Subsequent Metastasis Research Articles

Abstract C001: Cytomegalovirus infection modulates distinct immune cell dynamics across tumor-immune microenvironments and systemic macroenvironment during metastasis

Abstract Cytomegalovirus (CMV) is ubiquitously present worldwide and has been implicated in the modulation of cancer development and spread. Notably, CMV proteins have been detected in approximately 90% of lymph node and brain metastases in breast cancer, suggesting its potential influencing tumor invasiveness and metastases. This study investigates the effects of CMV infection on the tumor microenvironment and macroenvironment during metastatic progression in triple-negative breast cancer (TNBC). We employed a syngeneic TNBC mouse model designed to develop spontaneous metastases following primary tumor resection. Using multi-omics sequencing and comprehensive analysis tools, we characterized the tumor-immune landscape across multiple organs relevant to CMV infection and tumor metastasis, including blood, bone marrow, spleen, lungs, brain, and lymph nodes. Our results demonstrate that CMV infection systematically activated the immune response, suppressing primary tumor growth and subsequent metastasis. At the primary tumor site, prior to metastasis, CMV-infected mice exhibited significantly lower proportions of macrophages and plasma cells compared to uninfected counterparts, while CD8+ T cells were significantly enriched. In contrast, the proportions of neutrophils and dendritic cells did not significantly differ between the groups. Distinct patterns of immune cell dynamics were observed at metastatic sites. In the spleen of CMV-infected mice, a notable reduction in macrophages and elevated neutrophil levels were detected. Lung tissues displayed a marked increase in macrophages, CD8+ T cells, and dendritic cells in CMV-infected mice. Interestingly, in the blood, we noted a decreased proportion of natural killer cells in CMV-infected mice. However, no significant difference in plasma cell percentages was observed between CMV-infected and uninfected mice in metastatic lung tissues. The cell-cell interaction analysis further showed a complex crosstalk network between immune cells as well as tumor and immune cells. These findings highlight the profound impact of CMV infection on remodeling the immune landscape at both primary tumors and metastatic sites. The distinct immune cell dynamics orchestrated by CMV infection underscore the virus's role in modifying tumor-immune microenvironments and macroenvironments. Our study offers novel perspectives for developing targeted cancer therapies that consider the complex interactions between viral infections and the tumor immune axis. Further research is warranted to elucidate the mechanisms underlying CMV-mediated immune modulation at molecular level and its potential therapeutic implications in TNBC and other cancer types. Citation Format: Wenjuan Dong, Jianting Sheng, Shan Xu, Matthew Vasquez, Hong Zhao, Stephen T.C Wong. Cytomegalovirus infection modulates distinct immune cell dynamics across tumor-immune microenvironments and systemic macroenvironment during metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C001.

CNSC-35. TEMOZOLOMIDE POTENTIALLY POSTPONES THE DEVELOPMENT OF SUBSEQUENT METASTASES IN PEDIATRIC DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) PATIENTS

Abstract OBJECTIVE Surgical intervention is thought to increase the likelihood of subsequent dissemination in diffuse intrinsic pontine glioma (DIPG) patients. However, there is no study evaluating the factors influencing the timing of metastasis development. Hence, the present analysis was conducted to shed light on factors associated with subsequent dissemination timing. METHODS This analysis included 28 pediatric (age≤12) DIPG cases with metastasis treated at Sanjiu Brain Hospital between June 1, 2017 and June 30, 2023. The clinical data were retrospectively collected following the initial diagnosis. The diagnosis was established by typical imaging features of DIPG. The same three radiologists analyzed the imaging data independently. Time to subsequent metastasis was estimated using Kaplan–Meier analysis, and a log-rank test evaluated the differences between groups. RESULTS Of 28 patients, 13 (46.4%) were males and 15 were females. 23 (82.1%) underwent surgical intervention, while 5 (17.9%) did not receive surgery. The patients’ median age was 7 years (2-12 yrs.). The Kaplan-Meier method showed that the median time to metastasis was 5.8 months (95%CI 4.2-9.1). The log-rank test demonstrated that adjuvant temozolomide was the only variable that could significantly delay metastasis in the pediatric DIPG population (P=0.03). The median time to metastasis from the day of initial diagnosis for those who received adjuvant temozolomide was 6.8 months (95%CI 5-10.7) vs. 3 months for those who did not receive adjuvant temozolomide (95%CI 2.3-NA). Sex, age, surgical intervention, and concurrent irradiation and temozolomide were not associated with metastasis timing. CONCLUSION Adjuvant temozolomide administration might benefit DIPG patients by delaying metastasis, especially in those who are at higher risk for subsequent metastasis, such as those who underwent surgical intervention. However, prospective studies are warranted to confirm these results.

