Worse Overall Survival In Patients Research Articles

Different genetic profiles contribute to worse overall survival in patients with leptomeningeal metastases of non-small-cell lung cancer.

To assess the genetic characteristics of central nervous system (CNS) metastases from non-small-cell lung cancer (NSCLC), we gathered the genetic profiles of brain metastases (BM) and leptomeningeal metastases (LM). Our objective was to identify genetic factors contributing to poorer overall survival (OS) in NSCLC patients with LM. This study included 25 consecutive patients with BM and 52 patients with LM from Guangdong Sanjiu Brain Hospital. All participants underwent 168-target panel sequencing. Among the 25 patients with BM, TP53 was the most frequently mutated gene (44%), followed by driver genes such as EGFR and BRAF (40% and 20%, respectively). In patients with BM, EGFR_amp and CDK4 were also frequently mutated, with rates of 20% and 16%, respectively. The genetic landscape of patients with LM differed, with the top mutated genes being EGFR, TP53, EGFR_amp, CDKN2A, CCNE1, CDK4, PMS2, and PIK3CA, with mutation rates of 77%, 69%, 31%, 29%, 13%, 13%, 13%, and 12%, respectively. In our study, patients with LM exhibited significantly worse OS compared to those with BM (p = 0.029). The mutation rates of TP53, EGFR_amp, and CDKN2A varied between patients with LM and those with BM, at 69.23% vs. 44%, 30.77% vs. 20%, and 28.85% vs. 12%, respectively. Further exploration revealed that patients with BM with TP53 mutations had a shorter OS than patients without TP53 mutations (p = 0.014). Similarly, patients with LM and TP53 mutations presented with worse OS than those without TP53 mutations (p = 0.0067). LM patients with CDKN2A deletions had worse OS than those without CDKN2A deletions (p = 0.037). Additionally, patients with EGFR_amp had a shorter OS than those without EGFR_amp (p = 0.044). Patients with LM exhibited significantly worse OS than those with BM. Gene signatures, such as TP53, EGFR_amp, and CDKN2A, may account for shorter outcomes in patients with LM.

Abstract PO4-13-10: The anti-metastatic role of BMP4 through cholesterol biosynthesis inhibition and consequent interaction with statin benefit in breast cancer

Abstract We have previously identified a role for bone morphogenic protein 4 (BMP4) in reducing distant relapse risk after early breast cancer (BrCa) (1). We therefore set out to identify mechanisms underlying the protective effect of BMP4, looking to translate this finding for patient benefit. A highly metastatic variant of the triple negative MDA-MB-231 human BrCa line (231-HM-turboGFP) was transduced with BMP4, leading to sustained BMP4 secretion. These modified tumours were established in NSG mice, resected at a given size and turboGFP-positive cancer cells were recovered from primary tumours for RNA sequencing analysis. Gene set enrichment analysis (GSEA) was completed to identify signalling pathways that were significantly modulated by BMP4. The four most significantly downregulated gene sets were associated with cholesterol synthesis, with the overwhelming majority of genes in this pathway being downregulated. BMP4 downregulation of 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1, involved in cholesterol biosynthesis) was confirmed at the protein level by western blotting on whole tumour lysates. Forced expression of BMP4 also led to a significant reduction in the levels of free and total cholesterol. In a confirmatory analysis of the METABRIC human BrCa dataset, the expression of cholesterol biosynthesis-related genes inversely correlated with the expression of BMP4. Further, for the majority of these genes, expression was elevated in high-grade breast tumours, and predicted worse overall survival of patients. Finally, we tested the effect of a lipophilic statin, lovastatin, on the growth and metastasis of 231-HM-turboGFP tumours. Treatment did not affect the growth of primary tumours but significantly less metastases were observed in the lungs of treated mice, at least partially replicating the anti-metastatic effect of BMP4. Having identified inhibition of cholesterol biosynthesis as a potential mechanism of protective BMP4 action we then asked if BMP4 status interacted with any protective effect of co-administered statins. We therefore returned to the cohort initially employed to demonstrate BMP4 benefit (1) and looked at the interaction between BMP4 protein levels and statin usage with regards to recurrence. BMP4 protein and statin usage data were available on a cohort of 417 patients with early BrCa. Statin use compared to none led to a reduced risk of distant relapse (8 v 22%, 0.0029) at 15 years. BMP4 led to borderline reduction in distant relapse (16 v 24%, p=0.052). In BMP4 negative tumours, statin protected against any relapse (p=0.0025) whereas in BMP4 positive disease no significant risk reduction was not significant (p=0.074). Absence of BMP4 expression may be a biomarker of both higher relapse risk and statin benefit in early BrCa. 1. Eckhardt et al, Cancer Res. 2020;80(6):1304-1315 Citation Format: Lap Hing Chi, Andrew Redfern, Allan Burrows, Suraya Roslan, Leone Oh, Lisa Spalding, Robin Anderson. The anti-metastatic role of BMP4 through cholesterol biosynthesis inhibition and consequent interaction with statin benefit in breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-13-10.

Serum inflammatory markers as prognostic marker for nasopharyngeal carcinoma with liver metastasis: a multi-center retrospective study.

This retrospective study investigated the prognostic value of serum inflammatory markers in nasopharyngeal carcinoma (NPC) patients, focusing on their association with overall survival (OS) and liver metastasis-free survival (LMFS). The study included 314 NPC patients treated between 2010 and 2020. Clinical characteristics, treatment methods, and serum inflammatory markers were assessed. Patients were categorized into two groups of with and without liver metastasis. Univariate and multivariate Cox regression and Kaplan-Meier survival analyses were performed to investigate the prognostic value of serum inflammatory markers in NPC patients with and without liver metastasis. In the whole cohort, univariate Cox regression analysis singled out tumor necrosis factor-α (TNF-α) (HR = 1.57, 95% CI 1.44-4.90, p = 0.004) and neutrophil-to-lymphocyte ratio (NLR) (HR = 2.13, 95% CI 1.33-3.99, p = 0.009), which were significantly associated with poorer OS. In patients with liver metastasis, TNF-α and NLR could not independently predict OS. However, high TNF-α levels were independently associated with worse OS in patients without liver metastasis (HR (95% CI) = 2.75 (1.67-8.68), p < 0.001). High NLR levels could independently predict poor OS in both groups with (HR (95% CI) = 1.94 (1.77-6.38), p = 0.010) and without liver metastasis (HR (95% CI) = 1.58 (1.19-7.54), p = 0.009). Ultimately, TNF-α and NLR could not significantly predict LMFS. This study highlights the prognostic significance of TNF-α and NLR in NPC patients, especially in those with liver metastasis. These inflammatory markers could serve as valuable indicators for assessing the prognosis of NPC patients. Further research is warranted to validate their clinical utility and explore potential therapeutic implications.

