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Background: This study evaluated the prognostic impact of Trop-2, CD47, and CD163 expression on clinical outcomes in triple-negative breast cancer (TNBC) and investigated their interactions with tumor progression. Methods: A retrospective cohort of 92 patients with TNBC was analyzed. The expression scores for Trop-2, CD47, and CD163 were categorized as negative/low (0–3 points) or high (4–6 points). The primary endpoint was overall survival (OS). Results: The median age of the cohort was 50 years old. High Trop-2 expression was observed in 55.4% of the patients and was significantly associated with advanced disease stage (p < 0.001). High CD47 expression (44.6%) was correlated with advanced stage (p = 0.044), whereas high CD163 expression (45.7%) was associated with advanced stage (p = 0.021), absence of comorbidities (p = 0.022), and lower pT stage (p = 0.023). Moderate positive correlations were found between Trop-2 and CD47 (p = 0.022), Trop-2 and CD163 (p = 0.037), and CD47 and CD163 (p < 0.001), respectively. Kaplan–Meier survival analysis revealed that patients with low Trop-2 expression exhibited significantly prolonged OS (p = 0.021) and progression-free survival (PFS) (p = 0.026) compared to those with high Trop-2 expression. Univariate and multivariate analyses revealed significant associations between OS and PFS for Trop-2, lymphovascular invasion, and BRCA status. Conclusions: Trop-2 expression is a significant prognostic factor for TNBC and is correlated with worse outcomes. Although CD47 and CD163 showed trends for poorer prognosis, their significance was not confirmed. These findings offer promising prospects for future studies on combined antibody–drug conjugates (ADCs), as they may present opportunities to address multiple resistance mechanisms in the management of TNBC and enhance clinical outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Antibody–drug conjugates (ADCs) are a cutting-edge treatment for metastatic breast cancer, combining targeted therapy with chemotherapy to attack cancer cells more precisely. However, their success varies, and understanding what makes them effective for some patients but less so for others is critical. This review identifies key factors, like specific proteins on cancer cells, genetic changes, and the tumor environment, that influence ADC effectiveness. It also explores challenges like resistance to treatment and ways to overcome them, such as developing new ADCs and combining them with other therapies. These insights aim to refine patient care by personalizing ADC treatments, ultimately improving outcomes for individuals with advanced breast cancer. Antibody–drug conjugates (ADCs) have revolutionized the treatment landscape for metastatic breast cancer, offering targeted delivery of cytotoxic agents with improved efficacy and tolerability compared to conventional chemotherapy. This narrative review explores key predictive factors influencing the efficacy of ADCs, focusing on HER2-targeted therapies, such as trastuzumab emtansine and trastuzumab deruxtecan, as well as sacituzumab govitecan for triple-negative breast cancer. HER2 expression, TROP-2 levels, hormone receptor status, and the tumor microenvironment emerge as critical biomarkers for patient selection and therapeutic outcomes. Additionally, we discuss resistance mechanisms, such as antigen loss, impaired drug internalization, and the role of circulating tumor DNA in predicting ADC response. Finally, future perspectives on the sequential use of ADCs and potential combination therapies are highlighted, along with emerging agents targeting alternative antigens like HER3 and LIV-1. Overall, identifying predictive biomarkers and overcoming resistance mechanisms are essential for optimizing the use of ADCs in metastatic breast cancer, thereby improving patient outcomes. [ABSTRACT FROM AUTHOR]

The present review provides a detailed and comprehensive discussion on antibody–drug conjugates (ADCs) as an evolving new modality in the current therapeutic landscape of malignant diseases. The principle concepts of targeted delivery of highly toxic agents forsaken as stand-alone drugs are examined in detail, along with the biochemical and technological tools for their successful implementation. An extensive analysis of ADCs' major components is conducted in parallel with their function and impact on the stability, efficacy, safety, and resistance profiles of the immunoconjugates. The scope of the article covers the major classes of currently validated natural compounds used as payloads, with an emphasis on their structural and mechanistic features, natural origin, and distribution. Future perspectives in ADCs' design are thoroughly explored, addressing their inherent or emerging challenges and limitations. The survey also provides a comprehensive overview of the molecular rationale for active tumor targeting of ADC-based platforms, exploring the cellular biology and clinical relevance of validated tumor markers used as a "homing" mechanism in both hematological and solid tumor malignancies. [ABSTRACT FROM AUTHOR]

Mingyi Li,1,&ast; Meng Jin,2,&ast; Hao Peng,3 Haitao Wang,1 Qian Shen,2 Lei Zhang1,4 1Department of Pulmonary and Critical Care Medicine, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China; 2Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China; 3Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China; 4Xianning Medical College, Hubei University of Science & Technology, Xianning, Hubei, 437000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lei Zhang, Department of Pulmonary and Critical Care Medicine, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China, Email zhl930223@qq.com Qian Shen, Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China, Email shenqianoncology@163.comAbstract: Lung cancer is the leading cause of mortality worldwide, and non-small cell lung cancer accounts for the majority of lung cancer cases. Chemotherapy and radiotherapy constitute the mainstays of lung cancer treatment; however, their associated side effects involving the kidneys, nervous system, gastrointestinal tract, and liver further add to dismal outcomes. The advent of antibody‒drug conjugates (ADCs) could change this situation. Trophoblast surface antigen 2 (TROP-2), a human trophoblast surface antigen, is a tumor-associated antigen that is expressed at low levels in normal tissues and is overexpressed in a variety of malignant tumors. The differential expression of the TROP-2 protein in a variety of tumors makes tumor immunotherapy with ADCs targeting TROP-2 a promising approach. Previous studies have shown that the expression of TROP-2 is related to the prognosis of patients with lung cancer and that TROP-2 expression is different across different histological types; however, research on TROP-2 and TROP-2 ADCs in patients with lung cancer is not comprehensive. The aims of this study were to review the mechanism of action and clinical efficacy of TROP-2 and related drugs in the treatment of lung cancer, to elucidate the prognostic value of TROP-2 in lung cancer, and to discuss the future prospects of TROP-2 ADCs to provide a reference for the precise treatment of lung cancer.Keywords: TROP-2, antibody‒drug conjugates, lung cancer

Abstract Background Sacituzumab govitecan is an antibody-drug conjugate that is FDA approved for refractory metastatic triple-negative breast cancer. It targets the human trophoblastic cell-surface antigen 2 (Trop-2) with SN-38, a topoisomerase I inhibitor, attached to the antibody [1]. SN-38 breaks DNA strands and induces tumor apoptosis [2]. Acute kidney injury (AKI) is one of its adverse effects mainly prerenal due to gastrointestinal toxicity, but it has not been reported to cause acute tubulointerstitial nephritis (ATIN). Case Presentation This report describes a rare adverse effect of sacituzumab govitecan, the approach to diagnosing the etiology of the patient’s AKI, and the mechanism by which sacituzumab govitecan causes ATIN. A woman with metastatic ER positive, PR positive, HER2 negative breast cancer who was initiated on sacituzumab govitecan presents with vomiting and diarrhea, and findings of nephrotic-range proteinuria, negative anti-PLA2R antibody, and severe AKI requiring hemodialysis. She underwent kidney biopsy and pathology showed ATIN characterized by patchy interstitial inflammation alongside tubular injury without glomerular and vascular involvement. With intermittent renal replacement therapy, furosemide challenge, and a course of prednisone, the patient’s kidney function recovered. Conclusions Sacituzumab has a high affinity for Trop-2 protein which is also expressed within the collecting ducts, and to a lesser extent, the proximal tubule. Individuals, such as this patient, who express a homozygous genotype for UGT1A1*28 allele are at increased risk for AKI from sacituzumab govitecan due to decreased glucuronidation of SN-38.

