Common Site Of Metastasis Research Articles

CircLIFR-007 reduces liver metastasis via promoting hnRNPA1 nuclear export and YAP phosphorylation in breast cancer

Cancer metastasis is the major cause of death in patients with breast cancer (BC). The liver is a common site of breast cancer metastasis, and the 5-year survival rate of patients with breast cancer liver metastases (BCLMs) is only about 8.5 %. CircRNAs are involved in a variety of cancer-related pathological behaviors, and their unique structure and resistance to RNA degradation enable them to serve as ideal diagnostic biomarkers and therapeutic targets. Therefore, it is important to investigate the role and molecular mechanism of circRNAs in cancer metastasis. CircLIFR-007 was identified as a critical circular RNA in BC metastasis by circRNAs microarray and qRT-PCR experiment. Cell function assays were performed to explore the effect of circLIFR-007 in breast cancer cells. Experiments in vivo validated the function of circLIFR-007. Several molecular assays were performed to investigate the underlying mechanisms. We found that circLIFR-007 acted as a negative controller in breast cancer liver metastasis. CircLIFR-007 upregulates the phosphorylation level of YAP by exporting hnRNPA1 to promote the combination between hnRNPA1 and YAP in the cytoplasm. Overexpression of circLIFR-007 suppressed the expression of liver metastasis-related proteins, SREBF1 and SNAI1, which were regulated by transcription factor YAP. Functionally, circLIFR-007 inhibits the proliferation and metastasis of breast cancer cells both in vivo and in vitro.

The incorporation of acetylated LAP-TGF-β1 proteins into exosomes promotes TNBC cell dissemination in lung micro-metastasis

Triple-negative breast cancer (TNBC) stands as the breast cancer subtype with the highest recurrence and mortality rates, with the lungs being the common site of metastasis. The pulmonary microenvironment plays a pivotal role in the colonization of disseminated tumor cells. Herein, this study highlights the crucial role of exosomal LAP-TGF-β1, the principal form of exosomal TGF-β1, in reshaping the pulmonary vascular niche, thereby facilitating TNBC lung metastasis. Although various strategies have been developed to block TGF-β signaling and have advanced clinically, their significant side effects have limited their therapeutic application. This study demonstrates that in lung metastatic sites, LAP-TGF-β1 within exosomes can remarkably reconfigure the pulmonary vascular niche at lower doses, bolstering the extravasation and colonization of TNBC cells in the lungs. Mechanistically, under the aegis of the acetyltransferase TIP60, a non-canonical KFERQ-like sequence in LAP-TGF-β1 undergoes acetylation at the K304 site, promoting its interaction with HSP90A and subsequent transport into exosomes. Concurrent inhibition of both HSP90A and TIP60 significantly diminishes the exosomal burden of LAP-TGF-β1, presenting a promising therapeutic avenue for TNBC lung metastasis. This study not only offers fresh insights into the molecular underpinnings of TNBC lung metastasis but also lays a foundation for innovative therapeutic strategies.

Mutational Profiling by Next-Generation Sequencing in Patients with Metastatic Non-Small Cell Lung Carcinoma: Our Experience

Introduction According to GLOBOCAN 2020, overall lung cancer is the second most common cancer in both sexes (11.4%) accounting for highest cancer-related mortality (18%).1 Adenocarcinoma subtype of non-small cell lung cancer (NSCLC) is the most common subtype and is divided into further molecular subtypes based on oncogenic driver mutations. Overall survival in these patients is poor with the use of conventional platinum-based double chemotherapy and various recent studies on targeted therapy studies have showed improved survival. Therefore, broad panel-based testing like next-generation sequencing (NGS) is strongly recommended to identify these targetable driver mutations. Aims and Objectives The aim of this study was to evaluate the mutational profile in patients with metastatic NSCLC (mNSCLC) by NGS method. Materials and Methods A hospital-based prospective observational study done on 88 patients under the Department of Medical Oncology, State Cancer Institute during a period of 1 year. All patients above 18 years of age diagnosed as mNSCLC having Eastern Cooperative Oncology Group performance status 0 to 2 and evaluated for mutational profiling by NGS method were included. Five gene panel tests including endothelial growth factor receptor (EGFR), echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase (EML4-ALK), BRAF, mesenchymal epithelial transition (MET), and ROS proto-oncogene 1 (ROS1) were used. Results and Observations Majority of mNSCLC cases were in the age group of 41 to 50 years (n = 30, 34.1%) with average age at presentation being 53.74 years. Male: female ratio was 1.14:1 and most patients were nonsmokers. Adenocarcinoma subtype of mNSCLC cases had the highest mutational burden (n = 55, 62.5%). EGFR (n = 32, 56.14%) was the most common mutation followed by EML4-ALK (n = 19, 33.33%). Most common EGFR mutation was in Exon 19. Other rare mutations were ROS1 (n = 4), BRAF V600E (n = 1), and MET (n = 1). Skeleton was the most common site of metastasis across all driver mutations. Conclusion EGFR and EML4-ALK were the commonest targetable mutations detected in the study. As there is very limited data from North Eastern region of India regarding mutational status in mNSCLC, this study opens up possibilities for further studies targeting multiple mutations to give us more comprehensive understanding of the mutational landscape of mNSCLC in this era of precision medicine.

Establishment of Dual Fluorescent Labeled Human High Bone Metastasis Lung Adenocarcinoma Cell Line and Transcriptomic Characterization Analysis

