Tumor Metastatic Potential Research Articles

ZNF224 is a mediator of TGF-β pro-oncogenic function in melanoma.

The zinc finger protein ZNF224 plays a dual role in cancer, operating as both tumour suppressor and oncogenic factor depending on cellular and molecular partners. In this research we investigated the role of ZNF224 in melanoma, a highly invasive and metastatic cancer, and provided evidence for the involvement of ZNF224 in the TGF-β signalling as a mediator of the TGF-β pro-oncogenic function. Our results showed that ZNF224, whose expression increased in melanoma cell lines after TGF-β stimulation, potentiated the activation induced by TGF-β on its target genes involved in epithelial-mesenchymal transition (EMT). Accordingly, overexpression of ZNF224 enhanced the tumourigenic properties of melanoma cells, promoting cell proliferation and invasiveness, whereas ZNF224 knockdown had the opposite effect. Moreover, ZNF224 positively modulates the expression of TGF-β itself and its type 1 and 2 receptors (TβR1 and TβR2), thus highlighting a possible mechanism by which ZNF224 could enhance the endogenous TGFβ/Smad signalling. Our findings unveil a positive regulatory loop between TGF-β and ZNF224 to promote EMT, consequently increasing the tumour metastatic potential.

Surgery for pancreatic tumors in the midst of COVID-19 pandemic.

The spread of the new coronavirus (COVID-19) infection in 2020 has had a significant impact on the treatment of cancer worldwide. During the COVID-19 pandemic, the biggest challenge for pancreatic surgeons is the difficulty in providing oncological care. In this review article, from the standpoint of surgeons, we explain the concept of triaging of patients with pancreatic tumors under the COVID-19 pandemic, and the actual impact of COVID-19 on the treatment of patients with pancreatic tumors. The most vital points in selecting the best therapeutic approach for patients with pancreatic tumors during this pandemic are (1) Oncologists need to tailor the treatment plan based on the COVID-19 phase, tumor malignant potential, and patients’ comorbidities; and (2) Optimal treatment for pancreatic cancer should be planned according to the condition of each patient and tumor resectability based on national comprehensive cancer network resectability criteria. To choose the best therapeutic approach for patients with pancreatic tumors during this pandemic, we need to tailor the treatment plan based on elective surgery acuity scale (ESAS). Newly established ESAS for pancreatic tumor and flowchart indicating the treatment strategy of pancreatic cancer, are feasible to overcome this situation.

The oncogene and coagulome

Cancer is the second-leading cause of death globally, predominantly due to metastasis – the escape of tumour cells from their initial to a distant site. Importantly, thromboembolism associated with cancer is the second-leading cause of cancer mortality, and in non-fatal events, a major contributor to morbidity, interruption to therapy and healthcare resource utilisation. Adding to the complexity, patients with cancer are also at high risk of haemorrhagic events during the course of their disease and treatment. Further understanding of haemostatic dysregulation is a significant unmet need in oncology. The pathogenesis is complex and involves the interplay of multiple factors. However, there is growing evidence that interactions between malignancies and the coagulation system are not random but represent coordinated and clinically-significant adaptations that enhance tumour cell survival, proliferation and metastatic potential. Hence understanding the interactions between haemostatic systems, vascular stroma and metastasis may not only provide insight into strategies that could potentially reduce the incidence of thrombohaemorrhagic events, but also help design strategies that are capable of modifying tumour biology and metastatic potential, and thereby improve overall survival. This presentation will provide an overview of biological and clinical evidence linking oncogenic signalling and coagulation phenotypes, and the opportunity for impact.

Fumarate Hydratase Deficiency Should be Considered in the Differential Diagnosis of Uterine and Extrauterine Smooth Muscle Tumors of Uncertain Malignant Potential (STUMP).