Breast cancer remains a leading cause of cancer-related deaths among women worldwide, highlighting the need for novel therapeutic strategies. Trophoblast cell surface antigen 2 (Trop-2), a type I transmembrane glycoprotein highly expressed in various solid tumors including all subtypes of breast cancer, has emerged as a promising target for cancer therapy. This review focuses on recent advancements in Trop-2-targeted antibody-drug conjugates (ADCs) for breast cancer treatment. We comprehensively analyzed the structure and mechanism of action of ADCs, as well as the role of Trop-2 in breast cancer progression and prognosis. Several Trop-2-targeted ADCs, such as Sacituzumab Govitecan (SG) and Datopotamab Deruxtecan (Dato-DXd), have demonstrated significant antitumor activity in clinical trials for both triple-negative breast cancer (TNBC) and hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer. We systematically reviewed the ongoing clinical studies of these ADCs, highlighting their efficacy and safety profiles. Furthermore, we explored the potential of combining Trop-2-targeted ADCs with other therapeutic modalities, including immunotherapy, targeted therapies, and small molecule inhibitors. Notably, Trop-2-targeted ADCs have shown promise in reprogramming the tumor microenvironment through multiple signaling pathways, potentially enhancing antitumor immunity. This review aims to provide new insights and research directions for the development of innovative breast cancer therapies, offering potential solutions to improve treatment outcomes and quality of life for breast cancer patients. [ABSTRACT FROM AUTHOR]

Background: Sacituzumab govitecan is an antibody-drug conjugate that is FDA approved for refractory metastatic triple-negative breast cancer. It targets the human trophoblastic cell-surface antigen 2 (Trop-2) with SN-38, a topoisomerase I inhibitor, attached to the antibody [1]. SN-38 breaks DNA strands and induces tumor apoptosis [2]. Acute kidney injury (AKI) is one of its adverse effects mainly prerenal due to gastrointestinal toxicity, but it has not been reported to cause acute tubulointerstitial nephritis (ATIN). Case Presentation: This report describes a rare adverse effect of sacituzumab govitecan, the approach to diagnosing the etiology of the patient's AKI, and the mechanism by which sacituzumab govitecan causes ATIN. A woman with metastatic ER positive, PR positive, HER2 negative breast cancer who was initiated on sacituzumab govitecan presents with vomiting and diarrhea, and findings of nephrotic-range proteinuria, negative anti-PLA2R antibody, and severe AKI requiring hemodialysis. She underwent kidney biopsy and pathology showed ATIN characterized by patchy interstitial inflammation alongside tubular injury without glomerular and vascular involvement. With intermittent renal replacement therapy, furosemide challenge, and a course of prednisone, the patient's kidney function recovered. Conclusions: Sacituzumab has a high affinity for Trop-2 protein which is also expressed within the collecting ducts, and to a lesser extent, the proximal tubule. Individuals, such as this patient, who express a homozygous genotype for UGT1A1*28 allele are at increased risk for AKI from sacituzumab govitecan due to decreased glucuronidation of SN-38. [ABSTRACT FROM AUTHOR]

TROP-2, a tumor-associated antigen, has been implicated in the progression of various epithelial tumors. Due to its favorable expression profile, TROP-2 has emerged as a promising target for antibody–drug conjugates (ADCs) based anti-tumor therapies. Although ADCs have shown efficacy in cancer treatment, their application in solid tumors is hindered by their high molecular weight, poor tumor penetration, and release of cytotoxic molecules. Therefore, a recombinant immunotoxin was developed based on a shark-derived variable domain of immunoglobulin new antigen receptor (VNAR) antibody. VNARs are only one-tenth the size of IgG antibodies and possess remarkable tissue penetration capabilities and high stability. In this study, a shark VNAR phage display library was created, leading to the identification of shark VNAR-5G8 that targets TROP-2. VNAR-5G8 exhibited a high affinity and cellular internalization ability towards cells expressing high levels of TROP-2. Epitope analysis revealed that VNAR-5G8 recognizes a hidden epitope consisting of CRD and TY-1 on TROP-2. Subsequently, VNAR-5G8 was fused with a truncated form of Pseudomonas exotoxin (PE38) to create the recombinant immunotoxin (5G8-PE38), which exhibited significant anti-tumor activity in vitro and in vivo. Overall, this study highlights the promise of 5G8-PE38 as a valuable candidate for cancer therapy. A TROP2-binding nanobody (5G8) was identified from a VNAR phage display library. And an immunotoxin (5G8-PE38) was constructed, which showed effective anti-tumor activity. [Display omitted] [ABSTRACT FROM AUTHOR]

Objective: To evaluate the potential utility of antibody‐drug conjugates targeting trophoblast cell surface antigen‐2 (TROP‐2) in patients with primary penile squamous cell carcinoma (PSCC), patients with recurrence (REC cohort), and patient‐matched distant metastases (MET cohort), and to assess the potential use of TROP‐2 as a predictive non‐invasive biomarker in PSCC. Methods: A cohort comprising a PRIM (n = 37), REC (n = 5) and MET subcohort (n = 7), with MET including lymph node and lung metastases, was analysed using quantitative real‐time PCR, ELISA and immunohistochemical staining with evaluation of H‐score. Results: TROP‐2 mRNA and serum protein levels were significantly increased in primary and recurrent PSCC compared to cancer‐free controls (both P < 0.001). Immunohistochemical analysis revealed that most of the PRIM cohort (n = 34/37, median H‐score 260, interquartile range [IQR] 210–300), as well as all patients in the REC (median [IQR] H‐score 200 [165–290]) and MET cohorts (median [IQR] H‐score 280 [260–300]) exhibited moderate to strong membranous TROP‐2 expression. Additionally, The H‐score (membranous TROP‐2 expression) was positively correlated with TROP‐2 mRNA (ρ = 0.69, P < 0.0001, R2 = 0.70) and protein levels (ρ = 0.86, P < 0.0001, R2 = 0.59), indicating its potential as a non‐invasive biomarker in PSCC. Conclusion: In summary, our results support further studies on TROP‐2 as a diagnostic and therapeutic target in primary, recurrent and metastatic PSCC. [ABSTRACT FROM AUTHOR]

Introduction: Initial treatment for hormone-receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer (ABC) typically involves endocrine therapy (ET) combined with different targeted agents. When hormonal therapies fail, until recently, the only option available was chemotherapy (ChT), presenting a significant therapeutic challenge. However, the recent introduction of antibody–drug conjugates (ADCs) has provided new treatment alternatives in this context. Sacituzumab govitecan (SG), a novel trophoblast cell-surface antigen 2 (Trop-2)-targeting ADC, has been evaluated following disease progression to ET and ChT in HR+/HER2- ABC. Areas covered: This review examines the latest clinical trials, including phase I/II and III studies and evaluates the impact of SG on HR+/HER2- ABC. The literature search focused on clinical outcomes, particularly regarding efficacy and safety, comparing them with traditional ChT. Expert opinion: SG has demonstrated to be an effective treatment for patients with HR+/HER2- ABC after progression to ET and cyclin-dependent kinase 4/6 inhibitors (CDKi) in any setting, and at least two ChT-containing regimens in the advanced setting. With a manageable toxicity profile, SG represents a significant advancement in the treatment landscape for this patient population. However, further research is essential to optimize its application and establish long-term benefits. [ABSTRACT FROM AUTHOR]