Bone is a common site for metastasis in lung adenocarcinoma, but the mechanism behind lung adenocarcinoma bone metastasis is still unclear. And currently, there is a lack of easily traceable and stable lung adenocarcinoma bone metastasis cell models, which limits the research on the mechanism of lung adenocarcinoma bone metastasis. The establishment of human lung adenocarcinoma cell line that are highly metastatic to bone, labeled with green fluorescent proteins (GFP) and fireflies luciferase (LUC), along with transcriptomic characterization, would be beneficial for research on lung adenocarcinoma bone metastasis and provide new experimental methods. The human lung adenocarcinoma cell line A549-GFP-LUC was injected into nude mice via the left ventricle to construct a bone metastasis model, and was domesticated in vivo for three consecutive times to obtain the human high bone metastasis lung adenocarcinoma cell line A549-GFP-LUC-BM3; cell counting kit-8 (CCK-8), colony formation assay, scratch wound assays, Transwell assay and Western blot were used to compare the proliferation and invasion abilities of A549-GFP-LUC-BM3 with the parental cells. A549-GFP-LUC-BM3 cells and parental cells were further analyzed by transcriptomic sequencing. Human high-bone metastatic lung adenocarcinoma cells A549-GFP-LUC-BM3 was successfully established. Compared to parental cells, this cells exhibited a significantly higher incidence of bone metastasis and enhanced in vitro proliferation, migration, and invasion abilities. Transcriptomic sequencing results revealed that the A549-GFP-LUC-BM3 cell line had 2954 differentially expressed genes compared to the parental cells, with 1021 genes up-regulated and 1933 genes down-regulated. Gene Ontology (GO) functional enrichment analysis indicated that the differentially expressed genes were primarily localized in cellular components such as the cell periphery. The molecular functions identified as significantly enriched included signaling receptor activity, calcium ion binding, and extracellular matrix structural constituent. Additionally, the biological processes found to be enriched were cell adhesion and biological adhesion. The enrichment analysis conducted using the Kyoto Encyclopedia of Genes and Genomes (KEGG) revealed that the differentially expressed genes were primarily involved in the metabolism of xenobiotics by cytochrome P450, retinol metabolism, drug metabolism-cytochrome P450, cell adhesion molecules, steroid hormone biosynthesis, and the nuclear factor kappa B (NF-κB) signaling pathway. The highly bone-metastatic human lung adenocarcinoma cell line with GFP and luciferase double labeling was successfully established. The biological behavior and transcriptome sequencing of the cell line suggest that it has a high bone-metastatic potential.

Pancreatic ductal adenocarcinoma: exploring clinicopathological trends and racial disparities in a comprehensive U.S. population-based study.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy about 50% of PDAC are metastatic at presentation. In this study, we evaluated PDAC demographics, annual trend analysis, racial disparities, survival rate, and the role of different treatment modalities in localized and metastatic disease. A total of 144,824 cases of PDAC were obtained from the SEER database from 2000 to 2018. The median age was 69years, with a slightly higher incidence in males (52%) and 80% of all cases were white. Among cases with available data, 43% were grade III tumors and 57% were metastatic. The most common site of metastasis was the liver (15.7%). The annual incidence has increased steadily from 2000 to 2018. The overall observed (OS) 5-year survival rate was 4.4% (95% CI 4.3-4.6%), and 5years cause-specific survival (CSS) was 5% (95% CI 5.1-5.4%). The 5-year survival with multimodal therapy (chemotherapy, surgery, and radiation) was 22% (95% CI 20.5-22.8%). 5-year CSS for the blacks was lower at 4.7% (95% CI 4.2-5.1%) compared to the whites at 5.3% (95% CI 5.1-5.4%). Multivariate analysis found male gender and black race associated with worse prognosis. Kaplan-Meier survival analysis found multimodal therapy to have the best outcomes in all three stages. PDAC is an aggressive malignancy with male gender and black race are associated with a poor prognosis. Surgery with chemoradiation was associated with the best overall survival. With steadily increasing rates of PDAC, improved treatment modalities are paramount to improving survival in these patients.

Clinical features of patients with metastatic pheochromocytoma/paraganglioma

Objective: To analyze the clinical features of patients with metastatic pheochromocytoma/paraganglioma (PPGL). Methods: A follow-up study. The clinical data of 250 patients with metastatic PPGL treated at Peking Union Medical College Hospital from January 2018 to August 2023 were retrospectively analyzed, including 124 males and 126 females. The clinical features and treatment status of patients with metastatic PPGL were summarized and analyzed. Kaplan-Meier survival curve was used to evaluate patients' prognosis. Results: The age of onset, age of diagnosis, and age of tumor metastasis in patients with metastatic PPGL were (33.1±14.2) years, (35.4±15.2) years, and (40.7±15.3) years, respectively. Metastasis occurred in 26.4%(66/250) of patients at the time of initial diagnosis. Among patients without metastases at the time of initial diagnosis, the time from primary tumor resection to metastasis[M(Q1, Q3)] was 5.0 (3.0, 9.0) years, among which 20.1%(37/184) of patients had metastases more than 10 years after surgery. Most patients showed increased 24-hour urinary norepinephrine and plasma normetanephrine, accounting for 78.2%(176/225) and 78.7%(85/108), respectively. 42.3%(69/163) of patients had increased neuron specific enolase (NSE)levels. Germline mutations were screened in 201 patients, of which 55.2%(111/201) had germline pathogenic mutations. In patients with gene mutations, 76.5%(85/111) had SDHB mutations. 52.0%(130/250) of metastatic PPGL patients had primary sites outside the adrenal gland, with the Ki-67 index of 5% (3%, 8%). There were 85.6%(214/250) patients had multisystem metastasis, with bone metastasis being the most common site of metastasis, accounting for 60.8%(152/250). In terms of treatment, 32.8%(75/229) of patients underwent two treatment regimens and 8.7%(20/229) of patients underwent three treatment regimens. Most patients had a good prognosis, with a 5-year and 10-year survival rate of 88.0% and 84.0%, respectively. However, some patients had rapid disease progression, and as of August 2023, 30 patients died, and the time from diagnosis to death in deceased patients was 2.0 (1.0, 4.0) years. Conclusions: Patients with metastatic PPGL have a high rate of germline mutations, especially those with SDHB mutations. The metastatic PPGL is usually multisystem metastasis with the characteristics of mostly paraganglioma, large lesion diameter and high Ki-67 index.