Fumarate hydratase-deficient leiomyomas (dFH leiomyomas) often display atypical pathologic features yet exhibit a benign clinical course. Recent data suggest that dFH leiomyomas may be misclassified as smooth muscle tumors of uncertain malignant potential, a category that encompasses a heterogenous subgroup of uterine neoplasms with smooth muscle differentiation and atypical features that impart ambiguity regarding their expected clinical behavior. dFH leiomyomas can be seen in the context of hereditary leiomyomatosis and renal cell carcinoma syndrome or in the sporadic setting. In this retrospective study, we sought to examine the prevalence and clinicopathologic characteristics of dFH leiomyomas in 48 tumors previously diagnosed as smooth muscle tumors of uncertain malignant potential from 38 patients. Of these 48 tumors, 3 (6.3%) occurring in 2 patients were found to be deficient for FH by immunohistochemistry, including 1 uterine and 2 extrauterine (abdominopelvic) tumors. The 3 tumors showed histologic features typical of dFH leiomyomas, including hemangiopericytoma-like vessels, edema, macronucleoli, and atypia. Neither patient developed recurrent leiomyomas or renal cell carcinoma, and both were alive without disease at last follow-up. Our data suggest that dFH leiomyomas should be considered in the differential diagnosis of smooth muscle tumors of uncertain malignant potential, even in the context of extrauterine disease. Identification of FH deficiency in these tumors supports their classification as dFH leiomyomas despite their atypical morphologic features and/or clinical presentation. Importantly, detection of dFH in these cases may identify women at increased risk for hereditary leiomyomatosis and renal cell carcinoma who would benefit from genetic counseling and consideration for FH germline testing.

Association between cancer stem cell marker ALDH1 and clinical and morphological factors of colorectal cancer prognosis.

3522 Background: Cancer stem cells (CSCs) capable of self-sustaining and multipotent differentiation are considered among the most important factors limiting treatment effectiveness. ALDH1 is a marker of colorectal cancer (CRC) CSCs; it is involved in cell differentiation and proliferation, determines resistance to alkylating chemotherapeutic agents, and also induces epithelial-mesenchymal transition (EMT), which increases the invasive and metastatic potential of tumors. The purpose of the study was to assess the association between the expression of the ALDH1 CSC marker in tissues of CRC of different stages and clinical and morphological factors of the disease prognosis. Methods: The study included 299 patients (aged 42-86 years, mean age 64.2±1.7) with stage II-IV CRC T1-4N0-2M0-1; histologically verified G1-G3 adenocarcinoma in all patients. Tissues of surgically removed tumors were studied with IHC analysis using mouse monoclonal anti-ALDH1 antibodies (clone B-5, Santa Cruz Biotechnology) diluted 1:1800 and the Reveal Polyvalent HRP-DAB Detection System. The percentage of cells positively stained for ALDH1 among all tumor cells was assessed. Statistical analysis was performed using the STATISTICA 13.0 program (StatSoftInc., USA). Results: Positive ALDH1+ expression was registered in 52.5% of all patients, negative expression – in 47.5%. Statistically significant association was observed between the ALDH1 expression and the CRC stage, since the ALDH1+ expression increased from stage II to stage IV (p = 0.003). The ALDH1 expression was statistically significantly associated with the depth of tumor invasion (p = 0.018) and the presence of distant metastases (p < 0.001). No significant relationship was observed between the ALDH1 expression and regional lymph node metastasis (p = 0.788). Statistically significant association was registered between the ALDH1 expression and the tumor grade (p < 0.001), perineural invasion (p = 0.010) and lymphocytic infiltration (p < 0.001). No significant relationship was observed between the tumor histological structure (p = 0.979), lymphovascular invasion (p = 0.772) and ALDH1 expression. Tumor site was not statistically significantly associated with ALDH1 expression (p = 0.349). Conclusions: The study demonstrated statistically significant association between the ALDH1 expression and clinical and morphological characteristics of CRC, determining invasive and metastatic potential of the tumor, and ALDH1 may be an independent prognostic factor and a new therapeutic target for the regulation of the progression process.

Re-evaluating tumors of purported specialized prostatic stromal origin reveals molecular heterogeneity, including non-recurring gene fusions characteristic of uterine and soft tissue sarcoma subtypes.