Breast cancer remains the most prevalent malignancy among women globally, presenting significant challenges in therapeutic strategies due to tumor heterogeneity, drug resistance, and adverse side effects. Recent advances in targeted therapies, particularly antibody-drug conjugates (ADCs), have shown promise in addressing these challenges by selectively targeting tumor cells while sparing normal tissues. This study provides a comprehensive analysis of two innovative ADCs targeting HER2 and Trop-2, which are critical markers in various breast cancer subtypes. These conjugates combine potent cytotoxic drugs with specific antibodies, leveraging the antigens' differential expression to enhance therapeutic efficacy and reduce systemic toxicity. Our comparative analysis highlights the clinical applications, efficacy, and safety profiles of these ADCs, drawing on data from recent clinical trials. In addition, the paper discusses the potential of these ADCs in treating other types of cancers where HER2 and Trop-2 are expressed, as well as the toxicity risks associated with targeting these antigens in normal cells. Additionally, the paper discusses novel synthetic drugs that show potential in preclinical models, focusing on their mechanisms of action and therapeutic advantages over traditional chemotherapy. The findings underscore the transformative impact of targeted ADCs in breast cancer treatment, noting significant advancements in patient outcomes and management of side effects. However, ongoing issues such as resistance mechanisms and long-term safety remain challenges. The conclusion offers a forward-looking perspective on potential improvements and the future trajectory of ADC research. This study not only elucidates the current landscape of ADCs in breast cancer but also sets the stage for the next generation of oncological therapeutics. This study not only elucidates the current landscape of ADCs in breast cancer but also sets the stage for the next generation of oncological therapeutics, with particular attention to their broader applications and associated risks. [ABSTRACT FROM AUTHOR]

Background: Sacituzumab Govitecan (SG), a first-in-class anti-trophoblast cell surface antigen-2-directed antibody-drug conjugate (ADC), has shown clinically meaningful improvement in outcomes of patients with breast cancer (BC). However, it has also been accompanied by significant toxicity. Thus, we conducted a systematic review and meta-analysis to evaluate the safety and tolerability of SG in this patient population. Methods: We comprehensively searched PubMed, Embase, and Cochrane databases, and ASCO and ESMO websites for clinical trials (CTs) assessing the safety of SG in BC patients. All analyses were performed in R software (v.4.2.2) using random effects models. Heterogeneity was assessed using I2 test. Results: Seven studies – three randomized clinical trials (RCTs) and four single-arm phase I/II – were included, comprising 928 patients receiving SG and 576 on treatment of physician's choice (TPC). Most patients had triple negative BC (54.4 %, n = 505), metastatic disease (89.8 %, n = 833), and were heavily pretreated (at least two lines of prior therapy). Most common all-grade adverse events (AEs) were: neutropenia (70 %, 95 % CI, 64–76 %), followed by nausea (62 %, 95 % CI, 55–68 %), diarrhea (54 %, 95 % CI 47–60 %) and anemia (51 %, 95 % CI, 38–65 %). Regarding high-grade AEs, 46 % of patients developed grade ≥3 neutropenia. Compared to TPC, we observed a higher risk of neutropenia (OR 3.11, 95 % CI 1.62–5.99, I2 = 81 %; p

Triple-negative breast cancer (TNBC) represents a major therapeutic challenge due to its heterogeneous and aggressive phenotype, and limited target-specific treatment options. The trophoblast cell surface antigen (Trop-2), a transmembrane glycoprotein overexpressed in various cancers, has emerged as a promising target for TNBC. Sacituzumab govitecan (SG), an antibody-drug conjugate (ADC) that targets Trop-2, has recently entered treatment algorithms for advanced and metastatic TNBC, independently from Trop-2 expression status, with manageable toxicity. Despite the impressive results, questions remain unsolved regarding its efficacy, safety profile, and Trop-2 biological role in cancer. Currently, Trop-2 cannot be designated as a predictive biomarker in SG treatment, albeit its expression correlates with disease outcome, yet its levels are not uniform across all TNBCs. Additionally, data regarding Trop-2 expression variations in primary and metastatic sites, and its interplay with other biomarkers are still ambiguous but mandatory in light of future applications of SG in other indications and settings. This poses the questions of a careful evaluation of the efficacy and toxicity profile of SG in such early stages of disease, and in personalized and combinatorial strategies. Research and clinical data are mandatory to address SG drawbacks and minimize its benefits, to realize its full potential as therapeutic agent in different epithelial tumors. [ABSTRACT FROM AUTHOR]

Background: Ductal Adenocarcinoma (DAC) and Intraductal Carcinoma of the Prostate (IDC-P) respond poorly to all the currently available conventional therapies. Given their accurate and efficient elimination of cancer cells, Antibody-Drug Conjugates (ADCs) have become one of the most promising anticancer treatments. However, no ADCs have so far been approved for Prostate Cancer (PCa) treatment. This study investigated TROP-2, HER2, and CD46 expression in DAC/IDC-P samples, indirectly analyzing their preliminary feasibility as therapeutic targets for future treatment of the two conditions. Patients and methods: We conducted a retrospective study involving 184 participants (87 DAC/IDC-P patients and 97 Prostatic Acinar Adenocarcinoma (PAC) patients with a Gleason score ≥ 8) without prior treatment between August 2017 and August 2022. Immunohistochemical staining was employed to detect the differential protein expressions of TROP-2, HER2, and CD46 in DAC/IDC-P, PAC, and normal prostate tissues. Results: Compared to pure PAC tissues, TROP-2 expression was significantly higher in DAC/IDC-P and DAC/IDC-P-adjacent PAC tissues (H-score 68.8 vs. 43.8, p < 0.001, and 59.8 vs. 43.8, p = 0.022, respectively). No significant differences in HER2 expression were observed across different cancer tissues. Compared to both DAC/IDC-P-adjacent PAC and pure PAC tissues, CD46 expression was significantly higher in DAC/IDC-P tissues (42.3 vs. 28.6, p = 0.041, and 42.3 vs. 24.3, p = 0.0035, respectively). Conclusions: Herein, TROP-2 and CD46 expression was higher in DAC/IDC-P tissues than in pure PAC and normal prostate tissues. This finding implies that ADCs targeting the two proteins hold significant promise as potential future treatments for DAC/IDC-P. [ABSTRACT FROM AUTHOR]

Purpose: Improved survival rates have been observed in castration‐resistant prostate cancer (CRPC) due to advancements in treatment options. However, individuals with brain metastases still have limited therapeutic options and an unfavorable prognosis. Therefore, there is an urgent need to explore new therapeutic avenues, such as antibody‐drug conjugates (ADCs), which have demonstrated significant clinical activity against active brain metastases in solid tumors. Our objective was to determine the expression levels of the ADC targets Trop‐2 and NECTIN‐4 in cerebral metastasized CRPC (mCRPC). Methods: Immunohistochemical staining of Trop‐2 and NECTIN‐4 with evaluation of H‐score was performed in CRPC brain metastases (n = 31). Additionally, we examined Trop‐2 protein expression in prostate cancer cell lines and studied their responsiveness to the anti‐Trop‐2 ADC Sacituzumab govitecan (SG) in vitro. Results: Our analysis revealed that most patients exhibited moderate to strong Trop‐2 expression [n = 27/31 with H‐score ≥100, median H‐score 220 (IQR 180–280)], while NECTIN‐4 was absent in all cerebral metastases. Mechanistically, we demonstrated that the efficacy of SG depends on Trop‐2 expression levels in vitro. Overexpression of Trop‐2 in Trop‐2‐negative PC‐3 cells led to sensitization to SG, whereas CRISPR‐Cas9‐mediated knockdown of Trop‐2 in Trop‐2‐expressing DU‐145 cells conferred resistance to SG. Conclusion: The substantial expression of Trop‐2 in cerebral metastases, along with our preclinical in vitro results, supports the efficacy of SG in treating cerebral mCRPC. Thus, our results extend the understanding of the potential of ADCs in prostate cancer treatment and provide an additional treatment strategy for the challenging subset of patients with cerebral metastases. [ABSTRACT FROM AUTHOR]