Prognostic factors associated with early recurrence following liver resection for colorectal liver metastases: a systematic review and meta-analysis

BackgroundColorectal cancer (CRC) is the 3rd most common malignancy with the liver being the most common site of metastases. The recurrence rate of colorectal liver metastases (CRLM) after liver resection (LR) is notably high, with an estimated 40% of patients experiencing recurrence within 6 months. In this context, we conducted a meta-analysis to synthesize and evaluate the reliability of evidence pertaining to prognostic factors associated with early recurrence (ER) in CRLM following LR.MethodsSystematic searches were conducted from the inception of databases to July 14, 2023, to identify studies reporting prognostic factors associated with ER. The Quality in Prognostic Factor Studies (QUIPS) tool was employed to assess risk-of-bias for included studies. Meta-analysis was then performed on these prognostic factors, summarized by forest plots. The grading of evidence was based on sample size, heterogeneity, and Egger’s P value.ResultsThe study included 24 investigations, comprising 12705 individuals, during an accrual period that extended from 2007 to 2023. In the evaluation of risk-of-bias, 22 studies were rated as low/moderate risk, while two studies were excluded because of high risk. Most of the studies used a postoperative interval of 6 months to define ER, with 30.2% (95% confidence interval [CI], 24.1–36.4%) of the patients experiencing ER following LR. 21 studies were pooled for meta-analysis. High-quality evidence showed that poor differentiation of CRC, larger and bilobar-distributed liver metastases, major hepatectomy, positive surgical margins, and postoperative complications were associated with an elevated risk of ER. Additionally, moderate-quality evidence suggested that elevated levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19–9 (CA199), lymph node metastases (LNM) of CRC, and a higher number of liver metastases were risk factors for ER.ConclusionThis review has the potential to enhance the efficacy of surveillance strategies, refine prognostic assessments, and guide judicious treatment decisions for CRLM patients with high risk of ER. Additionally, it is essential to undertake well-designed prospective investigations to examine additional prognostic factors and develop salvage therapeutic approaches for ER of CRLM.

Abstract LB344: A novel approach to limit off-tumor toxicity of CAR-T cells targeting solid cancers

Abstract T cells genetically engineered to express a chimeric antigen receptor (CAR) specific for the molecule CD19 have achieved significant gains in the treatment of chemotherapy-resistant leukemia and lymphoma. Despite evidence of long-lived cures in patients with metastatic solid cancer after receiving tumor-specific T cells, no CAR-T cell treatment is currently approved for use against any solid cancer. A large majority of solid cancers express one of many tumor-associated antigens (TAAs) that are vulnerable to CAR T cell recognition. However, in nearly all cases those same TAAs are present in healthy tissues. Since CAR T cells cannot differentiate between cancer and normal cells, CAR T cell recognition of TAAs on healthy tissues provokes dose-limiting ‘on-target off-tumor’ toxicities at sites of endogenous expression (lung, intestine). Thus, there remains a pressing need to develop strategies to mitigate off-tumor toxicity of CAR T cells. To this end, we develop two immunocompetent models of CAR T cell transfer targeting TAAs abundant in metastatic colorectal cancer and pancreatic cancer. TAA-specific CAR T cells affected tumor shrinkage along with infiltrating and damaging sites of endogenous expression (primarily lung, pancreas, & colon). In both of our models, off-tumor toxicities were antigen-dependent and resulted in tissue damage, systemic inflammation, and host death that was titratable to CAR-T cell dose. TAA-specific CAR T cells infiltrated sites of endogenous expression such as the intestine, pancreas, and lungs. Notably, the respiratory system was the site of greatest pathology in both of our models, with massive CAR T cell accumulation and tissue destruction that resulted in systemic wasting and rapid weight loss. Remarkably, we found that the presence of an antigen-bearing tumor in the liver, but not other sites, greatly exacerbated CAR-T cell pulmonary infiltration, tissue destruction, and host mortality.The liver is the most common site of metastasis in patients with colorectal and pancreatic adenocarcinoma and the only site of metastasis in one-third of colorectal cancers. Our models indicated that TAA-specific CAR-T cells given for the treatment of liver metastasis result in dose-limiting pulmonary toxicity due to the presence of the TAA in the healthy lung. To address this translational barrier, we designed and validated a multiparameter genetic reprogramming targeting T cell trafficking and tissue residency introduced with the CAR to imbue CAR-T cells with liver tropism. In multiple models, CAR T cells programmed with liver-specific tropism augmented CAR T cell liver trafficking, decreased lung infiltration and toxicity, and effectively treated TAA+ liver metastasis. We aim to initiate a pilot clinical trial using tissue resident-programmed CAR T cells to treat colorectal liver metastasis. Citation Format: Alex Bartlett, Matthew Mcwhorter, Camille Collier, Chelsea Jenkins, Robert Eil. A novel approach to limit off-tumor toxicity of CAR-T cells targeting solid cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB344.

Metastatic patterns and hormone receptor status among breast cancer patients in Tanzania

Introduction: Metastatic breast cancer is a common presentation in Tanzania. Estrogen-receptor (ER)-positive tumors are known to metastasize to the bones and require hormonal treatment as first-line therapy. Challenges with accessing immunohistochemistry services can delay information on breast cancer subtypes, further delaying treatment with effective hormonal therapy. Objectives: This study aimed to assess the pattern of distribution of metastatic lesions in patients with metastatic breast cancer and evaluate its association with their hormone and HER-2 status, which could help provide recommendations on the use of front-line hormone therapy in areas where access to immunohistochemistry is a challenge. Methods: A retrospective study covering histologically confirmed breast cancer patients in 2020 with metastatic lesions and complete medical records at Ocean Road Cancer Institute. Clinical information on the number, state and sites of metastasis, presence of symptoms and treatment received, and pathological variables, including histology, ER, PR and HER-2 status, were documented. Results: Forty-nine (96.1%) of 51 patients analysed were female, with a mean age of 49.5 years. 47% presented with up-front metastatic disease. Lung was the most common metastatic site (76.5%) followed by bone/spine (53%). About half the patients had multiple sites involved. ER-positive tumors accounted for 47%, PR positive for 31% and HER-2 positive 39.2%. ER-positive tumors were more likely to present as a recurrence than up-front metastasis. ER-positive tumors were significantly more likely to be associated with bone and spine metastasis (59%) compared to ER-negative tumors (29%) Conclusion: The clinical and pathological features of MBC in Tanzanian women are similar in many ways to those in other African regions. However, the ER positivity rate is lower. This study found a significant association between ER-positive tumours and skeletal metastasis, which has implications for the up-front treatment of these patients, especially where access to immunohistochemistry can be a challenge.