Tumors of purported specialized prostatic stromal origin comprise prostatic stromal sarcomas (PSS) and stromal tumors of uncertain malignant potential (STUMP). Prior studies have described their clinicopathologic characteristics, but the molecular features remain incompletely understood. Moreover, these neoplasms are morphologically heterogeneous and the lack of specific adjunctive markers of prostatic stromal lineage make precise definition more difficult, leading some to question whether they represent a specific tumor type. In this study, we used next-generation DNA and RNA sequencing to profile 25 primary prostatic mesenchymal neoplasms of possible specialized prostatic stromal origin, including cases originally diagnosed as PSS (11) and STUMP (14). Morphologically, the series comprised 20 cases with solid architecture (11 PSS and 9 STUMP) and 5 cases with phyllodes-like growth pattern (all STUMP). Combined DNA and RNA sequencing results demonstrated that 19/22 (86%) cases that underwent successful sequencing (either DNA or RNA) harbored pathogenic somatic variants. Except for TP53 alterations (6 cases), ATRX mutations (2 cases), and a few copy number variants (-13q, -14q, -16q and +8/8p), the findings were largely nonrecurrent. Eight gene rearrangements were found, and 4 (NAB2-STAT6, JAZF1-SUZ12, TPM3-NTRK1 and BCOR-MAML3) were useful for reclassification of the cases as specific entities. The present study shows that mesenchymal neoplasms of the prostate are morphologically and molecularly heterogeneous and include neoplasms that harbor genetic aberrations seen in specific mesenchymal tumors arising in other anatomic sites, including soft tissue and the uterus. These data suggest that tumors of purported specialized prostatic stromal origin may perhaps not represent a single diagnostic entity or specific disease group and that alternative diagnoses should be carefully considered.

Concept of Keesa-e-Khusyat-ur-Rahem (Ovarian Cyst) in Unani medicine: A review

The ovaries are pelvic organ found in the female reproductive system situated at either side of the uterus that produces an ovum and the hormones. Hormones which are released by ovaries are estrogen and progesterone. These hormones responsible for growth of the female genital organs like breast, body shape, body hair, menstrual and pregnancy. There are so many diseases occur in the ovaries like Endometriosis, Ovarian cyst, Cancer, Ovarian, Ovarian Low Malignant Potential Tumor. In Unani system of the medicine the terminology for Keesa-e-Khusyat-ur-Rahem (Ovarian cyst). Disease not have been defined under the heading of Ovarain cyst as disease has been categorized recently just a century before. The description of the disease has been described by various Unani physicians under the heading of Ehtabas-Tams (Amenorrhoea). Uterine disorders mainly occur due to Su-e-Mizaj-e-Rahem (Abnormal temperament of the uterus) which is also responsible for formation of Su-e-Mizaj-e-Khusyat-ur-Reham (Abnormal temperament of the ovaries). According to the theory of the four Akhlat (Humours). Main Khilt for the development of the Ehtabas-Tams (Amenorrohea) is phlegm and black bile. Phlegm is responsible for the development of the Kees formation in the Khusyat-ur-Rahem.

Smooth Muscle Tumor of Uncertain Malignant Potential Arising from Renal Vein

Smooth muscle tumors (SMTs) typically fall under either benign leiomyoma or malignant leiomyosarcomas based on histologic characteristics. SMTs that cannot be diagnosed as benign or malignant are then labeled as smooth muscle tumors of uncertain malignant potential (STUMP). A 31-year-old male presented with the right abdominal pain for 6 months. Imaging showed an enhancing soft-tissue mass arising from the right renal vein. A pre-operative biopsy confirmed STUMP of renal vein, and the patient underwent surgical resection of the mass with partial nephrectomy. Imaging and pathologic findings play a crucial role in an accurate pre-procedural diagnosis of unusual SMTs.

Dysregulated Immunological Functionome and Dysfunctional Metabolic Pathway Recognized for the Pathogenesis of Borderline Ovarian Tumors by Integrative Polygenic Analytics.