Purpose: The prognostic and predictive role of trophoblast cell-surface antigen-2 (Trop-2) overexpression in human epidermal growth factor receptor 2-positive (HER2-positive) breast cancer is currently unknown. We retrospectively analyzed Trop-2 expression and its correlation with clinicopathologic features and pathological complete response (pCR) in HER2-positive early breast cancer (EBC) patients treated with neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab in the PHERGain study. Methods: Trop-2 expression at baseline was determined in formalin-fixed, paraffin-embedded primary tumor biopsies by immunohistochemistry and was first classified into expressing (Trop-2-positive) or not-expressing (Trop-2-negative) tumors. Then, it was classified by histochemical score (H-score) according to its intensity into low (0–9), intermediate (10–49), and high (≥ 50). The association between clinicopathologic features, pCR, and Trop-2 expression was performed with Fisher's exact test. Results: Forty-one patients with tissue evaluable for Trop-2 expression were included, with 28 (68.3%) Trop-2-positive tumors. Overall, 17 (41.46%), 14 (34.15%), and 10 (24.40%) tumors were classified as low, intermediate, and high, respectively. Trop-2 expression was significantly associated with decreased pCR rates (50.0% vs. 92.3%; odds ratio [OR] 0.05; 95% CI, 0.002–0.360]; p adjusted = 0.01) but was not correlated with any clinicopathologic features (p ≥ 0.05). Tumors with the highest Trop-2 H-score were less likely to obtain a pCR (OR 0.03; 95% CI, 0.001–0.290, p adjusted < 0.01). This association was confirmed in univariate and multivariate regression analyses. Conclusion: These findings suggest a potential role of Trop-2 expression as a biomarker of resistance to neoadjuvant chemotherapy plus dual HER2 blockade and may become a strategic target for future combinations in HER2-positive EBC patients. [ABSTRACT FROM AUTHOR]

Breast cancer remains a leading cause of cancer-related deaths among women worldwide, highlighting the need for novel therapeutic strategies. Trophoblast cell surface antigen 2 (Trop-2), a type I transmembrane glycoprotein highly expressed in various solid tumors including all subtypes of breast cancer, has emerged as a promising target for cancer therapy. This review focuses on recent advancements in Trop-2-targeted antibody-drug conjugates (ADCs) for breast cancer treatment. We comprehensively analyzed the structure and mechanism of action of ADCs, as well as the role of Trop-2 in breast cancer progression and prognosis. Several Trop-2-targeted ADCs, such as Sacituzumab Govitecan (SG) and Datopotamab Deruxtecan (Dato-DXd), have demonstrated significant antitumor activity in clinical trials for both triple-negative breast cancer (TNBC) and hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer. We systematically reviewed the ongoing clinical studies of these ADCs, highlighting their efficacy and safety profiles. Furthermore, we explored the potential of combining Trop-2-targeted ADCs with other therapeutic modalities, including immunotherapy, targeted therapies, and small molecule inhibitors. Notably, Trop-2-targeted ADCs have shown promise in reprogramming the tumor microenvironment through multiple signaling pathways, potentially enhancing antitumor immunity. This review aims to provide new insights and research directions for the development of innovative breast cancer therapies, offering potential solutions to improve treatment outcomes and quality of life for breast cancer patients.

Precise targeting has become the main direction of anti-cancer drug development. Trophoblast cell surface antigen 2 (Trop-2) is highly expressed in different solid tumors but rarely in normal tissues, rendering it an attractive target. Trop-2-targeted antibody-drug conjugates (ADCs) have displayed promising efficacy in treating diverse solid tumors, especially breast cancer and urothelial carcinoma. However, their clinical application is still limited by insufficient efficacy, excessive toxicity, and the lack of biological markers related to effectiveness. This review summarizes the clinical trials and combination therapy strategies for Trop-2-targeted ADCs, discusses the current challenges, and provides new insights for future advancements. [ABSTRACT FROM AUTHOR]

BACKGROUND: Papillary thyroid carcinoma (PTC) is the most frequent thyroid malignancy. Histopathological examination is widely accepted as the gold standard test for the diagnosis of PTC. However, the histopathological examination sometimes can't differentiate PTC from other thyroid diseases. Differentiating PTC from other thyroid diseases is essential for a therapeutic approach and prognosis. OBJECTIVES: The current study was performed to investigate the utility of TROP-2, SPL-2, and CXCL12 mRNA and protein expression in discriminating PTC from other thyroid diseases that mimic PTC. METHODS: The current study was performed on 75 cases of surgically resected thyroid glands. The cases were distributed in two groups: the PTC group and the non-PTC group. The PTC group consisted of 35 cases (25 patients of the classic PTC variant and 10 patients of the PTC follicular variant). The non-PTC group consisted of 40 cases (10 cases were multinodular goiter, 5 cases were Graves' disease, 5 cases were Hashimoto thyroiditis, 15 patients were follicular adenoma (FA) and 5 cases were follicular carcinoma). TROP-2, SPL-2, and CXCL12 mRNA expression were estimated by qRT-PCR, and protein expression was estimated by immunohistochemistry. RESULTS: There were upregulated TROP-2, SPL-2, and CXCL12 mRNA and protein expressions in PTC compared to non-PTC (P < 0.001, for each). There was a statistically significant upregulation in the mRNA expression of the three genes among PTC cases with larger tumor sizes (P < 0.001, for each), those with tumor stages III and IV (P = 0.008, 0.002 and < 0.001 respectively), and those with LN metastasis (P < 0.001, for each). Moreover, there was a statistically significant upregulation in CXCL-12 gene expression among PTC cases with extra-thyroid extension (P < 0.001). CONCLUSION: mRNA expression of TROP-2, SPL-2, and CXCL12 among PTC cases increased in larger tumor size, tumor stages III and IV, and LN metastasis. Moreover, there was an increase in CXCL-12 gene expression among PTC cases with extra-thyroid extension. Thus, TROP-2, SPL-2, and CXCL12 expressions could be possible diagnostic and prognostic markers in PTC. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) represents a major therapeutic challenge due to its heterogeneous and aggressive phenotype, and limited target-specific treatment options. The trophoblast cell surface antigen (Trop-2), a transmembrane glycoprotein overexpressed in various cancers, has emerged as a promising target for TNBC. Sacituzumab govitecan (SG), an antibody-drug conjugate (ADC) that targets Trop-2, has recently entered treatment algorithms for advanced and metastatic TNBC, independently from Trop-2 expression status, with manageable toxicity. Despite the impressive results, questions remain unsolved regarding its efficacy, safety profile, and Trop-2 biological role in cancer. Currently, Trop-2 cannot be designated as a predictive biomarker in SG treatment, albeit its expression correlates with disease outcome, yet its levels are not uniform across all TNBCs. Additionally, data regarding Trop-2 expression variations in primary and metastatic sites, and its interplay with other biomarkers are still ambiguous but mandatory in light of future applications of SG in other indications and settings. This poses the questions of a careful evaluation of the efficacy and toxicity profile of SG in such early stages of disease, and in personalized and combinatorial strategies. Research and clinical data are mandatory to address SG drawbacks and minimize its benefits, to realize its full potential as therapeutic agent in different epithelial tumors.