An audit of metastatic tumors to the liver highlighting the spectrum of differential diagnosis: A retrospective study from a tertiary cancer center in North India

ABSTRACT Background: Space-occupying lesions of the liver can broadly be divided into benign and malignant and further as primary and metastatic lesions. Among the malignant lesions of the liver, metastatic lesions of unknown primary origin present as one of the most common clinical dilemmas. Objectives: The primary objective was to study the histomorphological and immunohistochemical profiles of the secondaries to the liver. The secondary objective was to outline an approach toward an accurate diagnosis of the primary site and exclusion of the close differentials, especially in the case of round-cell tumors and spindle cell lesions. Materials and Methods: This retrospective cross-sectional study was conducted from May 2018 to September 2020 at the Department of Pathology, Homi Bhabha Cancer Hospital and Mahamana Pandit Madan Mohan Malaviya Cancer Center, Varanasi, Uttar Pradesh, India. All patients diagnosed with metastatic liver lesions were studied. The cases were reviewed for histomorphological and immunohistochemical findings, and the data were analyzed using Microsoft Excel. Results: A total of 452 cases were studied, and the mean age was 54.8 ± 13.5 (standard deviation) years with the age ranging from 7 months to 88 years (median, 56; interquartile range, 46-65 years) with female (n = 243, 53.8%) predominance. Adenocarcinomas (n = 302, 66.8%), followed by neuroendocrine lesions (n = 63, 13.9%), were the most common histology, while melanoma (n = 2, 0.4%) was the least common. The common sites of the primary were pancreaticobiliary (n = 231, 51.1%), lung (n = 58, 12.8%), breast (n = 31, 6.9%), and colorectal (n = 20, 4.4%). Less frequent lesions involving the liver, such as spindle cell lesions, lymphomas, melanomas, and germ cell tumors, were also noted. Conclusions: The liver is one of the most common sites of metastasis from various organs. Adenocarcinoma is the most common tumor, amid which metastasis from the pancreaticobiliary tract is the most common site of primary. Hence, a stepwise approach of immunohistochemistry in conjunction with clinicoradiological assessment is necessary for an apt diagnosis and treatment.

The long-term efficacy of imatinib with hepatic resection or other local treatment for gastrointestinal stromal tumours liver metastases: a retrospective cohort study.

The liver is the most common site of metastasis from gastrointestinal stromal tumors (GISTs). The authors aimed to evaluate imatinib (IM) combined with hepatic resection (HR) or other local treatments such as radiofrequency ablation (RFA) and transarterial chemoembolization (TACE), compared to IM monotherapy in long-term survival benefits in patients suffering from GIST liver metastases. Our research encompassed 238 patients diagnosed with liver metastases of GISTs from January 2002 to April 2022 at the First Affiliated Hospital of Sun Yat-Sen University. The oncological outcomes of concern included overall survival (OS), progression-free survival (PFS), and liver-specific PFS. Of all 238 patients, 126 were treated with IM alone (IM group), 81 with IM combined with HR (IM+HR group), and 31 with IM combined with RFA/TACE (IM+RFA/TACE group). The median follow-up time was 44.83 months. The median OS in the IM group was 132.60 months and was not reached in either the IM+HR group or the IM+RFA/TACE group. The 10-year OS rate in the IM+HR group was significantly superior to the IM group and the IM+RFA/TACE group (91.9% vs. 61.1% vs. 55.2%, respectively, P =0.015), and the liver-specific PFS ( P =0.642) and PFS ( P =0.369) in the three groups showed a beneficial trend in the combined treatment group. Multivariate analyses showed that age less than or equal to 60 years (HR 0.280, P< 0.001) and IM+HR (HR 0.361, P =0.047) were independently associated with better OS. Achieving no evidence of disease through surgical intervention was independently correlated with enhanced OS (HR 0.099, P =0.034), liver-specific PFS (HR 0.388, P =0.014), and PFS (HR 0.402, P =0.004). In patients with GIST liver metastases, IM combined with HR might improve OS in selected patients compared with IM alone and IM combined with RFA/TACE. Achieving no evidence of disease status with surgical treatment of patients results in significant prolonging of OS, liver-specific PFS, and PFS.

Sacituzumab Govitecan for the treatment of advanced triple negative breast cancer patients: a multi-center real-world analysis.

The objective of this multicenter, observational, retrospective analysis was to evaluate the safety and efficacy of sacituzumab govitecan in metastatic triple-negative breast cancer (mTNBC) patients managed according to common clinical practice in Italy. Data were retrieved by 7 sites. Triple-negative BC was defined by the lack of expression of estrogen receptor (ER <1%), progesterone receptor (PgR <1%) and human-epidermal growth factor receptor-2 (HER2 0, 1+, 2+ ISH-not amplified) according to standard ASCO-CAP criteria. Demographic and clinical characteristics were collected. Premedication, dose modifications and treatment schedule were based on the approved label of the product. Adverse events (AEs) were assessed according to NCI-CTCAE v5.0. Fifty-seven eligible patients who received sacituzumab govitecan for mTNBC were included. Median age was 53 years (range 25-75). Approximately 70% of patients had an initial diagnosis of TNBC. Median time from the diagnosis of metastatic BC to start of sacituzumab govitecan was 17 months (range 0-97) and median number of previous therapies was 3 (range 1-7). The most common sites of metastasis were lymph nodes (63.1% of patients), lung (57.9%), bone (50.8%) and liver (38.6%). Eight (14.0%) patients had a disease-free interval ≤12 months. A total of 32 (56.1%) deaths were observed and the median overall survival (OS) was 12.43 months (95% CI, 7.97 months-not reached). At a median follow-up of 10.6 months, 45 patients (78.9%) had progression and the median progression-free survival (PFS) was 4.9 months (95% CI, 3.7-7.1 months). Partialtumour response was observed in 19 patients (33.3%), stable disease in 16 (28.1%) and disease progression in 22 patients (38.6%). The most common treatment-related AEs were anemia (66.6% of patients), alopecia (66.6%), neutropenia (59.6%), nausea (42.1%) and diarrhea (38.6%). Neutropenia was the most common serious treatment-related AE: 21.0% and 8.7% of patients experienced grade 3 or 4 neutropenia, respectively. Twenty-two patients (38.6%) reduced the dose and 5.3% permanently discontinued treatment. The results of this real-world analysis showed that both safety and efficacy of sacituzumab govitecan in mTNBC patients are consistent with that previously reported in regulatory trials. The use of premedication and supportive measures was associated with a satisfactory toxicity profile.

The Safety and Effectiveness of Bevacizumab in Metastatic Colorectal Cancer With Unresectable Metastases: A Real-Life Study From the South of Morocco.