Prognostic significance of connective tissue growth factor expression in stromal cells in patients with diffuse‑type gastric cancer.

Connective tissue growth factor (CTGF) is a target gene of the Hippo signaling pathway. Its differential role in the histological types of gastric cancer (GC) remains unknown; therefore, the present study aimed to confirm the clinical significance of CTGF expression in cancer and stromal cells in patients with GC depending on the histological type. The present study enrolled 589 patients with GC. Immunohistochemistry was used to analyze CTGF expression in cancer and stromal cells. CTGF mRNA expression data and the corresponding clinical information of GC samples were collected from The Cancer Genome Atlas (TCGA) database. Subsequently, the associations between CTGF expression and several clinicopathological factors were investigated. In the present study, CTGF expression was mainly observed in the cytoplasm of cancer and stromal cells. CTGF expression in stromal cells was significantly associated with CTGF expression in cancer cells (P<0.001). CTGF positivity in stromal cells was also significantly associated with intestinal type, non-scirrhous type, tumor depth (T1-2), lymph node metastasis (negative), lymphatic invasion (negative) and tumor size (<5 cm). Low CTGF expression in stromal cells was independently associated with worse overall survival (OS). Furthermore, the OS of patients with low CTGF expression in stromal cells, especially in patients with diffuse-type GC, was significantly worse than patients with high CTGF expression (P=0.022). This trend was similar to that revealed by TCGA data analysis. In conclusion, low CTGF expression was associated with a significantly worse OS in patients with diffuse-type GC. These data indicated that CTGF, and its control by the Hippo pathway, may be considered potential treatment targets in diffuse-type GC.

SOX11/PRDX2 axis modulates redox homeostasis and chemoresistance in aggressive mantle cell lymphoma

Mantle cell lymphoma (MCL) is an incurable B-cell neoplasm characterized by an aggressive behavior, short responses to conventional therapies and SOX11 overexpression, which is associated with aggressive disease features and inferior clinical outcome of patients. Oxidative stress is known to induce tumorigenesis and tumor progression, whereas high expression levels of antioxidant genes have been associated with chemoresistance in different cancers. However, the role of oxidative stress in MCL pathogenesis and the involvement of SOX11 regulating redox homeostasis in MCL cells are largely unknown. Here, by integrating gene set enrichment analysis of two independent series of MCL, we observed that SOX11+ MCL had higher reactive oxygen species (ROS) levels compared to SOX11− MCL primary tumors and increased expression of Peredoxine2 (PRDX2), which upregulation significantly correlated with SOX11 overexpression, higher ROS production and worse overall survival of patients. SOX11 knockout (SOX11KO) significantly reduced PRDX2 expression, and SOX11KO and PRDX2 knockdown (PRDX2KD) had increased ROS levels and ROS-mediated tumor cell death upon treatment with drugs, compared to control MCL cell lines. Our results suggest an aberrant redox homeostasis associated with chemoresistance in aggressive MCL through SOX11-mediated PRDX2 upregulation, highlighting PRDX2 as promising target for new therapeutic strategies to overcome chemoresistance in aggressive MCLs.

Abstract 3923: Targeting immunosuppressive TREM2+tumor associated macrophages in prostate cancer

Abstract With over 250,000 new cases annually, prostate cancer (PCa) is amongst the most diagnosed cancers in the United States. Despite a near-perfect 5-year survival rate in patients with localized disease with androgen deprivation therapy (ADT), about 10-20% of patients on ADT eventually develop castration-resistant prostate cancer (CRPC). Immunotherapies are typically ineffective in treating these treatment-resistant patients due to the abundance of immunosuppressive tumor-associated macrophages (TAMs) and lack of infiltrating lymphocytes. We propose to target these immunosuppressive macrophages through the triggering receptor expressed on myeloid cells 2 (TREM2), which has been identified as a major mediator of suppressive macrophage function but has not been studied in the context of PCa and CRPC. For this study, we analyzed publicly available RNA-seq datasets to query for TREM2 expression amongst patients with a range of prostate cancer disease states and cell types, measured tumor growth kinetics in two subcutaneous models of prostate cancer, and compared tumor immune infiltrates by flow cytometry. Our analysis of the TCGA prostate adenocarcinoma (PRAD) and the Stand Up to Cancer/Prostate Cancer Foundation (SU2C/PCF) datasets implicate TREM2 expression with prostate cancer progression, by Gleason score and progression-free status, and with worse overall survival of patients with metastatic CRPC (mCRPC). Manual curation and analysis of 10 single-cell RNA-seq datasets with a total of 84 patients, encompassing primary PCa, CRPC, and mCRPC indicate that TREM2 is highly and specifically expressed on TAMs in prostate cancer, with macrophages from patient-matched tumor samples expressing higher TREM2 compared to normal adjacent tissue. B6CaP tumors, with a luminal cytokeratin profile, high AR expression, and high Myc expression, show slower tumor growth in Trem2−/− mice compared to tumors in Trem2wt mice. On the other hand, RM1 tumors show no difference in growth kinetics on Trem2−/− mice. A major difference between the B6CaP and RM1 tumor microenvironments is the level of macrophage infiltration, where only 2-5% of immune cells in RM1 tumors are macrophages, compared to the 40-50% in B6CaP tumors. RM1 cells co-implanted with Trem2−/− macrophages show slower tumor growth, compared to tumor cells co-implanted with Trem2wt macrophages, confirming the role of Trem2-expressing macrophages in mediating tumor growth. Consistent with previous reports of suppressive Trem2 signaling, we also observed higher levels of inflammatory cytokine production in ex vivo stimulated Trem2−/− TAMs. By targeting TREM2 in prostate cancer, we find that TAMs are less suppressive, more inflammatory, and permit cytotoxic lymphocyte infiltration to enhance anti-tumor responses by synergizing with chemo and immune checkpoint therapy. Citation Format: Alex J. Lee, Kenneth Adusei, Monali Praharaj, Fan Shen, Xiaoxu Wang, Kaavya Bhatia, Thomas Nirschl, Jelani C. Zarif. Targeting immunosuppressive TREM2+tumor associated macrophages in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3923.