The pathogenesis and molecular mechanisms of ovarian low malignant potential (LMP) tumors or borderline ovarian tumors (BOTs) have not been fully elucidated to date. Surgery remains the cornerstone of treatment for this disease, and diagnosis is mainly made by histopathology to date. However, there is no integrated analysis investigating the tumorigenesis of BOTs with open experimental data. Therefore, we first utilized a functionome-based speculative model from the aggregated obtainable datasets to explore the expression profiling data among all BOTs and two major subtypes of BOTs, serous BOTs (SBOTs) and mucinous BOTs (MBOTs), by analyzing the functional regularity patterns and clustering the separate gene sets. We next prospected and assembled the association between these targeted biomolecular functions and their related genes. Our research found that BOTs can be accurately recognized by gene expression profiles by means of integrative polygenic analytics among all BOTs, SBOTs, and MBOTs; the results exhibited the top 41 common dysregulated biomolecular functions, which were sorted into four major categories: immune and inflammatory response-related functions, cell membrane- and transporter-related functions, cell cycle- and signaling-related functions, and cell metabolism-related functions, which were the key elements involved in its pathogenesis. In contrast to previous research, we identified 19 representative genes from the above classified categories (IL6, CCR2 for immune and inflammatory response-related functions; IFNG, ATP1B1, GAS6, and PSEN1 for cell membrane- and transporter-related functions; CTNNB1, GATA3, and IL1B for cell cycle- and signaling-related functions; and AKT1, SIRT1, IL4, PDGFB, MAPK3, SRC, TWIST1, TGFB1, ADIPOQ, and PPARGC1A for cell metabolism-related functions) that were relevant in the cause and development of BOTs. We also noticed that a dysfunctional pathway of galactose catabolism had taken place among all BOTs, SBOTs, and MBOTs from the analyzed gene set databases of canonical pathways. With the help of immunostaining, we verified significantly higher performance of interleukin 6 (IL6) and galactose-1-phosphate uridylyltransferase (GALT) among BOTs than the controls. In conclusion, a bioinformatic platform of gene-set integrative molecular functionomes and biophysiological pathways was constructed in this study to interpret the complicated pathogenic pathways of BOTs, and these important findings demonstrated the dysregulated immunological functionome and dysfunctional metabolic pathway as potential roles during the tumorigenesis of BOTs and may be helpful for the diagnosis and therapy of BOTs in the future.

CORRELATION OF BIOPSY AND AgNOR COUNTS IN PREMALIGNANT AND MALIGNANT LESIONS OF CERVIX

Background- Cervical cancer is the commonest cancer among women in developing countries. Screening methods like cervical cytology has brought down the incidence of cervical cancer. AgNOR represents Nucleolar organizer regions stained with silver and are related to cell proliferation rate and tumor malignant potential. The present study was aimed at evaluating the diagnostic role of AgNOR in cervical carcinogenesis. Material and Methods- The present study was conducted in the Pathology department of Gajra Raja Medical College, Gwalior from January 2019 to May 2020 on 500 patients who attended the Gynae OPD. Women of suspected cervical pathology and who underwent Pap smear test followed by subsequent biopsies were included. Results- AgNOR count in chronic cervicitis was 2.72±0.32, in CIN I was 4.02±0.38, in CIN II was 5.47±0.21 in CIN III was 5.59±0.18, in Well differentiated KSCC was 6.48±0.40 and in adenocarcinoma was 6.93±0.21. The study showed that the mean AgNOR count per nucleus was signicantly higher in CIN and malignant cervical lesions. Conclusion- AgNOR count is reproducible, simple, efcient and inexpensive method which can be used as an adjunct to histopathology and cytology especially in differentiating doubtful cases of CIN.

Identification of potential markers for differentiating epithelial ovarian cancer from ovarian low malignant potential tumors through integrated bioinformatics analysis

BackgroundEpithelial ovarian cancer (EOC), as a lethal malignancy in women, is often diagnosed as advanced stages. In contrast, intermediating between benign and malignant tumors, ovarian low malignant potential (LMP) tumors show a good prognosis. However, the differential diagnosis of the two diseases is not ideal, resulting in delays or unnecessary therapies. Therefore, unveiling the molecular differences between LMP and EOC may contribute to differential diagnosis and novel therapeutic and preventive policies development for EOC.MethodsIn this study, three microarray data (GSE9899, GSE57477 and GSE27651) were used to explore the differentially expressed genes (DEGs) between LMP and EOC samples. Then, 5 genes were screened by protein–protein interaction (PPI) network, receiver operating characteristic (ROC), survival and Pearson correlation analysis. Meanwhile, chemical-core gene network construction was performed to identify the potential drugs or risk factors for EOC based on 5 core genes. Finally, we also identified the potential function of the 5 genes for EOC through pathway analysis.ResultsTwo hundred thirty-four DEGs were successfully screened, including 81 up-regulated genes and 153 down-regulated genes. Then, 5 core genes (CCNB1, KIF20A, ASPM, AURKA, and KIF23) were identified through PPI network analysis, ROC analysis, survival and Pearson correlation analysis, which show better diagnostic efficiency and higher prognostic value for EOC. Furthermore, NetworkAnalyst was used to identify top 15 chemicals that link with the 5 core genes. Among them, 11 chemicals were potential drugs and 4 chemicals were risk factors for EOC. Finally, we found that all 5 core genes mainly regulate EOC development via the cell cycle pathway by the bioinformatic analysis.ConclusionBased on an integrated bioinformatic analysis, we identified potential biomarkers, risk factors and drugs for EOC, which may help to provide new ideas for EOC diagnosis, condition appraisal, prevention and treatment in future.