Background Colorectal cancer constitutes a significant public health challenge, despite remarkable strides made in the last two decades, particularly in the medical management of metastatic stages. Notable progress has been achieved through targeted therapies such as anti-epidermal growth factor receptors or anti-angiogenic antibodies, as well as advancements in surgical approaches for hepatic metastases. This study seeks to assess the efficacy and safety of bevacizumab plus chemotherapy in individuals with metastatic colorectal cancer. Methodology This is an observational, cross-sectional, retrospective study of all patients who were followed up for metastatic colorectal cancer with unresectable metastases and were treated with bevacizumab in combination with standard chemotherapy from January 2010 until December 2019 in the medical oncology department of the Centre Hospitalier Universitaire (CHU) Souss-Massa of Agadir. Results Of the total 162 cases, 117 (72%) had metastatic disease, and 45 (28%) progressed to metastatic disease after initial treatment. The median age of the patients was 55 years (range = 23-79 years) with a sex ratio of 1.1 (M/F). The tumor was located in the left colon in 135 (83.3%)patients. The results represented adenocarcinoma in 137 (84.6)cases and mucinous subtype in 23 (14.19) cases. The three most common sites of metastasis were the liver (99, 61.1), peritoneum (67, 41.3), and lung (33, 20.3). In the first line, allpatients received bi-chemotherapy plus bevacizumab, i.e., fluorouracil, oxaliplatin, and leucovorin in 34 (20.9%) patients; capecitabine plus oxaliplatin in 88 (54.3%) patients; leucovorin, fluorouracil, and irinotecan in 17 (10.4%) patients; andcapecitabine plusirinotecan in 23 (14.1%) patients. Response after first-line treatment was progression in 74 (45.7) cases, stability in 42 (25.9) cases, partial response in 35(21.6) cases, and complete response in 11 (6.8) cases. Nine (6%) patients were able to benefit from surgical resection of metastatic lesions. Overall, 77 (47%)patients received second-line chemotherapy, i.e., 5-FU with irinotecan in 40 (51.8%)cases or with oxaliplatin in 30(38.8%) cases. Two patients developed undesirable side effects under bevacizumab (hypertension). The median progression-free survival and median overall survival of the study cohort were 9 months and 14 months, respectively. Nevertheless, patients who underwent primary tumor resection (p = 0.048), those with right‑sided tumors (p = 0.022), those who received a higher number of treatment cycles (p = 0.020), and those who received maintenance treatment (p = 0.001) had a longer median overall survival. Conclusions Chemotherapy combination with bevacizumab is considered as the cornerstone of metastatic colorectal cancer treatment in our region. With the new healthcare and social security systems, easier access to expensive treatments and molecular pathology tests is currently available. It is important to highlight that real-world data can offer valuable insights into the daily clinical practice of medical oncology.

Abstract 1503: Melanoma-derived lymphatic extracellular vesicles suppress dendritic cell differentiation and maturation in the sentinel lymph node

Abstract Spread to regional lymph nodes is the most common site of metastasis from melanoma and almost all solid tumors. Lymphatic metastases begin in the first lymph nodes draining from the primary tumor, i.e., the sentinel lymph nodes (SLN), preceded by the development of the premetastatic niche (PMN) initiated by primary cutaneous melanoma. Melanoma mediators are known to play a critical role in developing the PMN through the immune subversion in SLN. The DCs are a vital component of LN immunity that directly relates to eliciting T-cell functions. Our multiplex immunofluorescence (MxIF) analysis of SLNs indicates significantly decreased levels of DCs and cytotoxic-T cells in both core and interface areas of tumors in recurred patients treated with immunotherapy compared to non-recurred melanoma patients. The goal of this study is to determine whether the lymphatic extracellular vesicles (L-EVs) of melanoma patients regulate DC tolerization in SLN in order to stimulate the development of PMN. To identify whether L-EVs stimulate DC suppression, we extracted L-EVs from the lymphatic fluid of patients with melanoma downstream of primary cutaneous melanomas, compared it with controls (non-malignant post-operative fluid collected from the lymph node dissection field, and evaluated their effect on DC maturation by challenging these L-EVs in monocytic (CD14+) and hematopoietic stem cells (CD34+) cells. We found that L-EVs derived from melanoma patients suppress differentiation of CD11c+HLA-DR+ DCs and their maturation (defined by CD83 and CD86) compared to control L-EVs in CD14+ based DC maturation assay. We also found a reduction of conventional type 1 DC (cDC1) in CD34+-based DC maturation assay those challenged with patients’ L-EVs compared to control. To understand the mechanism of DC suppression in patients' L-EVs, we also conducted a total RNA sequencing analysis of subsets of DCs from maturation experiments to evaluate differently regulated transcriptomic profiles. The gene ontology analysis indicates that patient-derived L-EVs interfere with tRNA processing, oncostatin M &amp; IL-10 signaling, and other immunoregulatory pathways to alter the hematopoietic cell lineage pathways in the DC maturation. Furthermore, the proteomic analysis of L-EVs also indicated several differentially regulated cargo-identified proteins in patient L-EVs, which are associated with immunomodulation, including regulation of DC function compared to control L-EVs. In conclusion, our study revealed that the patient's L-EVs carry differential proteomic cargoes secreted by cutaneous melanoma, which may be involved in regulating DC differentiation and maturation to diminish their functions and support the developing PMN in SLN. Citation Format: Shankar Suman, Wendy K. Nevala, James W. Jakub, Ray Guo, Alexey A. Leontovich, Raymond M. Moore, Chathu L. Atherton, Liyi Geng, Jeffrey E. Johnson, Sarah A. McLaughlin, Svetomir N. Markovic. Melanoma-derived lymphatic extracellular vesicles suppress dendritic cell differentiation and maturation in the sentinel lymph node [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 1503.