CNSC-34. SURGICAL INTERVENTION ASSOCIATION WITH THE DEVELOPMENT OF SUBSEQUENT DISSEMINATION IN CHILDHOOD DIFFUSE INTRINSIC PONTINE GLIOMAS (DIPG)

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is one of the most aggressive pediatric central nervous system tumors, and currently, there are no curative treatment options available. With the increasing application of molecular diagnostics, more and more DIPG patients are recommended to undergo surgery; however, its correlation with dissemination needs to be better understood. Hence, we conducted this cohort to analyze the predictors of subsequent metastasis in pediatric DIPGs. METHODS The final analysis included 142 pediatric (age ≤ 12) DIPG patients treated at Sanjiu Brain Hospital between January 2017 and September 2023. The data were retrospectively collected following the initial diagnosis. Patients were followed up for 6 months. The primary endpoint was the occurrence of subsequent metastasis. Univariable and multivariable logistic regression analyses were utilized to identify statistically significant predictors of subsequent dissemination. All statistical assessments were two-tailed, and only P < 0.05 was deemed to be statistically significant. RESULTS Among 142 patients, 14(9.9%) developed metastasis within the follow-up time. There were 77(54.2%) males and 65(45.8%) females. The median age was 7 years (ranging 1 - 12 years). The overall cohort demonstrated that surgery was the only predictor of dissemination both in univariable (OR 4.567, 95%CI 1.351 – 20.901, P = 0.024) and multivariable (OR 5.501, 95%CI 1.560 – 26.105, P = 0.014) analyses. However, subgroup analysis involving patients who received surgical intervention showed that biopsy was not superior nor inferior to resection in terms of relative risk for subsequent dissemination (16.7% vs. 15.8%). CONCLUSION Surgical intervention increases the relative risk of dissemination occurrence to four times more than those who did not receive surgery. Surgical intervention is crucial given the potential of molecular analysis leading to improved therapeutic options. Nonetheless, patients should be informed about the risks associated with surgery, including subsequent metastasis.

Immunological Pre-Metastatic Niche in Dogs With Naturally Occurring Osteosarcoma.

Pre-metastatic niche (PMN) formation is essential for metastatic development and drives organotropism. Tumour-derived extracellular vesicles and soluble factors remodel the microenvironment of distant metastatic organs before subsequent metastasis. Dogs with osteosarcoma (OS) have proven to be excellent disease models for their human companions. Here, we show evidence of PMN formation in dogs with OS before metastasis. We necropsied and sampled lung tissues from dogs with naturally occurring treatment-naïve OS (n = 15) and control dogs without cancer (n = 10). We further divided dogs with OS into those having lung metastases (n = 5) and those without (n = 10). We stained formalin-fixed paraffin-embedded tissues using multiplex immunofluorescence to quantify the number of bone marrow-derived cells, monocytes and macrophages in the lung samples from each dog. The numbers of CD204+ macrophages, CD206+ macrophages and monocytes and CD11d+ bone marrow-derived cells (BMDCs) were significantly higher in the pre-metastatic lung of dogs with OS (n = 10) than in control dogs without cancer (n = 10). Furthermore, the total nucleated cell (DAPI+) density was higher before metastasis than in healthy lungs. In dogs with established metastases, the number of CD11d+ BMDCs was significantly lower than in the pre-metastatic lung, suggesting this recruitment is transient. Our study provides evidence of PMN existence in a naturally occurring cancer model similar to those observed in pre-clinical murine models. BMDCs are recruited to the lungs before metastases have developed. Dogs with OS may represent ideal candidates for assessing new PMN-targeting therapies.

Clinical, magnetic resonance imaging, histopathological features, treatment options and outcome of spinal ependymoma in dogs: 8 cases (2011-2022).

This study aims to report on the clinical magnetic resonance imaging, histological features, treatment options and outcomes of spinal ependymomas in dogs. Retrospective evaluation of medical records from dogs histologically confirmed spinal ependymomas with clinical presentations, magnetic resonance imaging findings, histological aspects, treatment options and outcomes. Eight dogs presented with acute to subacute onset of para- or tetraparesis. Magnetic resonance imaging findings included intramedullary oval-shaped space-occupying lesions that appeared hyperintense on T2-weighted images isointense on T1-weighted images and exhibited marked homogeneous or ring contrast enhancement. A peculiar feature, previously described only in human ependymomas, was observed in three patients - a T2-weighted hypointense rim, termed hemosiderin cap sign. Haematomyelia with necrotic foci was observed in one dog. Surgery, when performed, enabling a definitive intra-vitam diagnosis. Histological examination revealed that rosettes and pseudo-rosettes as disposition of neoplastic cells were the most common features reported. Furthermore, cerebrospinal fluid metastases were identified in one case. Clinical and histopathological findings in our case series were consistent with those previously reported in the literature. Magnetic resonance imaging features were fairly typical and highly suggestive of spinal ependymomas. The hemosiderin cap sign may aid in the presumptive intra-vitam diagnosis of these rare spinal tumours. Additionally, we described cerebrospinal fluid spread of neoplastic cells and subsequent multifocal or metastasis presentations. Surgery offered a dual benefit by facilitating intra-vitam diagnosis and, in some cases, extending survival time.