Additional Tissue Sampling Trials Did Not Change Our Thyroid Practice.

Simple SummarySome studies have suggested that the use of additional tissue blocks to diagnose follicular thyroid carcinoma (FTC) could increase the accuracy of diagnosis and improve prognosis, and entire capsule sampling was recommended for a definitive diagnosis of borderline thyroid tumors in 2016. We conducted a study in 2016 to examine whether additional tissue sampling of the encapsulated follicular tumor increases the diagnosis of malignant cases in our patient cohort. Furthermore, the diagnosis was reclassified according to the 4th edition of the World Health Organization’s classification system. The additional tissue sampling only had a slight impact on our thyroid practice and resulted in no benefits to the patient; therefore, we decided to cease it.This study aimed to determine whether additional tissue sampling of encapsulated thyroid nodules would increase the frequency of follicular thyroid carcinoma (FTC) diagnoses. We examined thyroid tissue specimens from 86 patients suspected of FTC (84.9% female; mean age, 49.0 ± 17.8 years). The number of tissue blocks created for pathological assessments ranged from 3 to 20 (mean, 9.1 ± 4.1); the numbers in the previous method recommended by the Japanese General Rules for the Description of Thyroid Cancer and additional blocks ranged from 1 to 12 (mean, 6.0 ± 2.8) and from 1 to 8 (mean, 3.1 ± 2.0), respectively. The additional blocks were subsequently examined to determine whether any diagnoses changed from those based on the previous method. Five patients were diagnosed with FTC using the previous method; however, additional tissue blocks led to the diagnosis of FTC in 6 patients, as 1 diagnosis was revised from follicular adenoma to FTC. It has been reported that increasing the number of tissue blocks used for pathological assessments can increase the frequency of FTC diagnoses; however, this was not clinically significant in thyroid carcinoma, which requires completion thyroidectomy and radioactive iodine treatment. It resulted in no benefits to the patient because all minimally invasive FTCs, follicular tumors of uncertain malignant potential (FT-UMP), and follicular adenomas are treated with lobectomy alone in Japan. Additional tissue sampling only had a slight impact on our thyroid practice; therefore, we decided to cease it.

Diagnostic, Predictive and Prognostic Molecular Biomarkers in Pancreatic Cancer: An Overview for Clinicians.

Simple SummaryPancreatic cancer is the fourth most common cancer-related cause of death in the United States and is usually asymptomatic in early stages. There is a scarcity of tests that facilitate early diagnosis or accurately predict the disease progression. To this end, biomarkers have been identified as important tools in the diagnosis and management of pancreatic cancer. Despite the increasing number of biomarkers described in the literature, most of them have demonstrated moderate sensitivity and/or specificity and are far from being considered as screening tests. More efficient non-invasive biomarkers are needed to facilitate early-stage diagnosis and interventions. Multi-disciplinary collaboration might be required to facilitate the identification of such markers.Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic malignancy and is associated with aggressive tumor behavior and poor prognosis. Most patients with PDAC present with an advanced disease stage and treatment-resistant tumors. The lack of noninvasive tests for PDAC diagnosis and survival prediction mandates the identification of novel biomarkers. The early identification of high-risk patients and patients with PDAC is of utmost importance. In addition, the identification of molecules that are associated with tumor biology, aggressiveness, and metastatic potential is crucial to predict survival and to provide patients with personalized treatment regimens. In this review, we summarize the current literature and focus on newer biomarkers, which are continuously added to the armamentarium of PDAC screening, predictive tools, and prognostic tools.