Abstract 6479: Metastases in uveal melanoma patients: Trends and risk factors

Abstract Purpose: Uveal melanoma has a high tendency to metastasize. Due to its rarity, there has not been large population studies that have demonstrated the effect of demographic variables on a patient’s risk to have metastases. Methods: The Nationwide Emergency Department Sample was queried from the last quarter of 2015 to 2019 to identify patients with a diagnosis of uveal melanoma. Multivariable logistic regression, with patient- and hospital-level characteristics as covariates, was used to identify factors associated with a higher chance of developing a metastasis and specific metastasis locations. Results: From the last quarter of 2015 to 2019, there were 7,561 ED encounters with a diagnosis of uveal melanoma. Of these patients, 5.8% had at least one metastasis. Most patients with a metastasis were at least 65 years of age (47.1%), male (54.4%), a Medicare beneficiary (45.2%), and belonged to a family in the highest income quartile (29.7%). The median age of these patients was 61 years (IQR: 32-74). Most patients presented to hospitals in the South (40.7%), with a Trauma Level I designation (56.1%), and to a metropolitan teaching hospital (72.9%). The most common sites of metastasis were liver (17.0%), brain (5.3%), and bone (2.0%). Multivariable logistic regression identified the following factors to be associated with increased risk of developing a metastasis: private insurance (odds ratio [OR]=1.62; p=0.012), highest income quartile (OR=2.30; p&amp;lt;0.001), and 2nd highest income quartile (OR=1.78; p=0.002). The following factors were associated with higher odds of developing a liver metastasis specifically: no-charge/charity work (OR=15.8; p=0.012), highest income quartile (OR=1.99; p=0.003), and second highest income quartile (OR=1.66; p=0.035). Presenting to a Trauma Level I hospital was associated with decreased risk of developing a liver metastasis (OR=0.57; p=0.016). Belonging to the highest income quartile was associated with a higher chance of developing a brain metastasis (OR=2.13; p=0.023) or a bone metastasis (OR=2.74; p=0.045). Among patients with a metastasis, the in-hospital mortality rate was 8.3%. Conclusion: Metastasis is an important complication to monitor in uveal melanoma patients. In this study, we have demonstrated that income and insurance status are factors that are associated with higher rates of metastases. Physicians should place special attention to these groups to ensure that metastases are minimized. Citation Format: Alice A. Beneke, Kamil Taneja, Lauren Ladehoff, Kevin Root, Eric Toloza. Metastases in uveal melanoma patients: Trends and risk factors [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 6479.

Abstract 635: Osteoclasts mediate chemotherapy resistance in a fully humanized microphysiologic system of prostate cancer bone metastases

Abstract Bone metastases (BM) are the most common sites of metastases in prostate cancer, occurring in ~85% of patients. Overall survival of men with castrate resistant prostate cancer with BM is less than 24 months. Docetaxel is the most commonly used therapy for patients with prostate cancer, but the response rate is only 30-40% and median duration of response is less than 9 months. Non-tumor components of the Tumor Microenvironment (TME) have been proposed to mediate treatment resistance, but few pre-clinical models capture the complex physiology of the human bone TME. We report the development of a bone TME using a humanized microphysiologic system to address this need. The LumeNEXT platform is a microphysiologic system that allows the 3-dimensional (3D) reconstitution and integrated analysis of a bone-specific TME microenvironment with functional microvasculature that traverses the chip and can be used to mimic drug delivery in patients. Primary human osteoclasts (OC) were differentiated from patient peripheral blood monocytes. LNCaP prostate cancer spheroids were grown in hanging droplets. We performed co-culture of OCs with 3D LNCaP spheroids and evaluated the efficacy of docetaxel-induced tumor cell killing in the presence of bone cells. OCs and PC spheroids were seeded into LumeNEXT devices in a collagen-based matrix and treated with 20 nM Docetaxel or DMSO vehicle for 48 hours. Docetaxel response was assessed using confocal microscopy for single spheroid diameter and cytotoxicity was measured using fluorescent cell death markers. Docetaxel-mediated killing of tumor spheroids was found to be significantly attenuated in the presence of OCs. In LNCaP only conditions, average Docetaxel-mediated cell death was 68.82%, compared to 53.86% in the LNCaP and OC co-culture condition (p&amp;lt;0.0001). Furthermore, Docetaxel treatment resulted in reduced tumor spheroid diameter compared to DMSO control when prostate cancer spheroids were cultured alone (p=0.0118). Additionally, the presence of OCs attenuated Docetaxel-induced morphological changes. Our data suggest that osteoclasts play a significant role in mediating chemotherapy response in prostate cancer. Future studies will examine transcriptional changes in prostate cancer cells that may be associated with Docetaxel resistance in the bone microenvironment and identify mechanisms of BM microenvironment-mediated drug resistance. Bioinformatic analysis of patient sequencing datasets is ongoing to identify osteoclast-associated signatures of treatment resistance. Citation Format: Adeline B. Ding, Erika Heninger, Shannon R. Reese, Cristina Sanchez-de-Diego, Ravi C. Yada, Nan Sethakorn, Sheena C. Kerr, Xavier T. Hazelberg, Marina N. Sharifi, David J. Beebe, Joshua M. Lang. Osteoclasts mediate chemotherapy resistance in a fully humanized microphysiologic system of prostate cancer bone metastases [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 635.

Abstract 4627: Metastatic renal cell carcinoma with occult primary: Clinical and biological evidence for a new entity of cancers of unknown primary that beneficiates from tissue-tailored treatment