Abstract 2547: KRAS Q61 mutations in patients with gastrointestinal malignancies and association with real-world clinical outcomes

Abstract Introduction: Gene-wide KRAS mutation has been associated with worse outcomes in multiple malignancies with newer data suggesting differential impact based on specific allele. Mutation at codon Q61 is relatively infrequent with clinical significance not well understood. Here we aim to investigate the clinical significance of KRASQ61 mutation in gastrointestinal (GI) malignancies. Methods: The Foundry software platform was used to retrospectively query electronic health records to identify patients diagnosed with colorectal (CRC), pancreatic (PDAC), appendiceal (AA), cholangiocarcinoma (CC) and gastroesophageal carcinoma who underwent clinical testing for KRAS mutations in our institution between 2002-2023; clinical, molecular, and overall survival (OS) data were collected. Results: KRAS mutation was tested in 9,088 patients with CRC, PDAC, CC, AA, and gastroesophageal carcinoma. Incidence of KRAS mutation was 47% (n= 3,181) for patient with CRC, 82% for PDAC (n= 579), 16% for CC (n= 76), 51% for AA (n= 236), and 7% for gastroesophageal carcinoma (n= 43). KRASQ61 mutation was in 5% (n=218) of patients with KRAS mutation (n= 4,115). Overall frequency of KRASQ61 was 2% (n= 156) for CRC, 5% (n= 36) for PDAC, 3% (n= 12) for CC, 2% (n= 10) for AA and 1% (n= 4) for gastroesophageal carcinoma. KRASQ61 fraction of KRAS mutations was 5% for CRC, 6% for PDAC, 16% for CC, 4% for AA, 9% for gastroesophageal carcinoma. KRASQ61H was the most frequent KRASQ61 mutation among all tumor types, 57%, 61%, 60%, 50% out of KRASQ61 for CRC, PDAC, AA, and gastroesophageal carcinoma respectively; followed by KRASQ61L (20%) for CRC, but KRASQ61R for PDAC (25%), AA (20%), and gastroesophageal (25%); Patients with CC showed exclusively KRASQ61H mutations. Compared to patients with KRAS wildtype, patients with KRASQ61 mutations had worse OS in PDAC (median OS=20 vs 37 months, HR=1.9, 95%CI=1.2-3, p=0.006), while (55 vs 63 months, HR=1.2, 95%CI=0.98-1.5, p=0.076) for CRC, (29 vs 25 months, HR=1.3, 95%CI=0.64-2.6, p=0.47) for CC, and (33 vs 52 months, HR=1.1, 95%CI=0.5-2.6, p=0.75) for AA. Compared to other KRAS mutations, KRASQ61 median OS was (55 vs 53 months, HR=1, 95%CI=0.81-1.3, p=0.96) for patients with CRC, (20 vs 26 months, HR=1.4, 95%CI=0.91-2.1, p=0.1) for PDAC, (25 vs 28 months, HR=1.1, 95%CI=0.54-2.5, p=0.72) for CC, (33 vs 78 months, HR=1.6, 95%CI=0.72-3.7, p=0.24) for AA. Conclusion: KRASQ61 mutations frequency varied from 1% to 5% across different GI malignancies, with highest frequency in PDAC and CC. KRASQ61 mutations had worse OS in patients with PDAC which may suggest different co-mutations rather than specific KRASQ61 activity difference. Further allele specific analysis of KRASQ61 and co-mutations landscape is underway. Citation Format: Mahmoud Yousef, Abdelrahman Yousef, Saikat Chowdhury, Mohammad Mahdi Fanaeian, Mark Knafl, Paul M. Roy, Ashwathy Pillai, Mohammad Zeineddine, Fadl Zeineddine, Jennifer Peterson, Brandon G. Smaglo, Robert A. Wolff, Shubham Pant, Michael Sangmin Lee, Jason A. Willis, Michael James Overman, Ethan Bernard Ludmir, Mark W. Hurd, John Paul Shen, Dan Zhao. KRAS Q61 mutations in patients with gastrointestinal malignancies and association with real-world clinical outcomes [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 2547.

Abstract 3914: IGSF8 is a novel innate immune checkpoint and cancer immunotherapy target