A phylogenetic conservation analysis of Trop-2 across vertebrate species showed a high degree of sequence conservation, permitting to explore multiple models as pre-clinical benchmarks. Sequence divergence and incomplete conservation of expression patterns were observed in mouse and rat. Primate Trop-2 sequences were found to be 95%--100% identical to the human sequence. Comparative three-dimension primate Trop-2 structures were obtained with AlphaFold and homology modeling. This revealed high structure conservation of Trop-2 (0.66 ProMod3 GMQE, 0.80--0.86 ± 0.05 QMEANDisCo scores), with conservative amino acid changes at variant sites. Primate TACSTD2/TROP2 cDNAs were cloned and transfectants for individual ORF were shown to be efficiently recognized by humanized anti-Trop-2 monoclonal antibodies (Hu2G10, Hu2EF). Immunohistochemistry analysis of Macaca mulatta (rhesus monkey) tissues showed Trop-2 expression patterns that closely followed those in human tissues. This led us to test Trop-2 targeting in vivo in Macaca fascicularis (cynomolgus monkey). Intravenously injected Hu2G10 and Hu2EF were well tolerated from 5 to 10mg/kg. Neither neurological, respiratory, digestive, urinary symptoms, nor biochemical or hematological toxicities were detected during 28-day observation. Blood serum pharmacokinetic (PK) studies were conducted utilizing anti-idiotypic antibodies in capture-ELISA assays. Hu2G10 (t1/2 = 6.5 days) and Hu2EF (t1/2 = 5.5 days) were stable in plasma, and were detectable in the circulation up to 3 weeks after the infusion. These findings validate primates as reliable models for Hu2G10 and Hu2EF toxicity and PK, and support the use of these antibodies as next-generation anti- Trop-2 immunotherapy tools. [ABSTRACT FROM AUTHOR]

Background: Triple-negative breast cancer (TNBC) is one of the most lethal malignant tumors among women, characterized by high invasiveness, high heterogeneity, and lack of specific therapeutic targets such as estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Trophoblast cell-surface antigen-2 (TROP-2) is a transmembrane glycoprotein over-expressed in 80% of TNBC patients and is associated with the occurrence, progress, and poor prognosis of TNBC. The TROP-2 targeted immunoPET imaging allows non-invasive quantification of the TROP-2 expression levels of tumors, which could help to screen beneficiaries most likely to respond to SG and predict the response. This study aimed to develop a 89Zr/177Lu-radiolabeled anti-TROP-2 antibody (NY003) for immunoPET and SPECT imaging, as well as radioimmunotherapy (RIT) in TROP-2 (+)TNBC tumor-bearing model. Based on the camelid antibody, we developed a TROP-2 targeted recombinant antibody NY003. NY003 was conjugated with DFO and DTPA for 89Zr and 177Lu radiolabelling, respectively. The theranostic potential of [89Zr]Zr-DFO-NY003/[177Lu]Lu-DTPA-NY003 was evaluated through immunoPET, SPECT imaging, and RIT studies in the subcutaneous TROP-2 positive TNBC xenograft mice model. Results: The high binding affinity of NY003 to TROP-2 was verified through ELISA. The radiochemical purity of [89Zr]Zr-DFO-NY003/[177Lu]Lu-DTPA-NY003 exceeded 95% and remained stable within 144h p.i. in vitro. ImmunoPET and SPECT imaging showed the specific accumulation of [89Zr]Zr-DFO-NY003/[177Lu]Lu-DTPA-NY003 in MDA-MB-231 tumors and gradually increased with the time tested, significantly higher than that in control groups (P < 0.05). The strongest anti-tumor efficacy was observed in the high-dose of [177Lu]Lu-DTPA-NY003 group, followed by the low-dose group, the tumor growth was significantly suppressed by [177Lu]Lu-DTPA-NY003, the tumor volumes of both high- and low-dose groups were smaller than the control groups (P < 0.05). Ex vivo biodistribution and histological staining verified the results of in vivo imaging and RIT studies. Conclusion: As a drug platform for radiotheranostics, 89Zr/177Lu-radiolabeled anti-TROP-2 antibody NY003 could not only non-invasively screen the potential beneficiaries for optimizing SG ADC treatment but also suppressed the growth of TROP-2 positive TNBC tumors, strongly supporting the theranostic potential of [89Zr]Zr-DFO-NY003/[177Lu]Lu-DTPA-NY003. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum (ER) retention of misfolded glycoproteins is mediated by the ER‐localized eukaryotic glycoprotein secretion checkpoint, UDP‐glucose glycoprotein glucosyl‐transferase (UGGT). The enzyme recognizes a misfolded glycoprotein and flags it for ER retention by re‐glucosylating one of its N‐linked glycans. In the background of a congenital mutation in a secreted glycoprotein gene, UGGT‐mediated ER retention can cause rare disease, even if the mutant glycoprotein retains activity ("responsive mutant"). Using confocal laser scanning microscopy, we investigated here the subcellular localization of the human Trop‐2‐Q118E, E227K and L186P mutants, which cause gelatinous drop‐like corneal dystrophy (GDLD). Compared with the wild‐type Trop‐2, which is correctly localized at the plasma membrane, these Trop‐2 mutants are retained in the ER. We studied fluorescent chimeras of the Trop‐2 Q118E, E227K and L186P mutants in mammalian cells harboring CRISPR/Cas9‐mediated inhibition of the UGGT1 and/or UGGT2 genes. The membrane localization of the Trop‐2 Q118E, E227K and L186P mutants was successfully rescued in UGGT1−/−cells. UGGT1 also efficiently reglucosylated Trop‐2‐Q118E‐EYFP in cellula. The study supports the hypothesis that UGGT1 modulation would constitute a novel therapeutic strategy for the treatment of pathological conditions associated to misfolded membrane glycoproteins (whenever the mutation impairs but does not abrogate function), and it encourages the testing of modulators of ER glycoprotein folding quality control as broad‐spectrum rescue‐of‐secretion drugs in rare diseases caused by responsive secreted glycoprotein mutants. [ABSTRACT FROM AUTHOR]

Trop-2 is a highly conserved one-pass transmembrane mammalian glycoprotein that is normally expressed in tissues such as the lung, intestines, and kidney during embryonic development. It is overexpressed in many epithelial cancers but is absent in non-epithelial tumors. Trop-2 is an intracellular calcium signal transducer that participates in the promotion of cell proliferation, migration, invasion, metastasis, and probably stemness. It also has some tumor suppressor effects. The pro-tumoral actions have been thoroughly investigated and reported. However, Trop-2's activity in chemoresistance is less well known. We review a possible relationship between Trop-2, chemotherapy, and chemoresistance. We conclude that there is a clear role for Trop-2 in some specific chemoresistance events. On the other hand, there is no clear evidence for its participation in multidrug resistance through direct drug transport. The development of antibody conjugate drugs (ACD) centered on anti-Trop-2 monoclonal antibodies opened the gates for the treatment of some tumors resistant to classic chemotherapies. Advanced urothelial tumors and breast cancer were among the first malignancies for which these ACDs have been employed. However, there is a wide group of other tumors that may benefit from anti-Trop-2 therapy as soon as clinical trials are completed. [ABSTRACT FROM AUTHOR]

