Patients were then classified into two groups according to ICA invasion by tumor or not. Survival was estimated by the Kaplan–Meier method with a five-year overall survival (OS) rate and five-year disease specific survival (DSS) rate. Results: A total of 191 patients with pathologically confirmed NPC were included in this study, with 54 patients in the ICA invasion group and 137 patients in the no ICA invasion group. The ICA invasion group showed a worse prognosis compared to the no ICA invasion group (p &lt; 0.001 in OS and DSS). Patients were stratified into a poor response group and good response group. OS and DSS in the poor response group had a significant difference compared to the good response group (both p &lt; 0.001). In multivariate analysis, NLR was an independently prognostic factor for OS (HR 2.430, 95% CI 1.040–5.678, p = 0.040 and HR 0.412, 95% CI 0.176–0.962, p = 0.040, respectively) and for DSS (HR 2.430, 95% CI 1.040–5.678, p = 0.040 and HR 0.412, 95% CI 0.176–0.962, p = 0.040, respectively). Conclusions: Locally advanced NPC patients with ICA invasion have a miserable outcome and NLR represents a significant prognostic factor that impacts treatment decisions and survival.