Abstract Background: Loss of MHC-I antigen presentation is often associated with T-cell excluded tumors, and represents a common mechanism of both primary and acquired resistance to immune checkpoint blockade (ICB) treatment. MHC-I normally acts as a marker of “self” and cells that lack MHC-I are recognized and killed by innate immunity. In this study, we investigated the mechanism of innate immune evasion in tumors with MHC-I antigen presentation defects. Methods: Integrating functional genomics, big data, and artificial intelligence, we discovered that IGSF8 expressed on cancer cells is an evolutionarily conserved innate immune checkpoint. IGSF8 is normally expressed in neuronal tissues and is not essential in vitro or in vivo. However, knockout of IGSF8 in B16-F10 melanoma cell line decreased tumor growth in vivo. For clinical relevance of IGSF8 in tumor immunity, we analyzed genomics, transcriptomics, and clinical data from The Cancer Genome Atlas (TCGA). We developed an antibody (GV20-0251) against IGSF8 and tested its function to induce immune cell killing of cancer cells in vitro and inhibit tumor growth in vivo. Results: IGSF8 has receptors on both natural killer (NK) cells and dendritic cells (DC) to strongly suppress NK cytotoxicity and antigen presentation. In the TCGA tumor profiles, IGSF8 has highest mRNA expression in melanoma and is significantly overexpressed in many cancer types. IGSF8 also shows frequent copy number amplifications. In addition, IGSF8 expression is associated with low antigen presentation, low immune infiltration, and worse overall survival in patients with low MHC class I expression. Immunohistochemistry staining of various cancers showed that IGSF8 expression was primarily observed in malignant cells with low MHC-I. We developed a cross-species reactive antibody against IGSF8 (GV20-0251) which blocks IGSF8 interaction with NK and DC. Flow cytometry of the tumor infiltrating CD45+ cells revealed that IGSF8 inhibition significantly increased NK and dendritic cell infiltration. GV20-0251 enhances NK killing of cancer cells in vitro and increases antigen presentation, NK-mediated cytotoxicity, and T cell signaling in vivo. In multiple syngeneic tumor models (B16-F10, CT26, LLC, 4T1 and EMT6), anti-IGSF8 shows single-agent efficacy and is synergistic with anti-PD1 in controlling tumor growth. Conclusions: IGSF8 is a novel innate immune checkpoint and cancer immunotherapy target. A phase 1 study is ongoing to explore the IGSF8 inhibitor GV20-0251 in patients with advanced or metastatic solid tumors (NCT05669430). Citation Format: X. Shirley Liu, Yulong Li, Xiangyang Wu, Hailing Liu, Huizhu Liu, Caibin Sheng, Qingyang Ding, Yixuan Tang, Chao Liu, Bin Xie, Xi Xiao, Quan Yu, Rongbin Zheng, Xihao Hu, Tengfei Xiao. IGSF8 is a novel innate immune checkpoint and cancer immunotherapy target [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 3914.

Abstract 2570: Gastric cancer with high neuron infiltration was associated with enhanced epithelial-to-mesenchymal transition, angiogenesis and poor clinical outcomes

Abstract Introduction: Neurons within the tumor microenvironment of gastric cancer (GC), as identified through immunohistochemistry, have been reported to be associated with worse overall survival (OS) of GC patients. However, histology-based analyses have limitations in quantifying nerve cells and investigating the underlying biology. Thus, we aim to study the clinical significance of intratumoral nerve cells in GC using computational deconvolution of transcriptomes from bulk tumors. Methods: Total of 807 GC patients from two independent cohorts (TCGA; n = 375, GSE84437; n = 432) were included, encompassing both clinical and transcriptomic profiles. The neuron infiltration fraction was determined using the xCell algorithm. Results: GC with high neuron infiltration was associated with high expressions of neurotransmitter receptors; beta-adrenaline, dopamine, muscarinic acetylcholine, and neurokinin receptors in TCGA cohort (all p &amp;lt; 0.02). It was associated with reduced mutation rate and increased intratumoral heterogeneity (all p ≦ 0.002), as well as less immune response; interferon-alpha and interferon-gamma, and with low infiltration of immune cells; CD4 memory, T-helper 1, M1 and M2 macrophages, and NK cells (all p ≦ 0.02). Further, neuron highly infiltrated GC enriched Epithelial-to-Mesenchymal Transition and Angiogenesis gene sets and had higher lymphatic and microvessel endothelial cells and pericyte infiltrations (all p ≦ 0.001). Conversely, GC with high neuron infiltration showed an inverse relationship with cell proliferation-related gene sets; E2F Targets, G2M Checkpoint, and MYC Targets v1 and v2, and had lower Ki67 gene expression (FDR &amp;lt; 0.25 and p &amp;lt; 0.001, respectively). High neuron infiltration in GC was associated with worse patient OS in TCGA cohort, which was validated in GSE84437 cohort (both p &amp;lt; 0.05). It was an independent prognostic factor of OS in both univariate and multivariate Cox-regression analysis in the TCGA cohort (hazard ratio [HR]: 1.46; 95% confidence interval [CI]: 1.01 to 2.12; p = 0.045 and [HR]:1.54; 95% CI: 1.05 to 2.26; p = 0.026). Conclusion: Our research indicates that high infiltration of neurons in GC correlates with high expressions of neurotransmitter receptors, high intratumoral heterogeneity, less immune response and immune cell infiltrations, and less cell proliferation. It enriched EMT and angiogenesis which may explain its association with worse patient survival. Citation Format: Kohei Chida, Masanori Oshi, Arya Mariam Roy, Jun Arima, Pia Sharma, Gabriella Kim Mann, Itaru Endo, Kenichi Hakamada, Kazuaki Takabe. Gastric cancer with high neuron infiltration was associated with enhanced epithelial-to-mesenchymal transition, angiogenesis and poor clinical outcomes [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 2570.

Association of Socioeconomic Status With Worse Overall Survival in Patients With Bone and Joint Cancer.

The effect of socioeconomic status (SES) on the outcomes of patients with metastatic cancer to bone has not been adequately studied. We analyzed the association between the Yost Index, a composite geocoded SES score, and overall survival among patients who underwent nonprimary surgical resection for bone metastases. This population-based study used data from the National Cancer Institute's Surveillance, Epidemiology, and End Results database (2010 to 2018). We categorized bone and joint sites using International Classification of Disease-O-3 recodes. The Yost Index was geocoded using a factor analysis and categorized into quintiles using census tract-level American Community Service 5-year estimates and seven measures: median household income, median house value, median rent, percent below 150% of the poverty line, education index, percent working class, and percent unemployed. Multivariate Cox regression models were used to calculate adjusted hazard ratios of overall survival and 95% confidence intervals. A total of 138,158 patients were included. Patients with the lowest SES had 34% higher risk of mortality compared with those with the highest SES (adjusted hazard ratio of 1.34, 95% confidence interval: 1.32 to 1.37, P < 0.001). Among patients who underwent nonprimary surgery of the distant bone tumor (n = 11,984), the age-adjusted mortality rate was 31.3% higher in the lowest SES patients compared with the highest SES patients (9.9 versus 6.8 per 100,000, P < 0.001). Patients in the lowest SES group showed more racial heterogeneity (63.0% White, 33.5% Black, 3.1% AAPI) compared with the highest SES group (83.9% White, 4.0% Black, 11.8% AAPI, P < 0.001). Higher SES patients are more likely to be married (77.5% versus 59.0%, P < 0.0001) and to live in metropolitan areas (99.6% versus 73.6%, P < 0.0001) compared with lower SES patients. Our results may have implications for developing interventions to improve access and quality of care for patients from lower SES backgrounds, ultimately reducing disparities in orthopaedic surgery.