Supplementation with Fish Oil and Selenium Protects Lipolytic and Thermogenic Depletion of Adipose in Cachectic Mice Treated with an EGFR Inhibitor.

Lung cancer and cachexia are the leading causes of cancer-related deaths worldwide. Cachexia is manifested by weight loss and white adipose tissue (WAT) atrophy. Limited nutritional supplements are conducive to lung cancer patients, whereas the underlying mechanisms are poorly understood. In this study, we used a murine cancer cachexia model to investigate the effects of a nutritional formula (NuF) rich in fish oil and selenium yeast as an adjuvant to enhance the drug efficacy of an EGFR inhibitor (Tarceva). In contrast to the healthy control, tumor-bearing mice exhibited severe cachexia symptoms, including tissue wasting, hypoalbuminemia, and a lower food efficiency ratio. Experimentally, Tarceva reduced pEGFR and HIF-1α expression. NuF decreased the expression of pEGFR and HIF-2α, suggesting that Tarceva and NuF act differently in prohibiting tumor growth and subsequent metastasis. NuF blocked LLC tumor-induced PTHrP and expression of thermogenic factor UCP1 and lipolytic enzymes (ATGL and HSL) in WAT. NuF attenuated tumor progression, inhibited PTHrP-induced adipose tissue browning, and maintained adipose tissue integrity by modulating heat shock protein (HSP) 72. Added together, Tarceva in synergy with NuF favorably improves cancer cachexia as well as drug efficacy.

1377P Association of anatomic proximity of brain parenchymal metastasis to the CSF space and upfront stereotactic radiosurgery to subsequent leptomeningeal metastasis development in brain metastatic NSCLC

1377P Association of anatomic proximity of brain parenchymal metastasis to the CSF space and upfront stereotactic radiosurgery to subsequent leptomeningeal metastasis development in brain metastatic NSCLC

Co-delivery of siRNA and cisplatin via electrospun Nanofibrous membranes for synergistic treatment of malignant melanoma

Tumor recurrence and metastasis remain formidable challenges in clinical oncology. Although surgery is an effective treatment for early-stage solid tumors, residual cancer cells can lead to subsequent recurrence or metastasis. Conventional treatments for melanoma, such as anti-tumor medications and gene therapy, have distinct limitations. The rapid systemic distribution of anti-tumor drugs poses a significant challenge, often resulting in notable side effects and inadequate drug concentrations at the tumor site. Melanoma (MM), a deadly form of skin cancer, is known for its high mortality rate. In this study, we propose a novel strategy for treating MM by combining the controlled release of chemotherapeutic drugs encapsulated within Metal-Organic Frameworks (MOFs) and liposomes with gene therapy targeting Minichromosome Maintenance Proteins 4 (MCM4) using electrospinning and surface modification techniques. In vitro and in vivo results confirmed that this hierarchical membrane system can effectively deliver therapeutic MCM4 siRNA and release cisplatin to inhibit tumor growth. Furthermore, we demonstrated that MCM4 silencing promoted the sensitivity of melanoma cells to ferroptosis both in vitro and in vivo. The proposed strategy, by allowing for a controlled and sustained release of medication, could alleviate the challenges in drug delivery and aid in prevent tumor recurrence.

CircRNAs expression profile and potential roles of circRERE-PMN in pre-metastatic lungs.