Abstract Background: Cancers of unknown primary (CUP) is a heterogenous group of malignancies characterized by distant metastases in the absence of detectable primary. Specifics subgroups of CUP that share similarities with cancers of known primary beneficiate from tissue-tailored therapeutic strategies. The objective of this study was to characterize the clinical and biological presentation of a cohort of patients with suspected CUP of renal origin (rCUP) and to evaluate their optimal therapeutic management. Methods: All Patients with rCUP identified prospectively between 2020 and 2023 within the French National Multidisciplinary Tumor Board for CUP were included. Centralized pathological review and immunohistochemical stainings were performed. Whole Exome Sequencing (WES), whole transcriptomic sequencing (RNAseq) and application of the deep-learning based algorithm TransCUPtomics for prediction of tissue of origin, and DNA methylation analysis were performed and compared to public renal cell carcinomas (RCC). Progression Free Survival (PFS) and Overall Survival (OS) were calculated using Kaplan-Meier estimates. Results: 23 patients were included. The median age at diagnosis was 57 yo and 17/23 were male. The most common metastatic sites were the bones (N=17) and the lymph nodes (N=14). 19/23 patients presented with at least two distinct distant metastatic sites. Genomic analyses performed in 10 patients led to the identification of recurrent inactivating mutations in genes commonly altered in RCC, including NF2 (N=7), SETD2 (N=3), or VHL (N=1). 10/11 samples analyzed by RNAseq were predicted as RCC by the TransCUPtomics classifier based on their gene expression profiles. DNA methylation profiling performed in 7 samples showed major similarity with known RCC subtypes.Centralized pathological review and integration of molecular characteristics led to the final diagnoses of papillary RCC (N=2), clear cell RCC (N=7), renal medullary carcinoma (N=1), TFEB-amplified RCC (N=1) and unclassified RCC (N=12). 20/23 patients received at least one line of systemic treatment based on the renal origin, including anti-angiogenic TKI, anti-PD1/PDL1 antibody, anti-CTLA4 antibody or mTOR inhibitor. The median PFS under the first renal-oriented systemic treatment was 5 months and 10 patients remained progression-free for more than 6 months under tailored-treatment. The median OS was 31 months, and 11 patients are still alive in October 2023. Conclusions: This study shows that rCUP represent a new entity within CUPs that shares major similarities with classical RCC despite the more frequent presentation of unfavorable prognostic factors. Prolonged survival can be observed with renal-tailored systemic treatment, supporting the individualization of these patients within CUP. Citation Format: Nicolas Jacquin, Julien Masliah-Planchon, Guillaume Grisay, Ronan Flippot, Riwan Brillet, Célia Dupain, Maud Kamal, Isabelle Guillou, Nadège Gruel, Nicolas Servant, Pierre Gestraud, Jennifer Wong, Vincent Cockenpot, Andreia Goncalves, Janick Selves, Hélène Blons, Etienne Rouleau, Oliver Delattre, Christophe Le Tourneau, Ivan Bièche, Yves Allory, Laurence Albigès, Sarah Watson. Metastatic renal cell carcinoma with occult primary: Clinical and biological evidence for a new entity of cancers of unknown primary that beneficiates from tissue-tailored treatment [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 4627.

Abstract 6135: Racial and ethnic differences in site of de novo metastases in patients with colorectal cancer: A SEER analysis

Abstract Purpose: Disparities in colorectal cancer (CRC) mortality may be driven by differences in access to care, tumor biology, and propensity to spread to distant sites. We examine differences in patterns of de novo metastases by race/ethnicity and age. Methods: We identified 248,732 CRC patients listed in the Surveillance, Epidemiology, and End Results (SEER) database diagnosed with a first primary invasive CRC from 2010-2020, aged 20+ years at diagnosis, with complete data on SEER summary stage, and not diagnosed only by autopsy/death certificate. Outcomes included de novo metastatic site (no metastasis, liver, lung, brain, bone) and pattern (no metastasis, liver only, lung only, liver and lung, other). We used logistic regression to calculate odds ratios (OR) and 95% confidence intervals (95% CI) for the associations between 1) demographic and tumor characteristics (site, side, T stage, N stage) and site of de novo metastases , and 2) race/ethnicity and site of de novo metastases stratified by age (20-49, 50-74, 75+). We used multinomial logistic regression to assess the association between demographic and tumor characteristics and pattern of metastasis. Models adjusted for age, race/ethnicity, sex, site (colon, rectum), side (left, right), T stage, and N stage. Results: 62,844 stage IV CRC cases were diagnosed from 2010-2020, and liver was the most common metastatic site (72%). Relative to age 50-74, age 20-49 at diagnosis was more strongly associated with de novo liver metastases (OR: 1.07; 95% CI: 1.02-1.11) and less with lung (OR: 0.86; 95% CI: 0.80-0.92) or brain (OR: 0.69; 95% CI: 0.52-0.93) metastases. Relative to Non-Hispanic White (NHW) patients, Non-Hispanic American Indian/Alaskan Native (AI/AN) patients had a higher risk of lung metastases (OR: 1.33; 95% CI: 1.07-1.65), Non-Hispanic Asian/Pacific Islander (API) patients had lower risks of liver (OR: 0.87; 95% CI: 0.83-0.92) and brain (OR: 0.67; 95% CI: 0.48-0.95) metastases, and Non-Hispanic Black (NHB) patients had higher risks of liver (OR: 1.35; 95% CI: 1.29-1.41), lung (OR: 1.36; 95% CI: 1.27-1.45), and bone (OR: 1.23; 95% CI: 1.08-1.41) metastases. In age-stratified analyses, the risks for NHB patients persisted across groups, while lower risks for API patients were not observed in the 20-49 group. API patients aged 20-49 had a higher risk of de novo lung (OR: 1.31; 95% CI: 1.06-1.61) and bone (OR: 1.63; 95% CI: 1.13-2.37) metastases, and the increased risk of lung metastases for AI/AN patients was larger in magnitude (OR: 2.26; 95% CI: 1.39-3.68). Age 20-49 was more strongly associated with a liver-only pattern (OR: 1.14; 95% CI: 1.09-1.19) and with less common distant sites (OR: 1.33; 95% CI: 1.25-1.41). Conclusions: Racial/ethnic differences in de novo metastatic CRC patterns exist overall and across age groups. These findings are consistent with disparities in risk of stage IV CRC and can inform surveillance priorities in CRC survivors. Citation Format: Nicole C. Loroña, Mariana C. Stern, Stephanie L. Schmit, Jane C. Figueiredo. Racial and ethnic differences in site of de novo metastases in patients with colorectal cancer: A SEER analysis [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 6135.