Frequency and oncologic outcomes of KRAS mutations in circulating tumor DNA of patients with pancreatic ductal adenocarcinoma.

636 Background: KRAS genetic alterations have been reported in more than 90% of pancreatic ductal adenocarcinoma (PDAC). The association of KRAS mutation subtypes detected in circulating tumor DNA (ct-DNA) with survival remains unclear. We investigated the rate of liquid biopsy detected KRAS mutation subtypes, and their association with overall survival (OS) in patients with PDAC. Methods: The Foundry software platform was used to retrospectively query a single-institution Electronic Health Records to identify patients with PDAC who underwent ct-DNA liquid biopsy from 2018 to 2023 and extract their oncologic outcomes. Results: Liquid biopsies were performed for 313 patients with PDAC; 58% (n=181) were diagnosed with stage IV disease. The median follow-up was 25 months, with median OS 24 months (95%CI=21-29). Overall, 52% (n=162) tested positive for KRAS mutations. Among patients with metastatic disease at diagnosis (n=181), 66.7% (n= 120) tested positive for KRAS mutations. In contrast, only 31.8% (n= 42) of patients with stage I to III disease at diagnosis (n=132) tested positive. Among patients with metastatic disease, those with KRAS positive disease had significantly shorter OS (median OS 13 vs 27 months, HR=2.7, 95%CI=1.7-4.3, P&lt;0.0001). In patients with non-metastatic disease, the median OS was 28 vs 43 months, respectively (HR=1.7, 95%CI=0.97-2.8, P=0.064). The most frequent KRAS mutation was G12D (n=66, 40.7% of KRAS mutations) followed by G12V (n=58, 35.8%), G12R (n=15, 9.3%), and Q61H (n=10, 6.2%). Among KRAS mutations allelic subtypes, KRAS G12D and Q61 mutations had significantly worse OS with median OS 13 and 10 months respectively (P &lt;0.001). The most frequently co-occurring mutations detected in KRAS positive patients were TP53 (n=126, 77.8%), CDKN2A (n=34, 21%), SMAD4 (n=33, 20.4%), and ARID1A (n=12, 7.4%). Examining the prognostic significance of co-occurring mutations among patients with metastatic disease, only detection of co-occurring CDKN2A mutation was associated with worse OS as compared to patients with KRAS mutations without co-occurring CDKN2A mutations (median OS 8 vs 14 months, HR=2, 95%CI=1.1-3.5, P value=0.015). Conclusions: Detection of KRAS mutation in liquid biopsies of patients with metastatic PDAC is associated with worse OS. KRAS G12D/Q61 alterations detection is associated with worse OS compared to other KRAS mutation subtypes. Ct-DNA detection of co-occurring CDKN2A mutation is associated with worse OS in patients with KRAS positive metastatic disease.

Abstract C059: Hub gene analysis identifies CAD as a potential mediator for drug resistance in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) has a complex disease pathobiology and poor treatment options, emphasizing the need for novel therapeutic targets. Hub genes have high connectivity (i.e., exceptionally many interaction partners), for example, certain proteases with numerous interaction partners. Thereby, hub genes are often central biological regulators and dysregulated proteolysis is indeed a key trait of malignant tissues. Here, we aimed to identify novel protease-related hub genes with potential involvement in pancreatic cancer. We applied an integrative computational approach to compartment-specific multiOMIC profiles of laser-capture micro-dissected human PDAC tissues (n = 32) and queried associations of identified candidate genes with clinical outcomes in early (n = 186) and advanced PDAC patients (n = 253). This identified 20 protease-related genes with ≥ 10 physically verified interaction partners in pancreatic cancer. Among these, the pyrimidine biosynthesis regulator gene CAD emerged as a potentially druggable target in pancreatic cancer. CAD expression was nearly restricted to the malignant PDAC epithelium. Furthermore, higher CAD expression was associated with significantly worse overall survival in patients with advanced but not resectable disease, suggesting a role in treatment response rather than disease progression. Moreover, patients with higher CAD expression specifically demonstrated poor response to mFFX but not Gemcitabine-nab-Paclitaxel treatment, which is in line with previous reports on CAD expression being protective against 5-Fluouracil, a component of FFX. Moving forward, we will interrogate the role of CAD in PDAC tissue biology and scrutinize its involvement in FFX resistance, using patient-derived organoids. Citation Format: Foram Vyas, Barbara Grünwald, Kazeera Aliar, Gun Ho Jang, Grainne O'Kane, Thomas Kislinger, Steven Gallinger, Benjamin Haibe-Kains, Rama Khokha. Hub gene analysis identifies CAD as a potential mediator for drug resistance in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C059.