The successful pulmonary metastasis of malignant cancer cells depends on the survival of circulating tumor cells in a distant and hostile microenvironment. The formation of a pre-metastatic niche (PMN) creates a supportive environment for subsequent metastasis. Circular RNAs (circRNAs) are increasingly acknowledged as crucial elements in the mechanisms of metastasis due to their stable structures and functions, making them promising early metastasis detection markers. However, the specific expression patterns and roles of circRNAs in the lungs before metastasis remain largely unexplored. Our research aims to chart the circRNA expression profile and assess their impact on the lung PMN. We developed a lung PMN model and employed comprehensive RNA sequencing to analyze the differences in circRNA expression between normal and pre-metastatic lungs. We identified 38 significantly different circRNAs, primarily involved in metabolism, apoptosis, and inflammation pathways. We then focused on one specific circRNA, circ:chr4:150406196 - 150406664 (circRERE-PMN), which exhibited a significant change in expression and was prevalent in myeloid-derived suppressor cells (MDSCs), alveolar epithelial cells, and macrophages within the pre-metastatic lung environment. CircRERE-PMN was found to potentially regulate apoptosis and the expression of cytokines and chemokines through its interaction with the downstream target HUR in alveolar epithelial cells. Overall, our study highlights the crucial role of circRNAs in the formation of lung PMNs, supporting their potential as diagnostic or therapeutic targets for lung metastasis.

Uterine tumors mimicking ovarian sex cord tumors with rhabdoid differentiation: a clinicopathologic study of 4 cases: A case series analysis.

Uterine tumors resembling ovarian sex cord tumors (UTROSCT) with rhabdoid features are uncommon mesenchymal neoplasms exhibiting diverse histological patterns, including significant rhabdoid morphology. A thorough comprehension of their clinicopathologic features is crucial for precise diagnosis and effective management. This study presents 4 cases of UTROSCT with rhabdoid features, diagnosed in patients aged 31 to 58. Varied recurrence patterns were observed, including similar recurrent lesions to the primary tumors with subsequent mortality, initial invasion and lymph node metastasis, and presence of only primary tumor. Histopathological examination revealed diverse morphological patterns, prominently featuring rhabdoid differentiation. Immunohistochemical analysis showed expression of hormone receptors, sex cord, smooth muscle, and epithelial markers, notably WT1, CD56, and CD99. Molecular analysis identified ESR1-NCOA2 fusions and ESR1 and NCOA2/3 rearrangements, indicating a potential association between these genetic alterations and extensive rhabdoid differentiation. Various treatments were administered post-recurrence, including chemotherapy and targeted therapies. However, poor clinical outcomes were observed in all cases. Despite aggressive treatments, including chemotherapy and targeted therapies, poor clinical outcomes were observed, highlighting the aggressive nature of UTROSCT with significant rhabdoid differentiation. This case series emphasizes the importance of detailed pathological reporting, comprehensive molecular testing, and thorough tumor staging in UTROSCT cases with rhabdoid features. Enhanced understanding of the clinicopathologic characteristics of UTROSCT with rhabdoid differentiation is crucial for accurate diagnosis, prognostication, and management strategies.

Dynamic cell culture modulates colon cancer cell migration in a novel 3D cell culture system

The progression of cancer cell migration, invasion and subsequent metastasis is the main cause of mortality in cancer patients. Through creating more accurate cancer models, we can achieve more precise results, which will lead to a better understanding of the invasion process. This holds promise for more effective prevention and treatment strategies. Although numerous 2D and 3D cell culture systems have been developed, they poorly reflect the in vivo situation and many questions have remained unanswered. This work describes a novel dynamic 3D cell culture system aimed at advancing our comprehension of cancer cell migration. With the newly designed cultivation chamber, 3D tumor spheroids were cultivated within a collagen I matrix in the presence of fluid flow to study the migration of cancer cells from spheroids in the matrix. Using light sheet microscopy and histology, we demonstrated that the morphology of spheroids is influenced by dynamic culture and that, in contrast to static culture, spheroids in dynamic culture are characterized by the absence of a large necrotic core. Additionally, this influence extends to an increase in the size of migration area, coupled with an increase in expression of some genes related to epithelial-mesenchymal transition (EMT). The results here highlight the importance of dynamic culture in cancer research. Although the dynamic 3D cell culture system in this study was used to investigate migration of one cell type into a matrix, it has the potential to be further developed and used for more complex models consisting of different cell types or to analyze other steps of metastasis development such as transendothelial migration or extravasation.

Tumor-derived exosomal ICAM1 promotes bone metastasis of triple-negative breast cancer by inducing CD8+ T cell exhaustion