ARID1A and CTNNB1/β-Catenin Molecular Status Affects the Clinicopathologic Features and Prognosis of Endometrial Carcinoma: Implications for an Improved Surrogate Molecular Classification.

Simple SummaryTranslation of the molecular characterization of endometrial cancer into the clinical practice is emerging as a challenge. This study investigates the feasibility and the prognostic impact of the novel surrogate TCGA molecular classification of endometrial carcinoma into the clinical setting proposing an immuno-molecular algorithm supplemented with ARID1A and CTNNB1/β-catenin analysis. The integrated clinicopathologic and molecular approach developed in this study could represent a workable and useful method in routine clinical practice for improving risk stratification and patient management.The collaborative Cancer Genome Atlas (TCGA) project identified four distinct prognostic groups of endometrial carcinoma (EC) based on molecular alterations: (i) the ultramutated subtype that encompasses POLE mutated (POLE) cases; (ii) the hypermutated subtype, characterized by MisMatch Repair deficiency (MMRd); (iii) the copy-number high subtype, with p53 abnormal/mutated features (p53abn); (iv) the copy-number low subtype, known as No Specific Molecular Profile (NSMP). Although the prognostic value of TCGA molecular classification, NSMP carcinomas present a wide variability in molecular alterations and biological aggressiveness. This study aims to investigate the impact of ARID1A and CTNNB1/β-catenin alterations by targeted Next-generation sequencing (NGS) and immunohistochemistry (IHC) in a consecutive series of 125 molecularly classified ECs. NGS and IHC were used to assign surrogate TCGA groups and to identify molecular alterations of multiple target genes including POLE, PTEN, ARID1A, CTNNB1, TP53. Associations with clinicopathologic parameters, molecular subtypes, and outcomes identified NSMP category as the most heterogeneous group in terms of clinicopathologic features and outcome. Integration of surrogate TCGA molecular classification with ARID1A and β-catenin analysis showed NSMP cases with ARID1A mutation characterized by the worst outcome with early recurrence, while NSMP tumors with ARID1A wild-type and β-catenin alteration had indolent clinicopathologic features and no recurrence. This study indicates how the identification of ARID1A and β-catenin alterations in EC represents a simple and effective way to characterize NSMP tumor aggressiveness and metastatic potential.

Nerve growth factor receptor increases the tumor growth and metastatic potential of triple-negative breast cancer cells.

Cellular heterogeneity and the lack of metastatic biomarkers limit the diagnosis of and development of therapies for metastatic triple-negative breast cancer (TNBC). Thus, development of new clinically relevant markers is urgently needed. By using RNA-seq analysis, we found that nerve growth factor receptor (NGFR) was highly expressed in metastatic lung clones of MDA-MB-231 cells. This high level of NGFR expression was necessary for TNBC cells to grow into tumor spheres under nonadhesive conditions, resist anoikis, promote primary tumor growth and increase metastasis in mice. NGFR was also expressed at a high level in a greater number of TNBC patients (45%) than non-TNBC patients (23%), enriched in higher grade tumors, and negatively correlated with the overall survival of TNBC patients. Mechanistic analysis indicated that NGFR exerted its prometastatic effects by binding with neurotrophic receptor tyrosine kinase 3 (TrkC) mainly through a ligand-independent manner, which activated the MEK-ERK1-ZEB1 and PI3K-AKT signaling pathways, increased the level of fibronectin, and decreased the expression of PUMA. Notably, we observed that NGFR expression in TrkC-positive metastatic clones reduced cellular sensitivity to anti-Trk therapy. Moreover, WNT family member 5a (WNT5A) and TrkC activated NGFR transcription in a ZEB1-dependent manner. Taken together, this study identified NGFR as a novel driver for transforming TNBC into higher grade metastatic tumors. Our findings provide the basis for the future development of NGFR as a diagnostic and prognostic marker for determining the metastatic potential of TNBC and as a therapeutic target for treating TNBC patients.