Effect of subsequent bladder cancer on survival in upper tract urothelial carcinoma patients post-radical nephroureterectomy: a systematic review and meta-analysis

BackgroundRadical nephroureterectomy (RNU) is the primary treatment strategy for upper tract urothelial carcinoma (UTUC). However, the intravesical recurrence occurs in 20–50% of all patients. The specific effect of subsequent bladder cancer (SBCa) on survival remains unclear. Therefore, we investigated the effect of SBCa following RNU in patients with UTUC.MethodsPubMed, EMBASE, and Cochrane Library were exhaustively searched for studies comparing oncological outcomes between SBCa and without SBCa. Standard cumulative analyses using hazard ratios (HR) with 95% confidence intervals (CI) were performed using Review Manager (version 5.3).ResultsFive studies involving 2057 patients were selected according to the predefined eligibility criteria. Meta-analysis of cancer-specific survival (CSS) and overall survival (OS) revealed no significant differences between the SBCa and non-SBCa groups. However, subgroup analysis of pT0-3N0M0 patients suggested that people with SBCa had worse CSS (HR = 5.13, 95%CI 2.39–10.98, p < 0.0001) and OS (HR = 4.00, 95%CI 2.19–7.31, p < 0.00001).ConclusionsSBCa appears to be associated with worse OS in patients with early stage UTUC. However, caution must be taken before recommendations are made because this interpretation is based on very few clinical studies and a small sample size. Research sharing more detailed surgical site descriptions, as well as enhanced outcome data collection and improved reporting, is required to further investigate these nuances.

Downregulated CDH3 is correlated with a better prognosis for LUAD and decreases proliferation and migration of lung cancer cells.

CDH3 is a glycoprotein with a single-span transmembrane domain that mediates cell-to-cell adhesion. Abnormal expression of CDH3 is associated with a poor prognosis in patients with breast, thyroid, colorectal carcinomas and glioblastoma. Soluble CDH3 in pleural effusions can be used as a marker for real-time monitoring of resistance to first- and second-generation EGFR-TKIs. The CDH3 mechanism underlying lung adenocarcinomas (LUADs) has not been established. This study analyzed the correlation between CDH3 expression and lung cancer prognosis and the effect of down-regulation CDH3 expression on the proliferation and migration of lung cancer cells. CDH3 expression was studied using the Oncomine, TIMER, PanglaoDB, and GEPIA databases. The effect of CDH3 on clinical prognosis was assessed with GEPIA, the PrognoScan database, and Kaplan-Meier plotter. The relationship between CDH3 to immune infiltrating cells was explored using TIMER and TISIDB. The function of CDH3 in lung cancer cell lines was determined by CCK-8 and wound healing assays in vitro. Furthermore, RNA sequencing was used to identify key signaling pathways and differentially-expressed genes. LUAD tissues had higher CDH3 expression compared with normal tissues and were associated with worse overall survival in patients with LUAD. CDH3 expression had positive associations with infiltration of CD4 + T cells, Tregs and exhausted T cells, but negative associations with infiltration of B cells in patients with LUAD. CCK-8 and wound healing assays revealed that downregulation of CDH3 inhibited the proliferation and migration of cells. KEGG analysis revealed that the TGF-beta signaling pathways were demonstrated to be enriched pathways for genes negatively regulated by knockdown of CDH3. CDH3 expression affects proliferation and migration of lung cancer cells and might serve as a potential prognostic marker in LUAD patients.

Epigenetic Modifiers MMSET and EZH2 Physically Interact and Cooperate to Support Multiple Myeloma Pathophysiology

Multiple myeloma (MM) is a malignant B cell dyscrasia characterized by the accumulation of clonal plasma cells (PC) within the bone marrow (1). Genome sequencing studies have revealed great heterogeneity and genomic instability, a complex mutational landscape and a branching pattern of clonal evolution (2-4). Epigenetic factors are also involved in MM initiation, progression, and occurrence of chemoresistance (5). Among them, EZH2 and MMSET are associated with poor prognosis values and contribute to MM disease. EZH2 is the main catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) and deposits H3K27me3 on chromatin (6), whereas MMSET, coded by the gene NSD2, which is the target oncogene of t(4;14) primary translocation, is a histone methyltransferase that methylates H3K36me2 (7). Using proteomics analysis of EZH2-immune precipitates, we identified a constitutive interaction between EZH2 and MMSET independently of t(4;14) translocation and mutational status of EZH2 in MM cells. Furthermore, MAK-683, an allosteric inhibitor of EZH2, disrupted this interaction, but not EPZ-6438, a catalytic inhibitor of EZH2, suggesting that MMSET-EZH2 interaction may be mediated by other PRC2 factors, but is independent of the PRC2 activity. Analysis of EZH2 expression levels and t(4;14) translocation status in 3 independent cohorts of MM patients (CoMMPass (N=674), UAMS-TT2 (N=345), Mtp-Daratumumab (N=51)) identified a worse overall survival of patients with high EZH2 expression combined with t(4;14) chromosomal translocation than patients with only one of these genetic events. We identified 355 differentially expressed genes in this “ EZH2 High t(4;14) +” subgroup compared to other patients. GSEA analysis of up-regulated genes in this subgroup identified a significant enrichment for genes involved in cell cycle, KRAS signaling, Cell-Cell signaling, Hypoxia and Epithelial-Mesenchymal transition. These results indicate that EZH2-MMSET interaction is of clinical interest in t(4;14) MM patients. To better understand the molecular relationship between EZH2 and MMSET, we generated MMSET-depleted clones by CRISPR-Cas9. MMSET depletion did not significantly alter cell proliferation and survival, but reduced the clonogenic capacity of MM cells compared to non-depleted cells. Moreover, after IL-6 or serum starvation, IL-6 and IGF-1 sensitivity was significantly affected in MMSET-depleted clones compared to the parental cell line, indicating that MMSET overexpression confers a cell growth advantage to MM cells under stress conditions and an independence of growth factors produced by bone marrow microenvironment Additionally, MMSET depletion induced changes in PRC2 nuclear localization in MM cells, a decrease of H3K36me3 and a concomitant increase in H3K27me3 levels, which altered the transcriptional program of cells showing, among others, a specific enrichment in genes up-regulated in t(4;14) MM subgroup of patients. Finally, we demonstrated that disrupting EZH2-MMSET interaction with MAK-683 may be of therapeutic interest, since MAK-683 combination with conventional drugs used in MM treatment, including melphalan and Panobinostat or BRD4 inhibitors, synergized to kill MM cells. Taken together, our data identified an “ EZH2 High t(4;14) +” signature in MM patients with a poor outcome who may benefit from combination therapy of MAK-683 with melphalan or epidrugs.