Exosomes, which are nanosized extracellular vesicles, have emerged as crucial mediators of the crosstalk between tumor cells and the immune system. Intercellular adhesion molecule 1 (ICAM1) plays a crucial role in multiple immune functions as well as in the occurrence, development and metastasis of cancer. As a glycoprotein expressed on the cell membrane, ICAM1 is secreted extracellularly on exosomes and regulates the immunosuppressive microenvironment. However, the role of exosomal ICAM1 in the immune microenvironment of breast cancer bone metastases remains unclear. This study aimed to elucidated the role of exosomal ICAM1 in facilitating CD8+ T cell exhaustion and subsequent bone metastasis in triple-negative breast cancer (TNBC). We demonstrated that TNBC cells release ICAM1-enriched exosomes, and the binding of ICAM1 to its receptor is necessary for the suppressive effect of CD8 T cell proliferation and function. This pivotal engagement not only inhibits CD8+ T cell proliferation and activation but also initiates the development of an immunosuppressive microenvironment that is conducive to TNBC tumor growth and bone metastasis. Moreover, ICAM1 blockade significantly impairs the ability of tumor exosomes to bind to CD8+ T cells, thereby inhibiting their immunosuppressive effects. The present study elucidates the complex interaction between primary tumors and the immune system that is mediated by exosomes and provides a foundation for the development of novel cancer immunotherapies that target ICAM1 with the aim of mitigating TNBC bone metastasis.

Photothermal Temperature-Modulated Cancer Metastasis Harnessed Using Proteinase-Triggered Assembly of Near-Infrared II Photoacoustic/Photothermal Nanotheranostics.

Here we demonstrate that cancer metastasis could be modulated by the judicious tuning of physical parameters such as photothermal temperature in nanoparticle-mediated photothermal therapy (PTT). This is supported by theranostic nanosystem design and characterization, in vitro and in vivo analyses, and transcriptome-based gene profiling. In this work, the highly efficient near-infrared II (NIR-II) photoacoustic image (PA)-guided PTT are selectively activated using our developed matrix metalloproteinase (MMP)-triggered in situ assembly of gold nanodandelions (GNDs@gelatin). Unlike other "always-on" NIR PTT agents lacking specific bioactivation and suffering from the intrinsic nonspecific pseudosignals and treatment-related side effects such as metastasis, our GNDs@gelatin possesses important advantages while deployed in cancer PTT that include the following: (1) The theranostic effects could be "turned on" only after specific MMP-2/-9 activity and with acidity in the tumor microenvironment. (2) The quantitative PA diagnosis allows for precise PTT planning for better cancer treatment. (3) GNDs@gelatin could noninvasively quantify MMP activity and efficiently harness NIR-I (808 nm) and NIR-II (1064 nm) energies for tumor ablation. (4) The multibranched nanostructures reabsorb scattered laser photons, thus enhancing the surface plasmons for the pronounced photothermal conversion of aggregated GNDs@gelatin in situ. (5) It is noteworthy that in situ tumor eradication at higher PTT temperature (>55 °C) mediated by GNDs@gelatin could induce subsequent metastasis, which could be otherwise abolished at lower PTT temperatures (50 °C > T > 43 °C). (6) Furthermore, the gene profiling using transcriptome-based microarray including GO and KEGG analyses revealed that 315 differentially expressed genes were identified in higher PTT temperature treated tumors compared with lower PTT temperature ones. These were enriched into some well-known cancer-related pathways, such as cell migration pathway, signal transductions, cell proliferation, wound healing, PPAR signaling, and metabolic pathways. These observations suggest a new perspective of "moderate-is-better" in nanoparticle-mediated PTT for maximizing its therapeutic/prognosis benefits and translational potential with metastasis inhibition.

Parecoxib and 5-Fluorouracil Synergistically Inhibit EMT and Subsequent Metastasis in Colorectal Cancer by Targeting PI3K/Akt/NF-κB Signaling.

Colorectal cancer is one of the most common causes of cancer mortality worldwide, and innovative drugs for the treatment of colorectal cancer are continually being developed. 5-Fluorouracil (5-FU) is a common clinical chemotherapeutic drug. Acquired resistance to 5-FU is a clinical challenge in colorectal cancer treatment. Parecoxib is a selective COX-2-specific inhibitor that was demonstrated to inhibit metastasis in colorectal cancers in our previous study. This study aimed to investigate the synergistic antimetastatic activities of parecoxib to 5-FU in human colorectal cancer cells and determine the underlying mechanisms. Parecoxib and 5-FU synergistically suppressed metastasis in colorectal cancer cells. Treatment with the parecoxib/5-FU combination induced an increase in E-cadherin and decrease in β-catenin expression. The parecoxib/5-FU combination inhibited MMP-9 activity, and the NF-κB pathway was suppressed as well. Mechanistic analysis denoted that the parecoxib/5-FU combination hindered the essential molecules of the PI3K/Akt route to obstruct metastatic colorectal cancer. Furthermore, the parecoxib/5-FU combination could inhibit reactive oxygen species. Our work showed the antimetastatic capacity of the parecoxib/5-FU combination for treating colorectal cancers via the targeting of the PI3K/Akt/NF-κB pathway.

Magnetic resonance imaging-based prognostic model for subsequent distant metastasis in patients with ipsilateral breast tumor recurrence following breast-conserving surgery.