Abstract OT-12-01: The FLEX real-world data platform explores new gene expression profiles and investigator-initiated protocols in early stage breast cancer

Abstract Background: Genomic expression profiles have implications for the personalized treatment of breast cancer beyond clinical and pathological features by enabling the classification of breast cancers into molecular subtypes and providing prognostic information about the metastatic potential of tumors. However, full genome expression data should be combined with comprehensive clinical information to precisely stratify tumors into clinically actionable subgroups. The FLEX Registry aims to aggregate a large, real-world dataset, which will enable the discovery of novel genomic profiles to improve precision in the management of breast cancer, particularly in underrepresented patient subsets in traditional clinical trials. Trial Design: The FLEX Registry (NCT03053193) is a multi-center, prospective, observational trial for patients with stage I-III breast cancer whose primary tumor is analyzed by MammaPrint, with or without BluePrint.The primary objective of FLEX is to create a large scale, population-based registry that links comprehensive clinical data with full genome expression data to elucidate new prognostic and/or predictive gene associations in a real-world setting. The FLEX Registry employs a shared study infrastructure to develop and investigate hypotheses for targeted subset analyses and/or clinical trials based on full genome expression data. The adaptable protocol is designed to be amended with the inclusion of additional targeted sub-studies. Patients enrolled in the initial study are eligible for inclusion in sub-studies for which they meet all eligibility criteria and additional consent is not required. Data will be collected on patients from diagnosis through10 years of follow-up and any necessary additional clinical data will be collected as specified in the appendix protocols. The target enrollment of FLEX is a minimum of 10,000 patients; over 5,000 patients have enrolled sinceApril 2017 at more than 85 sites, including eight National Cancer Institute-designated comprehensive cancer centers. The FLEX collaborative platform allows participating investigators the opportunity to author their own sub-study protocols, as approved by the FLEX Review Committee. Sub-study research categories include: Age and Breast Cancer, Optimizing Therapy Strategies, Breast Cancer and MetabolicSyndrome, ctDNA and Liquid Biopsy, Genomics and Subtypes, Social and Ancestry, and Neoadjuvant Therapy and Surgery. To date, twenty-five investigator-initiated sub-studies have been approved.Trial contact information: NCT03053193FLEX@agendia.com Citation Format: Laura Lee, Sami Diab, Julie Barone, Jennifer A Crozier, Margret Chen, Rakshanda L Rahman, Robert Maganini, Douglas Marks, Amy M Truitt, Lisa Blumencranz, Erin Yoder, Sarah Untch, William Audeh, Bastiaan van der Baan, FLEX Investigators Group. The FLEX real-world data platform explores new gene expression profiles and investigator-initiated protocols in early stage breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-12-01.

Abstract PD15-04: Trop-2 inactivation of E-cadherin drives triple negative breast cancer relapse

Abstract Hundreds of proteins/genes have been linked to the metastatic phenotype. However, consistent markers of tumour aggressiveness and metastatic potential in breast cancer patients were not identified, not even including proteomic analysis and large-scale genome sequencing.Metastasis-associated genes were predicted to include not only drivers of the metastatic phenotype, but also secondary events, together with adaptive, counterbalancing changes. Thus, to identify candidates with a required role in metastatic diffusion, we looked for genes that were concordantly dysregulated across orthogonal cancer metastasis settings. This led us to identify Trop-2 as uniquely upregulated and associated to metastasis in experimental models of breast cancer, as well as in other solid tumors. We identified functional inactivation of E-cadherin by Trop-2 as the main motor of metastatic diffusion of such metastatic systems. Trop-2 binding to E-cadherin inactivated its cell-cell adhesion function, through release from the cytoskeleton, for activation of β-catenin transcriptional activity. This led to anti-apoptotic signaling, increased cell migration capacity and enhanced cancer cell survival. We showed that this mechanism led to metastatic diffusion of xenotransplants growing in immunosuppressed mice. An E-cadherin-inactivation metastasis program was then shown to be recapitulated in breast cancer patients, as well as in other solid tumors, over 24 independent case series, encompassing 13,042 primary tumours. Aggressive triple-negative breast cancers were shown to be driven toward global relapse by Trop-2 overexpression, through E-cadherin inactivation and activation of β-catenin transcriptional activity. No disease recurrence was observed in control cases over +12 years of follow-up. These finding lead to a novel paradigm of a Trop-2-driven, E-cadherin-inactivation program as a main metastasis driver in solid tumors. This may open far-reaching perspectives in diagnostic procedures and anti-cancer therapies. Citation Format: Saverio Alberti, Marco Trerotola, Valeria Relli, Rossano Lattanzio, Martina Ceci, Khouloud Boujnah, Valeria Garbo, Antonino Moschella, Patrizia Querzoli, Massimo Pedriali, Laura Antolini, Emanuela Guerra. Trop-2 inactivation of E-cadherin drives triple negative breast cancer relapse [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD15-04.