Class III Obesity Is Associated with Worse Overall Survival in Previously Untreated Younger Patients with Acute Myeloid Leukemia Enrolled on SWOG 1203

Mohamed Sorror and Mary-Elizabeth Percival contributed equally to this project. Introduction: There has been inconsistent evidence supporting the association between obesity and outcomes in patients with newly diagnosed acute myeloid leukemia (AML). Prior studies have studied obesity as defined by body mass index (BMI) ≥ 30. However, this general definition of obesity can be further subdivided into class I obesity (BMI 30 to &amp;lt;35), class II obesity (BMI 35 to &amp;lt;40) and class 3 obesity (BMI ≥40). Given the high prevalence of obesity in the United States (41.9%; with class III obesity 9.2%), distinctions in degree of obesity may be associated with outcomes for patients with AML (Stierman et al, 2021). We were interested in studying outcomes in patients with AML stratified by class I, class II and class III obesity after induction chemotherapy and allogeneic hematopoietic cell transplant (HCT). Identification of at-risk patient populations could aid in design of future interventions. Methods: We retrospectively reviewed a group of 738 previously untreated subjects with AML randomized to daunorubicin and cytarabine (DA), idarubicin and cytarabine (IA), and IA with vorinostat as part of clinical trial SWOG 1203, conducted by the SWOG Cancer Research Network between 2012 and 2015. Subjects with adverse risk cytogenetics were recommended to receive HCT in their first complete remission (CR1); subjects with intermediate risk cytogenetics were selected for HCT in CR1 per local institutional standards. Nine patients who did not receive protocol therapy or had missing BMI were excluded (final cohort 729 patients). Early death was defined as death within 56 days of induction chemotherapy. Multivariable time-dependent Cox regression model and Fisher's exact test were used for analysis of overall survival (OS). HCT in first complete remission (CR1) was included as a time-dependent covariate. Results: The median age was 49 years (range, 18 to 60), 51% were male, 90% had de novo disease, and 88% had a performance status (PS) of 0-1 (Table 1). Among these patients, 1% (n=9) were underweight, 25% (n=182) were normal weight, 31% (n=225) were overweight, 20% (n=145) had class I obesity, 11% (n= 82) had class II obesity and 12% (n= 86) had class III obesity. There was no difference in the rate of achieving composite CR (CR with or without count recovery) between different weight categories (p=0.17). There was no clear trend in early death rate by weight (underweight: 11%; normal weight: 4%; overweight: 6%;class I obesity: 7%; class II obesity: 4%; class III obesity: 17%), though class III obesity had a significantly higher early death rate as compared to all the other groups combined (p=0.004). In multivariable Cox regression analyses, class III obesity was significantly associated with worse OS when compared to normal weight (hazard ratio (HR) 2.56, 95% confidence interval (CI) 1.68-3.90; p&amp;lt;0.001); though not statistically significant, we identified a trend towards worse OS for patients with class I (HR 1.40, 95% CI 0.95-2.06; p=0.09) and class II obesity (HR 1.48, 95% CI 0.95-2.31; p=0.09) (Figure 1). Other co-variates with a significant association with OS included age (HR 1.03, 95% CI 1.01-1.04; p&amp;lt;0.001), intermediate cytogenetic risk (HR 2.45, 95% CI 1.33-4.51; p=0.004), and adverse cytogenetic risk (HR 5.86, CI 3.10-11.06; p&amp;lt;0.001). HCT during CR1 was not found to be significantly associated with OS (HR 0.88, CI 0.67-1.15; p=0.3). No significant difference was identified in time to HCT based on BMI category. In patients who underwent HCT during CR1, class III obesity (HR 2.32, 95% CI 1.22-4.43; p=0.01) and older age (HR 1.02, 95% CI 1.00-1.04; p=0.01) were significantly associated with worse OS; in contrast no significant association was identified between OS and class I obesity (HR 1.30, 95% CI 0.77-2.20;p=0.32), while a higher HR and a trend existed for class II obesity (HR 1.76, 95% CI 0.97-3.17; p=0.06). Conclusions: Our retrospective analysis suggests that among newly diagnosed younger patients with AML, those with class III obesity are at increased risk of early death and shorter overall survival. Future directions include assessing lean body mass in addition to BMI in patients with newly diagnosed AML, as sarcopenic obesity is known to portend poor outcomes. Identifying this at-risk patient population may help guide future investigation of early weight management interventions in patients with newly diagnosed AML.

The value of MRI in quantification of parametrial invasion and association with prognosis in locally advanced cervical cancer: the "PLACE" study.

This retrospective observational study aims to evaluate the association between the extent of parametrial invasion (PMI) and disease-free survival (DFS) and cancer-specific survival (CSS) in patients with locally advanced cervical cancer (LACC). This study included patients with LACC showing parametrial invasion at Magnetic Resonance Imaging (MRI). They were treated with neoadjuvant chemo-radiotherapy (CT/RT) before undergoing radical hysterectomy. The staging MRIs were reviewed retrospectively. Measurements of maximum PMI (PMImax) and parametrial length were taken bilaterally. After that, PMIratio was calculated by dividing PMImax by parametrial length. Analysis was conducted on homogeneous subsets of patients, grouped based on their pathological lymph nodal evaluation (N- and N+). Correlations between PMImax and PMIratio with DFS and CSS were evaluated in both the N- and N+ groups, employing univariable Cox regression analysis. Out of 221 patients, 126 (57%) had non-metastatic lymph nodes (N-), while 95 (43%) had metastatic lymph nodes (N+). The median observation period for all these patients was 73 months (95% confidence interval [CI]: 66-77). The 5-year DFS and CSS probability rates were 75% and 85.7%, respectively, for the N- group and 54.3% and 73.6%, respectively, for the N+ group. A higher PMImax (hazard ratio [HR] = 1.09) and PMIratio (HR = 1.04) correlated with worse overall survival in patients in the N- group (p= 0.025 and p= 0.042). These parameters did not show a significant statistical association in the N+ group. The degree of PMI evaluated on MRI affects outcome in N- patients with LACC. The degree of MRI parametrial invasion affects disease-free survival and cancer-specific survival in patients with the International Federation of Gynecology and Obstetrics (FIGO) stage IIB cervical cancer. This MRI finding can be easily incorporated into routine clinical practice. • Visual assessment of parametrial invasion on MRI was not significantly associated with prognosis in locally advanced cervical cancer (LACC). • A greater degree of parametrial invasion is associated with poorer disease-free survival and cancer-specific survival in patients with LACC without metastatic lymph node involvement. • The degree of parametrial invasion at MRI has no correlation with prognosis in LACC with metastatic lymph nodes.