A phylogenetic conservation analysis of Trop-2 across vertebrate species showed a high degree of sequence conservation, permitting to explore multiple models as pre-clinical benchmarks. Sequence divergence and incomplete conservation of expression patterns were observed in mouse and rat. Primate Trop-2 sequences were found to be 95%–100% identical to the human sequence. Comparative three-dimension primate Trop-2 structures were obtained with AlphaFold and homology modeling. This revealed high structure conservation of Trop-2 (0.66 ProMod3 GMQE, 0.80–0.86 ± 0.05 QMEANDisCo scores), with conservative amino acid changes at variant sites. Primate TACSTD2/TROP2 cDNAs were cloned and transfectants for individual ORF were shown to be efficiently recognized by humanized anti-Trop-2 monoclonal antibodies (Hu2G10, Hu2EF). Immunohistochemistry analysis of Macaca mulatta (rhesus monkey) tissues showed Trop-2 expression patterns that closely followed those in human tissues. This led us to test Trop-2 targeting in vivo in Macaca fascicularis (cynomolgus monkey). Intravenously injected Hu2G10 and Hu2EF were well tolerated from 5 to 10 mg/kg. Neither neurological, respiratory, digestive, urinary symptoms, nor biochemical or hematological toxicities were detected during 28-day observation. Blood serum pharmacokinetic (PK) studies were conducted utilizing anti-idiotypic antibodies in capture-ELISA assays. Hu2G10 (t1/2 = 6.5 days) and Hu2EF (t1/2 = 5.5 days) were stable in plasma, and were detectable in the circulation up to 3 weeks after the infusion. These findings validate primates as reliable models for Hu2G10 and Hu2EF toxicity and PK, and support the use of these antibodies as next-generation anti-Trop-2 immunotherapy tools.

Background and objective: Sacituzumab govitecan (SG), the first antibody-drug conjugate targeting human trophoblast cell-surface antigen 2 (Trop-2), has been approved by the Food and Drug Administration (FDA) for the treatment of advanced or metastatic breast cancer and urothelial cancer. However, there is currently a dearth of information regarding the safety profiles of SG in a large sample cohort. The objective of the present study is to investigate SG-related adverse events (AEs) in real-world settings leveraging the FDA Adverse Event Reporting System (FAERS) database to guide the safety management of clinical medication. Methods: The FAERS database was retrospectively queried to extract reports associated with SG from April 2020 to March 2023. To identify and evaluate potential AEs in patients receiving SG, various disproportionality analyses such as reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) were employed. Results: Overall, 2069 reports of SG as the "primary suspect" were identified. Noteworthy, SG was significantly associated with an increased risk of blood lymphatic system disorders (ROR, 7.18; 95% CI, 6.58-7.84) and hepatobiliary disorders (ROR, 2.68; 95% CI, 2.17-3.30) at the System Organ Class (SOC) level. Meanwhile, 61 significant disproportionality preferred terms (PTs) simultaneously complied with all four algorithms were adopted. Therein, anemia, thrombocytopenia, neutropenia, leukopenia, diarrhea, asthenia, alopecia, and electrolyte imbalance were consistent with the common AEs described in the clinical trials and specification of SG. Furthermore, unexpected significant AEs include colitis (ROR, 12.09; 95% CI, 9.1-16.08), heart rate increased (ROR, 5.11; 95% CI, 3.84-6.79), sepsis (ROR, 4.77; 95% CI, 3.59-6.34), cholestasis (ROR, 6.28; 95% CI, 3.48-11.36), blood bilirubin increased (ROR, 4.65; 95% CI, 2.42-8.94) and meningitis (ROR, 7.23; 95% CI, 2.71-19.29) were also be detected. The median time to onset of SG-related AEs was 14 [interquartile range (IQR), 7-52] days, with the majority occurring within the initial month of SG treatment. Conclusion: Our study validates the commonly known AEs and also found some potentially emerging safety issues related to SG in real-world clinical practice, which could provide valuable vigilance evidence for clinicians and pharmacists to manage the safety issues of SG. [ABSTRACT FROM AUTHOR]

Background: Trophoblast cell-surface antigen 2 (TROP-2) is a transmembrane glycoprotein expressed in epithelial cells that has been associated with malignant progression in most carcinomas. Accordingly, the genetic complexity of gastrointestinal tumors necessitates the investigation of new biomarkers with potential prognostic value. The aim of this systematic review is to assess the effect of TROP-2 on the overall survival of patients who underwent surgery for gastrointestinal malignancy. Methods: The present systematic review was designed using the PRISMA and AMSTAR guidelines. We searched the Pubmed, EMBASE and CENTRAL databases from their inception to September 2023. Results: Ten studies that enrolled 2293 patients were included for qualitative analysis. Six studies evaluated patients with colorectal cancer, two studies included patients with gastric carcinoma, patients with pancreatic cancer were included in one study and one study included hepatobiliary cancer patients. TROP-2 was positive in 1005/2293 samples of the immunohistochemically evaluated biopsies and was associated with poor overall survival in all studies. High intensity was also associated with more aggressive histopathological characteristics, such us deep tissue invasion, lymph node metastasis and cell atypia. The prognostic value of TROP-2 was shown to be enhanced in patients with advanced disease and poor histological differentiation. Conclusion: TROP-2 was expressed at high levels in gastrointestinal tumors, which was associated with both tumor development and pathological aggressiveness. Therefore, TROP-2 could be used as a biomarker to determine clinical prognosis and as a potential therapeutic target in malignancies of the gastrointestinal tract, but further studies need to validate it. [ABSTRACT FROM AUTHOR]

Trop-2, a transmembrane glycoprotein, has been identified in human epithelial cells as a contributor to tumor growth and unfavorable prognosis in breast cancer (BC). Our study aimed to assess the expression of Trop-2 protein via immunohistochemistry (IHC) and correlate it with clinicopathological features in early luminal-like BC. We conducted a cross-sectional study evaluating Trop-2 protein expression in tissue microarrays using IHC. The expression was evaluated by the H-score and the following categorization was used: H-Score 0 to <100 as low, H-Score 100 to 200 as intermediate, and H-Score >200 to 300 as high. The study included 84 patients with a median age of 57, of whom 70% had invasive ductal carcinomas, 75% were classified as T2, and 47.6% had no affected lymph nodes. Trop-2 expression was high in 56% of patients and intermediate in 38%. None of the patients had an H-Score of zero. No correlation was observed between Trop-2 expression and clinicopathological features, including age, histological subtype, grade, Ki67, tumor size, nodal status, lymphovascular invasion, tumor subtype, and pathological staging. We demonstrated that Trop-2 is highly expressed in early luminal-like BC and is not influenced by clinicopathological features. [ABSTRACT FROM AUTHOR]

Purpose: Vulvar squamous cell carcinoma (VSCC) is a rare malignancy of the female genital tract with increasing incidence rates. Etiologically, HPV-dependent and HPV-independent VSCC are distinguished. Surgical treatment and/or radiotherapy represent the therapeutic mainstay for localized disease. For recurrent or metastatic VSCC, treatment options are limited. Research has identified trophoblast cell surface antigen 2 (TROP-2) to be broadly expressed across different tumor entities. The aim of the present study was to systematically investigate the expression of TROP-2 in VSCC. Methods: TROP-2 protein expression was investigated by immunohistochemistry in a cohort comprising n = 103 patients with primary VSCC. A four-tier scoring system (0: no staining, 1 + : low staining, 2 + : moderate staining, 3 + : high staining) was applied for quantification of protein expression. For further analyses, two groups (low TROP-2 expression: 0/1 + ; high TROP-2 expression: 2 + /3 +) were generated. The entire study cohort, as well as HPV-dependent and HPV-independent VSCC were considered separately. Results: In the entire VSCC study cohort, TROP-2 expression was present in 97.1% of all cases (n = 100) with 74.8% displaying high TROP-2 expression (2 + /3 +). Only 2.9% of tumors showed absent TROP-2 expression. Of note, all HPV-dependent VSCC (n = 18) demonstrated high TROP-2 expression (2 + /3 +). In the subgroup of HPV-independent VSCC (n = 70), high TROP-2 expression was associated with favorable clinical outcomes based on log rank test and univariate cox analysis. Conclusion: TROP-2 protein expression is of prognostic value in HPV-independent VSCC. The broad expression of TROP-2 in VSCC indicates the TROP-2 directed ADC Sacituzumab govitecan as a potential new therapeutic strategy for VSCC patients. [ABSTRACT FROM AUTHOR]

Although breast cancer has a good prognosis compared with various cancers, metastatic breast cancer has an aggressive disease course and remains incurable. Therefore, treatment of early breast cancer to prevent recurrence and metastasis is crucial. Recently, the development of anti-cancer drugs, such as targeted agents and immuno-oncology, has been accelerating. Antibody-drug conjugates (ADCs) are also building a new paradigm. Particularly, ADCs targeting Trop-2 were approved for their efficacy in metastatic triple-negative breast cancer patients who received ≥2 prior systemic therapies and showed significant results in heavily pretreated hormone receptor-positive/HER2-negative breast cancer. In this brief review, we provide an overview of ongoing clinical trials of ADCs targeting Trop-2 in early breast cancer, specifically sacituzumab govitecan.