Ipsilateral breast tumor recurrence (IBTR) following breast-conserving surgery (BCS) has been considered a risk factor for distant metastasis (DM). Limited data are available regarding the subsequent outcomes after IBTR. Therefore, this study aimed to determine the clinical course after IBTR and develop a magnetic resonance imaging (MRI)-based predictive model for subsequent DM. We retrospectively extracted quantitative features from MRI to construct a radiomics cohort, with all eligible patients undergoing preoperative MRI at time of primary tumor and IBTR between 2010 and 2018. Multivariate Cox analysis was performed to identify factors associated with DM. Three models were constructed using different sets of clinicopathological, qualitative, and quantitative MRI features and compared. Additionally, Kaplan-Meier analysis was performed to assess the prognostic value of the optimal model. Among the 183 patients who experienced IBTR, 47 who underwent MRI for both primary and recurrent tumors were enrolled. Multivariate analysis demonstrated that the independent prognostic factors were human epidermal growth factor receptor 2 (HER2) status [hazard ratio (HR) =5.40] and background parenchymal enhancement (BPE) (HR =7.94) (all P values <0.01). Furthermore, four quantitative MRI features of recurrent tumors were selected through the least absolute shrinkage and selection operator (LASSO) method. The combined model exhibited superior performance [concordance index (C-index) 0.77] compared to the clinicoradiological model (C-index 0.71; P=0.006) and radiomics model (C-index 0.70; and P=0.01). Furthermore, the combined model successfully categorized patients into low- and high-risk subgroups with distinct prognoses (P<0.001). The clinicopathological and MRI features of IBTR were associated with secondary events following surgery. Additionally, the MRI-based combined model exhibited the highest predictive efficacy. These findings could be helpful in risk stratification and tailoring follow-up strategies in patients with IBTR.

Assessment of Molecular Markers in Pediatric Ovarian Tumors: Romanian Single-Center Experience.

Pediatric ovarian tumors exhibit unique diagnostic and therapeutic challenges. This study evaluates the expression of SALL4 and OCT3/4 biomarkers in pediatric ovarian tumors and their associations with tumor subtype, stage, and clinical outcome. A retrospective analysis was conducted on 64 patients under 18 years old, examining demographic data, tumor characteristics, immunohistochemical staining, and clinical outcomes. Our results show that SALL4 was significantly expressed in adenocarcinoma, dysgerminoma (DSG), mixed germ cell tumors (GCTs), and immature teratoma, while OCT3/4 was highly expressed in DSG and mixed GCTs. Both markers are associated with a higher tumor grade and stage, indicating a more aggressive disease. The SALL4 positivity expression was correlated with high alpha fetoprotein (AFP) and lactate dehydrogenase (LDH) levels, while OCT3/4 positivity significantly predicted the risk of subsequent metastasis. The mean progression-free survival (PFS) was notably shorter in patients with positive markers. These findings underscore the diagnostic and prognostic value of SALL4 and OCT3/4 in pediatric ovarian tumors, aligning with previous research and supporting their use in clinical practice for better disease management and patient outcomes.

DIPG-20. SURGICAL INTERVENTION’S CORRELATION WITH SUBSEQUENT METASTASIS DEVELOPMENT IN CHILDREN WITH DIFFUSE INTRINSIC PONTINE GLIOMAS (DIPG)

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brain tumor with a poor prognosis. Currently, there is no curative treatment option available for these patients. These patients often undergo surgery to confirm the diagnosis pathologically. However, the relationship between surgery and dissemination is to be confirmed. This retrospective cohort determines if surgical intervention increases the risk of dissemination and what other factors may also be associated. METHODS The final analysis included 142 pediatric (age ≤ 12) DIPG patients treated at Sanjiu Brain Hospital between January 2017 and June 2023. The data were retrospectively collected following the initial diagnosis. The diagnosis was established based on imaging studies. Three radiologists analyzed the imaging data. The endpoint was the occurrence of subsequent metastasis. Univariable and multivariable logistic regressions were performed to identify predictors of subsequent dissemination. All statistical assessments were two-tailed; only P &amp;lt; 0.05 was considered statistically significant. RESULTS Of 142 patients, 28 (19.7%) developed metastasis, and 114 (80.3%) had no evidence of metastasis. There were 77 (54.2%) males and 65 (45.8%) females. The patients’ median age was 7 years (1-12 yrs.). Patients were followed up for at least 6 months or until they developed subsequent metastasis or died without developing metastasis. Univariate logistic regression analysis demonstrated that surgery (OR 4.277, 95%CI 1.753 - 11.607, P=0.002), adjuvant temozolomide (OR 2.891, 95%CI 1.097 - 9.106, P=0.045), and adjuvant bevacizumab (OR 10.278, 95%CI 3.759 - 9.444, P=0.003) were the potential predictor of metastasis development. Multivariate logistic regression analysis showed that surgery (OR 5.061, 95%CI 1.966 - 14.508, P=0.001) and administration of adjuvant bevacizumab (OR 3.020, 95%CI 1.196 - 8.065, P=0.022) were the independent predictors of dissemination. CONCLUSION Surgery and adjuvant bevacizumab may increase the risk of subsequent metastasis in the pediatric DIPG population.