Abstract 927: Real-world (RW) biomarker characteristics and clinical outcomes in pre-treated non-MSI-H/dMMR metastatic colorectal cancer (mCRC) patients

Abstract Introduction: Given sparse RW evidence, we assessed biomarker characteristics &amp; clinical outcomes in community oncology practices among pre-treated non-MSI-H/dMMR mCRC patients. Methods: This retrospective cohort study used structured &amp; chart review data from iKnowMed, The US Oncology Network electronic health record data &amp; included non-MSI-H/dMMR adult mCRC patients pre-treated with standard of care (SoC) chemo who initiated subsequent systemic anticancer treatment (SACT), best supportive care (BSC) or neither from 1/1/2016 - 12/31/2021. Index date for SACT users was the regimen start date post SoC chemo &amp; for patients on BSC &amp; no SACT/BSC, it was last chemo administration date. Patients were followed from index date until 8/31/2022 for overall survival (OS) &amp; real-world progression-free survival (rwPFS). KM analyses assessed outcomes, overall &amp; stratified by treatment, RAS status &amp; metastasis sites. Results: Of mCRC patients with &amp;gt;2 visits, 70.9% received MSI/MMR testing. In 292 eligible chart review patients, 69.5% received SACT in pre-treated setting (regorafenib 14.8%, trifluridine/tipiracil (TAS-102) 12.3%, other 72.9%), 28.8% received BSC &amp; 1.7% neither. 76.7% reported KRAS/NRAS testing with 60.7% wild-type &amp; 39.3% mutant. Common metastasis sites were liver-only (44.2%), liver &amp; lung (10.3%) &amp; lung-only (8.9%). Median (range) duration of follow-up was 5.2 (2.7, 10.0) months for regorafenib, 5.3 (2.5, 8.6) for TAS-102 &amp; 10.7 (5.3, 18.0) for the other treatments group. Median OS was 7.4 (95% CI: 5.8, 8.8) months &amp; median rwPFS was 3.5 (95% CI: 3.2, 4.3) months (outcomes data in Table). Conclusions: 29.1% pre-treated, mCRC patients did not receive guideline recommended MSI/MMR testing, highlighting the need to improve testing. Outcomes varied by treatment, RAS status, &amp; metastatic sites. The modest RW clinical benefit for SoC regorafenib &amp; TAS-102, was consistent with trials &amp; other RW studies; all highlighting an unmet need. Cohorts Median (95% CI) OS (months) Median (95% CI) rwPFS1 (months) Overall 7.4 (5.8, 8.8) 3.5 (3.2, 4.3) Regorafenib 5.6 (3.1, 9.7) 2.4 (1.8, 3.0) TAS-102 5.9 (3.4, 8.6) 3.0 (2.1, 3.4) Other SACT2 12.8 (9.8, 17.2) 4.9 (3.7, 5.8) BSC 2.4 (1.8, 3.2) - RAS mutation Wild-type 8.6 (6.6, 11.5) 4.0 (3.3, 4.9) Mutant 5.4 (3.4, 9.5) 3.2 (2.1, 4.6) Metastatic sites Liver only 8.0 (5.7, 11.7) 3.9 (3.0, 4.9) Lung only 17.0 (7.8, 35.6) 7.9 (3.3, 10.5) Liver &amp; lung only 5.4 (2.4, 7.2) 3.5 (2.1, 5.4) Other 6.7 (4.1, 9.4) 3.2 (2.7, 3.9) Abbreviation: CI: confidence interval, TAS-102: trifluridine/tipiracil, OS: overall survival, rwPFS: real-world progression-free survival, SACT: systemic anticancer treatment 1Overall rwPFS was calculated among patients receiving subsequent SACT only (n = 203) 2Top 2 “other SACT” included irinotecan- or oxaliplatin-based treatment Citation Format: Mayur M. Amonkar, Sneha Sura, Kaushal Desai, Rishi Jain, Zhimei Liu, Nicole Niehoff, Thomas W. Wilson, Gregory Patton, David Cosgrove. Real-world (RW) biomarker characteristics and clinical outcomes in pre-treated non-MSI-H/dMMR metastatic colorectal cancer (mCRC) patients [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 927.

Abstract 880: Identifying ANKRD22 and fostamatinib as a theragnostic target and drug candidate for metastatic pancreatic cancer through in silico analysis

Abstract Introduction: Pancreatic cancer (PC) presents significant clinical challenges, marked by a low 5-year survival rate and frequent distant metastasis. When PC metastasizes to other organs, it leads to a notable decrease in the 5-year survival rate for PC in metastasis, dropping from 11% to 3%. Despite the effectiveness demonstrated by advanced anti-cancer therapies targeting these mutated genes, the improvement in survival rates remains modest. Another critical consideration is the rising resistance to Gemcitabine, a standard drug used for treating PC. Hence, it is imperative to gain a more profound understanding of the comprehensive mechanisms underlying metastatic pancreatic cancer (mPC) and actively explore novel drugs for its treatment. Methods: First, we reanalyzed the RNA-seq of three of PC's most common metastatic sites, including liver, lung, and peritoneum. Using the Galaxy platform, we identified DEGs (differentially expressed genes) between metastatic sites. After that, we further utilized other web-based tools and databases, such as GEPIA, TIMER 2.0, Alphafold, PubChem, Drugbank, and Chembl, to identify ANKRD22 and perform molecular docking of Fostamatinib binds to this gene. Results: Our research focused on exploring the role of ANKRD22, which contains four copies of L-shaped ankyrin motifs, an emerging oncogenic molecule associated with various cancers. In the current study, we identified that ANKRD22 exhibited significant expression in the pancreatic adenocarcinoma (PAAD) cohort, correlating with deteriorating OS rates in PC patients. Moreover, it displayed distinct expression patterns in advanced stages of the disease compared to early stages, Furthermore, we uncovered a noteworthy correlation between ANKRD22 and the Kras, TP53, CDKN2A, and SMAD4 genetic anomaly, linked to diminished survival rates, as widely recognized, in the initiation and progression of PC, these four genes stand out as the most frequently mutated. Mechanistically, ANKRD22 exhibited associations with KRAS dependency signature, U12 type spliceosome assembly, multivesicular body routing, cell invasion, tumor cell line invasion, and tumor cell line migration, all indicative of PC progression and dissemination. Expanding our investigation through the DrugBank and ChEMBL databases, we delved into fostamatinib, an FDA-approved drug known as a spleen tyrosine kinase (SYK) inhibitor. Molecular docking experiments revealed the potential interaction between ANKRD22 and fostamatinib, suggesting its candidacy to treat mPC. Conclusion: Our findings identify ANKRD22 as a pivotal oncogenic factor promoting metastasis in PC and propose fostamatinib as a potential inhibitory treatment. Citation Format: Huong Thi Luu Kim Huynh, Hendrick Gao-Min Lim, Yuan-Chii Gladys Lee, Chien-Hsin Chen, Alexander T.H. Wu. Identifying ANKRD22 and fostamatinib as a theragnostic target and drug candidate for metastatic pancreatic cancer through in silico analysis [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 880.