Effects of socioeconomic status and race on survival and treatment in metastatic breast cancer.

Race and socioeconomic factors affect outcomes in breast cancer. We aimed to assess the effect of race and neighborhood socioeconomic status (SES) on overall survival and treatment patterns in patients with metastatic breast cancer (MBC). This is a retrospective cohort study involving patients (N = 1246) with distant breast cancer metastases diagnosed at UPMC Magee Women's Breast Cancer Clinic from 2000-2017. Overall survival and treatment patterns were compared between races (Blacks and whites) and SES groups (defined using Area Deprivation Index). Low SES, but not tumor characteristics, was associated with Black race (P < 0.001) in the study population. Low SES (Median [Interquartile Range, IQR] survival 2.3[2.2-2.5] years vs high SES 2.7[2.5-3.1] years, P = 0.01) and Black race (Median [IQR] survival 1.8[1.3-2.3] years, vs white 2.5[2.3-2.7] years P = 0.008) separately were associated with worse overall survival in patients with MBC. In the Cox Proportional Hazard model with SES, race, age, subtype, number of metastases, visceral metastasis, and year of diagnosis as covariates, low SES (Hazard ratio 1.19[1.04-1.35], P = 0.01), but not Black race (Hazard ratio 1.19[0.96-1.49], P = 0.12), independently predicted overall survival in MBC. Moreover, patients from low SES neighborhoods and Black race received fewer lines of chemotherapy than high SES and whites. In conclusion, low neighborhood SES is associated with worse outcomes in patients with MBC. Poor outcomes in Black patients with MBC, at least in part is driven by socioeconomic factors. Future studies should delineate the interplay between neighborhood SES, race, and their effects on tumor biology in MBC.

ABCB1 Regulates Immune Genes in Breast Cancer.

Resistance to standard chemotherapy is a critical problem for breast cancer patients. The ATP-binding cassette (ABC) superfamily transporters actively pump out drugs and play an important role in chemoresistance. ABCB1 (ABC subfamily B, member 1, also named as multidrug resistance protein 1, MDR1) and suppressive myeloid-derived suppressor cells (MDSCs) potentially involve in chemoresistance of breast cancer. The relationship between ABCB1 and immune genes in breast cancer has not been widely studied. Microarray and RNA sequencing data were obtained from The Cancer Genome Atlas Breast Invasive Carcinoma in Genomic Data Commons Data Portal and Gene Expression Omnibus database. A patient-derived xenograft (PDX) model of HER2+ breast cancer was established to investigate the association between ABCB1 and immune genes in breast cancer. Expression of ABCB1 increased in doxorubicin-selected MCF-7/ADR cells. High expression of ABCB1 mRNA is correlated with lymph-node metastasis and worse overall survival in patients with breast cancer. ABCB1 is positively correlated with IL6, CSF1, CSF3, and PTGS2. In the HER2+ stage IIA breast cancer PDX model, both doxorubicin and paclitaxel suppressed growth of P2 tumors. IL6, CSF1, CSF3, and PTGS2 expression were suppressed by paclitaxel but not doxorubicin. Intrasplenic MDSCs, including CD11b+Ly6G+ and CD11b+Ly6C+ cells, were more abundant than intratumor MDSCs in PDX-carrying nude mice. Clinically, the patient developed cancer recurrence after adjuvant chemotherapy with doxorubicin-based regimen and was well controlled after paclitaxel-trastuzumab combined therapy. ABCB1 was a poor predictor of HER2+ LN- breast cancer. Regulation of immune genes by ABCB1 contributed to cancer recurrence and treatment effect. The PDX model was suitable for investigation the expression of target genes and expansion of immune cells.

Developing sarcopenia during neoadjuvant therapy is associated with worse survival in esophageal adenocarcinoma patients

BackgroundSarcopenia in cancer patients has been associated with mixed postoperative outcomes. The aim of this study was to evaluate whether the development of sarcopenia during the neoadjuvant period is predictive of postoperative mortality in esophageal adenocarcinoma patients. MethodsWe queried a prospective database to retrieve the sarcopenic status of patients with esophageal adenocarcinoma who underwent cross-sectional imaging of the third lumbar vertebra at diagnosis and within 2 months of undergoing an esophagogastrectomy between 2014 and 2022. ResultsOf the 71 patients included in the study, 36 (50.7%) presented with sarcopenia at diagnosis. Of the 35 non-sarcopenic patients, 14 (40%) developed sarcopenia during the neo-adjuvant period. Patients who were not sarcopenic at diagnosis but developed sarcopenia preoperatively had significantly worse overall survival than patients sarcopenic at diagnosis and not sarcopenic preoperatively and patients experiencing no change in sarcopenic status (median 18 vs 47 vs 31 months; P = .02). Diagnostic and preoperative sarcopenic status alone were not significantly associated with overall survival (P = .48 and P = .56, respectively). Although 37 (52.1%) patients died, the cause of death was often not cancer-related (54.1%) and included acute respiratory failure, pneumonia, and cardiac arrest. No significant survival difference was observed when stratified by >10% weight loss (P = .9) or large loss in body mass index (P = .8). ConclusionDeveloping sarcopenia during the neo-adjuvant period may be associated with worse overall survival in patients requiring esophagogastrectomy.