Immunotherapy-based neoadjuvant therapy followed by concurrent chemoradiotherapy in locally advanced and advanced cervical cancer: A real-world study.

e17509 Background: Locally advanced and advanced cervical cancer (CC), characterized by extensive local invasion and potential distant metastasis, present substantial clinical challenges. Although concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced CC, a considerable proportion (23%-34%) of treated pts experienced recurrence or subsequent metastasis. Recently, neoadjuvant therapy (NAT) has been proposed to increase the radiosensitivity and decreases the fraction of hypoxic cells. Particularly, immunotherapy (IO)-based NAT has shown high activity in treating CC. Moreover, IO plus CRT has shown promise in enhancing both local control and systemic response. Hence, we analyzed the efficacy and safety of IO-based NAT followed by CCRT for locally advanced and advanced CC in a real-world setting. Methods: This study retrospectively analyzed data from pts with locally advanced and advanced CC who underwent IO-based NAT followed by CCRT at Shengjing Hospital of China Medical University from January 2022 to January 2024. Outcome measures included complete response (CR), partial response (PR), objective response rate (ORR), progression free survival (PFS), and safety. Tumor responses after neoadjuvant or CCRT therapy were evaluated using RECIST v1.1 and PFS was analyzed with the Kaplan-Meir method. Safety was assessed by adverse events (AEs) referring to CTCAEs v 5.0. Results: A total of 20 pts (median age 57 years, range, 39-72) were included in this analysis, with 15% at stage IIIB, 60% at IIIC, 10% at IVA, and 15% at IVB. Eight (40%) pts received 1 cycle of neoadjuvant IO, 8 (40%) received 1-4 cycles of neoadjuvant IO + chemotherapy, and 4 (20%) received 2 cycles of neoadjuvant IO + bevacizumab (Bev) + chemotherapy. After NAT, all 20 pts received CCRT. In the overall population, ORR after NAT was 55% (11/20), with 5% CR and 50% PR. Regarding different IO-based NAT regimens, objective responses were achieved in 1 of 8 (12.5%) pts receiving neoadjuvant IO, 6 of 8 (75%) pts receiving neoadjuvant IO + chemotherapy, and 4 of 4 (100%) pts receiving neoadjuvant IO + Bev + chemotherapy. After CCRT, 6 (30%) pts had a CR and 7 (35%) pts had a PR, resulting in an ORR of 65.0%. At a median follow-up of 14.9 months, the median PFS was not reached, with a 12-month and 24-month PFS rates of 68% and 56%, respectively. The most common treatment-related AEs during NAT were white blood cell count decreased (50%) and neutrophil count decreased. Conclusions: IO-based NAT followed by CCRT were effective and well-tolerated for pts with locally advanced and advanced CC. This treatment modalities may provide a potential therapeutic strategy for locally advanced and advanced CC.

Prognostic significance of SIRI in patients with late-stage lung adenocarcinoma receiving EGFR-TKI treatment

ObjectiveIn this study, we examined the relationship between the Systemic Inflammatory Response Index (SIRI) and the overall prognosis of patients with late-stage lung adenocarcinoma who harbor epidermal growth factor receptor (EGFR) mutations and are undergoing first-line treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKIs). MethodsA cohort comprising 52 patients with late-stage lung adenocarcinoma, who received treatment at Jinzhou Central Hospital between January 2018 and December 2022, were carefully selected. Patient data spanning from pre-treatment assessments through follow-up periods were meticulously collected from electronic medical records and subsequently subjected to a comprehensive retrospective analysis. The collected data was subjected to in-depth processing and analyzed using SPSS 27.0 statistical software. To determine the optimal cut-off value of the pre-treatment SIRI, a receiver operating characteristic (ROC) curve was employed. Survival analysis was performed using the Kaplan-Meier method, and both univariate and multivariate prognostic analyses were conducted using Cox regression. ResultsThe optimal SIRI cut-off value was determined to be 1.659 (with a specificity of 0.964 and sensitivity of 0.652, P = 0.000). Based on this value, patients were categorized into high and low SIRI groups. Chi-squared tests demonstrated that SIRI exhibited statistically significant correlations with patient age and smoking history (P < 0.05). Survival analysis revealed that the group with a lower SIRI had a significantly extended progression-free survival (PFS) (P < 0.001). Cox univariate analysis identified hypertension, pleural metastasis, liver metastasis, and SIRI as factors associated with PFS (P < 0.05). In the subsequent multivariate analysis, liver metastasis and SIRI ≥ 1.659 (P < 0.001) were identified as independent risk factors for patients. ConclusionPre-treatment SIRI holds predictive significance for the prognosis of patients with late-stage lung adenocarcinoma with EGFR mutations undergoing first-line treatment EGFR-TKI treatment.