AI-Based Radiological Imaging for HCC: Current Status and Future of Ultrasound.

Hepatocellular carcinoma (HCC) is a common cancer worldwide. Recent international guidelines request an identification of the stage and patient background/condition for an appropriate decision for the management direction. Radiomics is a technology based on the quantitative extraction of image characteristics from radiological imaging modalities. Artificial intelligence (AI) algorithms are the principal axis of the radiomics procedure and may provide various results from large data sets beyond conventional techniques. This review article focused on the application of the radiomics-related diagnosis of HCC using radiological imaging (computed tomography, magnetic resonance imaging, and ultrasound (B-mode, contrast-enhanced ultrasound, and elastography)), and discussed the current role, limitation and future of ultrasound. Although the evidence has shown the positive effect of AI-based ultrasound in the prediction of tumor characteristics and malignant potential, posttreatment response and prognosis, there are still a number of issues in the practical management of patients with HCC. It is highly expected that the wide range of applications of AI for ultrasound will support the further improvement of the diagnostic ability of HCC and provide a great benefit to the patients.

Genomic and Epigenomic Profile of Uterine Smooth Muscle Tumors of Uncertain Malignant Potential (STUMPs) Revealed Similarities and Differences with Leiomyomas and Leiomyosarcomas.

Uterine smooth muscle tumors of uncertain malignant potential (STUMPs) represent a heterogeneous group of tumors that cannot be histologically diagnosed as unequivocally benign or malignant. For this reason, many authors are working to obtain a better definition of diagnostic and prognostic criteria. In this work, we analyzed the genomic and epigenomic profile of uterine smooth muscle tumors (USMTs) in order to find similarities and differences between STUMPs, leiomyosarcomas (LMSs) and leiomyomas (LMs), and possibly identify prognostic factors in this group of tumors. Array-CGH data on 23 USMTs demonstrated the presence of a more similar genomic profile between STUMPs and LMSs. Some genes, such as PRKDC and PUM2, with a potential prognostic value, were never previously associated with STUMP. The methylation data appears to be very promising, especially with regards to the divergent profile found in the sample that relapsed, characterized by an overall CGI hypomethylation. Finally, the Gene Ontology analysis highlighted some cancer genes that could play a pivotal role in the unexpected aggressive behavior that can be found in some of these tumors. These genes could prove to be prognostic markers in the future.

Prognostic significance of atypical mitotic figures in smooth muscle tumors of uncertain malignant potential (STUMP) of the uterus and uterine adnexa.

We aimed to assess whether the presence of atypical mitotic figures (AMF) in smooth muscle tumors of uncertain malignant potential (STUMP) of the uterus and uterine adnexa is associated with increased risk of recurrence, and the association of AMF with the Stanford criteria, that is, significant cytologic atypia, mitotic index≥10/10HPF, and coagulative tumor cell necrosis (CTCN). A systematic review was performed to identify all studies reporting the presence of AMF and oncologic outcomes in STUMP series. Fisher's exact test was used to assess the association of AMF with the three Stanford parameters. Kaplan-Meier and Cox regression survival analyses with hazard ratio (HR) calculation were performed to assess the association between AMF and STUMP recurrence. A p-value<0.05 was considered significant. Five studies with 80 STUMPs were included, out of which 23.8% had AMF. AMF were significantly associated with the presence of significant atypia (p=0.023), but not with the presence of a mitotic index≥10/10HPF (p=0.769), CTCN (p=1), or more than one Stanford parameter (p=0.171). AMF was not significantly associated with the risk of STUMP recurrence at both univariate (HR=0.366; p=0.188) and multivariate analyses (HR=0.528; p=0.463). In STUMP of the uterus and uterine adnexa, AMF are more common in the case of significant cytologic atypia, but do not seem to increase the risk of recurrence. Further studies are necessary in this regard.