Simple Summary: We sought recognition of Trop-2 within difficult-to-reach, densely packed tumor sites. The 2EF mAb was developed, and demonstrated efficient access to Trop-2 at cell–cell junctions in breast cancer cells in culture and in prostate tumors that were not accessible to benchmark anti-Trop-2 antibodies. The 2EF antibody was shown to inhibit the growth of cancer cells in vitro, with the highest activity at high cell density. Correspondingly, 2EF showed the highest anticancer activity on densely packed, Trop-2-expressing tumors. The 2EF mAb enhances the activity of the cancer-only binding 2G10 mAb against tumors in vivo, opening novel avenues for Trop-2-targeted therapy. Trop-2 proteolytic processing in cancer cells exposes epitopes that were specifically targeted by the 2G10 antibody. We sought additional recognition of Trop-2 within difficult-to-reach, densely packed tumor sites. Trop-2 deletion mutants were employed in immunization and screening procedures, and these led to the recognition of a novel epitope in the N-terminal region of Trop-2, by the 2EF antibody. The 2EF mAb was shown to bind Trop-2 at cell–cell junctions in MCF-7 breast cancer cells, and in deeply seated sites in prostate cancer, that were inaccessible to benchmark anti-Trop-2 antibodies. The 2EF antibody was shown to inhibit the growth of HT29 colon tumor cells in vitro, with the highest activity at high cell density. In vivo, 2EF showed anticancer activity against SKOv3 ovarian, Colo205, HT29, HCT116 colon and DU-145 prostate tumors, with the highest impact on densely packed tumor sites, whereby 2EF outcompeted benchmark anti-Trop-2 antibodies. Given the different recognition modes of Trop-2 by 2EF and 2G10, we hypothesized the effective interaction of the two mAb in vivo. The 2EF mAb was indeed demonstrated to enhance the activity of 2G10 against tumor xenotransplants, opening novel avenues for Trop-2-targeted therapy. We humanized 2EF by state-of-the-art CDR grafting/re-modeling, yielding the Hu2EF for therapy of Trop-2-expressing tumors in patients. [ABSTRACT FROM AUTHOR]

The advent of high throughput DNA sequencing is providing massive amounts of tumor-associated mutation data. Implicit in these analyses is the assumption that, by acquiring a series of hallmark changes, normal cells evolve along a neoplastic path. However, the lack of correlation between cancer risk and global exposure to mutagenic factors provides arguments against this model. This suggested that additional, non-mutagenic factors are at work in cancer development. A candidate determinant is TROP2, that stands out for its expression in the majority of solid tumors in human, for its impact on the prognosis of most solid cancers and for its role as driver of cancer growth and metastatic diffusion, through overexpression as a wild-type form. The Trop-2 signaling network encompasses CREB1, Jun, NF-kB, Rb, STAT1 and STAT3, through induction of cyclin D1 and MAPK/ERK. Notably, Trop-2-driven pathways vastly overlap with those activated by most functionally relevant/ most frequently mutated RAS and TP53, and are co-expressed in a large fraction of individual tumor cases, suggesting functional overlap. Mutated Ras was shown to synergize with the TROP2-CYCLIND1 mRNA chimera in transforming primary cells into tumorigenic ones. Genomic loss of TROP2 was found to promote carcinogenesis in squamous cell carcinomas through modulation of Src and mutated Ras pathways. DNA methylation and TP53 status were shown to cause genome instability and TROP gene amplification, together with Trop-2 protein overexpression. These findings suggest that mutagenic and the TROP2 non-mutagenic pathways deeply intertwine in driving transformed cell growth and malignant progression of solid cancers. [ABSTRACT FROM AUTHOR]

Metastatic hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) breast cancer survival outcomes have improved significantly; however, once endocrine resistance develops, response rates to systemic treatments are limited. Within the developing field of antibody-drug conjugates, the TROPiCS-02 study showed a significant improvement in progression-free survival with sacituzumab govitecan compared with physician's choice of chemotherapy in patients with endocrine-resistant, metastatic, HR+/HER2-breast cancer. Additionally, overall survival similarly improved (14.4 months versus 11.2 months, respectively). We discuss the role of sacituzumab govitecan and its role in practice, looking at the direct impact it has in metastatic HR+/HER2-breast cancer. [ABSTRACT FROM AUTHOR]

The advent of high throughput DNA sequencing is providing massive amounts of tumor-associated mutation data. Implicit in these analyses is the assumption that, by acquiring a series of hallmark changes, normal cells evolve along a neoplastic path. However, the lack of correlation between cancer risk and global exposure to mutagenic factors provides arguments against this model. This suggested that additional, non-mutagenic factors are at work in cancer development. A candidate determinant is TROP2, that stands out for its expression in the majority of solid tumors in human, for its impact on the prognosis of most solid cancers and for its role as driver of cancer growth and metastatic diffusion, through overexpression as a wild-type form. The Trop-2 signaling network encompasses CREB1, Jun, NF-κB, Rb, STAT1 and STAT3, through induction of cyclin D1 and MAPK/ERK. Notably, Trop-2-driven pathways vastly overlap with those activated by most functionally relevant/most frequently mutated RAS and TP53, and are co-expressed in a large fraction of individual tumor cases, suggesting functional overlap. Mutated Ras was shown to synergize with the TROP2-CYCLIND1 mRNA chimera in transforming primary cells into tumorigenic ones. Genomic loss of TROP2 was found to promote carcinogenesis in squamous cell carcinomas through modulation of Src and mutated Ras pathways. DNA methylation and TP53 status were shown to cause genome instability and TROP gene amplification, together with Trop-2 protein overexpression. These findings suggest that mutagenic and the TROP2 non-mutagenic pathways deeply intertwine in driving transformed cell growth and malignant progression of solid cancers.