Abstract PO2-02-13: A Mechanical Conditioning gene expression (MeCo) score detects the patients that benefit from neoadjuvant anti-fibrotic therapy in early HER2-negative breast cancer (HER2negBC)

Abstract Background: Extracellular matrix (ECM) stiffness in the tumor microenvironment is associated with aggressive features that lead to adverse clinical outcomes, including metastasis. Mechanical conditioning (MC) is the phenomenon whereby cancer cells that have grown in a fibrotic-like stiff ECM acquire aggressive features which can be maintained after metastasis in distant sites (Cell Rep.; 35:109293). MeCo Score is a gene expression signature that measures the response to ECM stiffness in early tumors which is associated with subsequent metastasis. We sought to study whether MeCo Score is associated with pathologic complete response (pCR) in early HER2negBC, and whether anti-fibrotic treatment with nintedanib (a multikinase VEGFR1-3, FGFR1-3 and PDGFRA/B inhibitor approved for idiopathic lung fibrosis) is able to mitigate the impact of MC. Methods: Baseline tumor samples from patients (N=130) from a randomized phase II clinical trial (Clin Cancer Res 23: 1432-42) in early HER2negBC trial comparing weekly paclitaxel monotherapy (85 mg/m2 x 12 courses; N=65; Arm A) versus the same treatment plus nintedanib (150 mg p.o. bid, continuous schedule; Arm B) were analyzed by RNAseq. MeCo Score was computed as previous described (Cell Rep.; 35:109293), and intrinsic PAM50 subtypes were determined using the R package genefu. Clinical, demographic and pathologic variables were gathered for all patients; pCR was graded according to the Residual Cancer Burden (RCB) score, RCB=0. Regression models were built using the variables RCB, T, N, G, age, intrinsic subtype, Ki67, MeCo Score and treatment arm. Bi-variate correlations were analyzed with the Pearson coefficient. All statistic tests were two-sided. Results: MeCo Score was successfully determined in 76 women (50% from each arm); the average score was 0.34 (range: 0.052 – 0.617). Of them, 48.6% were Luminal A, 34.2% Luminal B, 14.5% Basal-like, and 2.7% Normal according to PAM50. Median age was 49 y.o. (range: 30.6 – 79.2); tumor size distribution was T1:3.0%; T2:68.2%; T3:24.3%; T4: 4.5%; 47% of the patients were N0, 47% were N1 and 6% were N2. Most patients (85%) were ER and/or PR positive; 15% were “triple-negative”. Histological grade distribution was G1/G2/G3: 15%/62%/23%. The average Ki67 was 28.7% (range: 1%-98%). pCR was 10.8% and 4.5% in arms A and B. The average MeCo Score by intrinsic subtype was 0.26 (LumA); 0.43 (LumB) and 0.38 (Basal), LumB vs LumA P&amp;lt; 0.001; LumB vs Basal: P=0.037. We did not find correlation between MeCo Score and G, T, N, age or Ki67, neither in the Luminal subgroup or the whole cohort. In Arm A, patients with high MeCo Score (i.e., above median) had a 0% pCR rate compared to 10.5% pCR rate for those with low MeCo Score (P=0.035); however, in the nintedanib arm (Arm B) no differences were found: 10.5% versus 11.1% pCR rate in high versus low MeCo Score (P=0.4). Conclusions: Among early HER2negBC, Luminal B cases display the highest MeCo Scores. MeCo Score was independent of all classic prognostic variables. High MeCo Score is associated with lack of pCR to neoadjuvant paclitaxel monotherapy, but concurrent administration of the anti-fibrotic agent nintedanib rescues this association. Citation Format: Miguel Quintela-Fandino, Adam Watson, Adam Grant, Gus Mouneimne, Maria J. Bueno, Silvana Mouron. A Mechanical Conditioning gene expression (MeCo) score detects the patients that benefit from neoadjuvant anti-fibrotic therapy in early HER2-negative breast cancer (HER2negBC) [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 PO2-02-13.