Refractory or relapsing metastatic triple‐negative breast cancer (mTNBC) has a poor prognosis. Sacituzumab govitecan (SG) is a novel antibody‐drug conjugate, targeting human trophoblast cell‐surface antigen 2 (Trop‐2). This is the first report of SG's efficacy and safety in Chinese patients with mTNBC. EVER‐132‐001 (NCT04454437) was a multicenter, single‐arm, Phase IIb study in Chinese patients with mTNBC who failed ≥2 prior chemotherapy regimens. Eligible patients received 10 mg/kg SG on Days 1 and 8 of each 21‐day treatment cycle, until disease progression/unacceptable toxicity. The primary endpoint was objective response rate (ORR) assessed by the Independent Review Committee. Secondary endpoints included: duration of response (DOR), clinical benefit rate (CBR), progression‐free survival (PFS), overall survival (OS) and safety. Eighty female Chinese patients (median age 47.6 years; range 24‐69.9 years) received ≥1 SG dose with a median of 8 treatment cycles by the cutoff date (August 6, 2021). Median number of prior systemic cancer treatments was 4.0 (range 2.0‐8.0). ORR and CBR were reported 38.8% (95% confidence interval [CI]: 28.06‐50.30) and 43.8% (95% CI, 32.68‐55.30) of patients, respectively. The median PFS was 5.55 months (95% CI, 4.14‐N/A). SG‐related Grade ≥3 treatment‐emergent adverse events (TEAEs) were reported in 71.3%, the most common were neutrophil count decreased (62.5%), white blood cell count decreased (48.8%) and anemia (21.3%); 6.3% discontinued SG because of TEAEs. SG demonstrated substantial clinical activity in heavily pretreated Chinese patients with mTNBC. The observed safety profile was generally manageable. [ABSTRACT FROM AUTHOR]

Simple Summary: Metastasis is the root cause of cancer death, responsible for roughly 90% of all cancer-related fatalities. Therefore, treating metastatic cancer is essential for optimal clinical management of these patients. Although there is currently no effective treatment for metastatic breast cancer, high-throughput approaches have identified novel molecules that are critical to tumor growth and metastasis in recent years. Novel therapies that target these molecules, such as immunotherapy, have been evaluated in both preclinical and clinical settings and have proven to be very promising in prolonging survival and relieving symptoms of metastatic disease, thereby enhancing the quality of life of patients. Due to the high intertumoral and intratumoral heterogeneity of cancer, the development of subtype-specific therapeutics and the use of combination treatments to simultaneously target multiple oncogenic signaling pathways may overcome drug resistance and achieve better clinical outcome for metastatic breast cancer. Breast cancer is now the most common cancer worldwide, and it is also the main cause of cancer-related death in women. Survival rates for female breast cancer have significantly improved due to early diagnosis and better treatment. Nevertheless, for patients with advanced or metastatic breast cancer, the survival rate is still low, reflecting a need for the development of new therapies. Mechanistic insights into metastatic breast cancer have provided excellent opportunities for developing novel therapeutic strategies. Although high-throughput approaches have identified several therapeutic targets in metastatic disease, some subtypes such as triple-negative breast cancer do not yet have an apparent tumor-specific receptor or pathway to target. Therefore, exploring new druggable targets in metastatic disease is a high clinical priority. In this review, we summarize the emerging intrinsic therapeutic targets for metastatic breast cancer, including cyclin D-dependent kinases CDK4 and CDK6, the PI3K/AKT/mTOR pathway, the insulin/IGF1R pathway, the EGFR/HER family, the JAK/STAT pathway, poly(ADP-ribose) polymerases (PARP), TROP-2, Src kinases, histone modification enzymes, activated growth factor receptors, androgen receptors, breast cancer stem cells, matrix metalloproteinases, and immune checkpoint proteins. We also review the latest development in breast cancer immunotherapy. Drugs that target these molecules/pathways are either already FDA-approved or currently being tested in clinical trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Trophoblast cell surface antigen-2 (Trop-2) is a widely expressed glycoprotein on a variety of different tumours. Trop-2 is considered as a marker of germ cells and is associated with regenerative ability in several tissues. Some studies demonstrated both oncogenic and tumour suppressor roles for Trop-2. In recent years, the therapeutic value of Trop-2 was identified and various studies with drug–antibody conjugates have been pursued in cancer patients. In this work, we reviewed both the pre-clinical and clinical activities of anti-Trop-2 therapy to highlight the future developments of these therapies. Trophoblast cell surface antigen-2 (Trop-2) is a glycoprotein that was first described as a membrane marker of trophoblast cells and was associated with regenerative abilities. Trop-2 overexpression was also described in several tumour types. Nevertheless, the therapeutic potential of Trop-2 was widely recognized and clinical studies with drug–antibody conjugates have been initiated in various cancer types. Recently, these efforts have been rewarded with the approval of sacituzumab govitecan from both the Food and Drug Administration (FDA) and European Medicines Agency (EMA), for metastatic triple-negative breast cancer patients. In our work, we briefly summarize the various characteristics of cancer cells overexpressing Trop-2, the pre-clinical activities of specific inhibitors, and the role of anti-Trop-2 therapy in current clinical practice. We also review the ongoing clinical trials to provide a snapshot of the future developments of these therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: Trop-2 is an exciting, new target for the treatment of breast cancer. Trop-2 is found at high levels in multiple cancers such as prostate, pancreatic, urothelial, lung, and breast cancer. Among different breast cancer subtypes, Trop-2 is most highly expressed in triple negative breast cancer. Drugs that inhibit Trop-2 are now an important treatment option for patients with metastatic triple negative breast cancer, for whom few treatment options exist. The benefit of Trop-2 inhibitors has also been observed in patients with hormone receptor positive breast cancer, whose tumors are resistant to standard treatments. Ongoing studies are working to understand if patients can benefit from different drug combinations with Trop-2 inhibitors in the metastatic setting and if Trop-2 inhibition can benefit patients with early stage disease. The emergence of Trop-2 as a therapeutic target has given rise to new treatment paradigms for the treatment of patients with advanced and metastatic breast cancer. Trop-2 is most highly expressed in triple negative breast cancer (TNBC), but the receptor is found across all breast cancer subtypes. With sacituzumab govitecan, the first FDA-approved, Trop-2 inhibitor, providing a survival benefit in patients with both metastatic TNBC and hormone receptor positive breast cancer, additional Trop-2 directed therapies are under investigation. Ongoing studies of combination regimens with immunotherapy, PARP inhibitors, and other targeted agents aim to further harness the effect of Trop-2 inhibition. Current investigations are also underway in the neoadjuvant and adjuvant setting to evaluate the therapeutic benefit of Trop-2 inhibition in patients with early stage disease. This review highlights the significant impact the discovery Trop-2 has had on our patients with heavily pretreated breast cancer, for whom few treatment options exist, and the future direction of novel Trop-2 targeted therapies. [ABSTRACT FROM AUTHOR]

Urothelial carcinoma is the second most frequent genitourinary malignancy. Despite the poor prognosis, new treatment options have emerged and have expanded the therapeutic landscape for the disease. Although major improvements have been achieved, many patients experience rapid disease progression and low responses in subsequent lines of therapy. Sacituzumab govitecan is an ADC that targets Trop-2, which is highly expressed in urothelial cancers. Promising results in early clinical trials have led to further drug development which confirmed encouraging efficacy. Sacituzumab govitecan has been given accelerated approval in 2021 for patients with locally advanced and metastatic urothelial cancer who previously received a platinum containing chemotherapy and either a programmed death receptor-1 or programmed death ligand inhibitor. The results are promising, with encouraging efficacy and safety, however responses are not universal. There is a growing comprehension of mechanisms of resistance and predictive biomarkers that are crucial to improving outcomes. In this review, we summarize the current knowledge on antibody–drug conjugates and the clinical findings that led to the approval of Sacituzumab govitecan and discuss the therapeutic potential of new combinations, mechanisms of resistance and predictive biomarkers. [ABSTRACT FROM AUTHOR]

Although breast cancer has a good prognosis compared with various cancers, metastatic breast cancer has an aggressive disease course and remains incurable. Therefore, treatment of early breast cancer to prevent recurrence and metastasis is crucial. Recently, the development of anti-cancer drugs, such as targeted agents and immuno-oncology, has been accelerating. Antibody-drug conjugates (ADCs) are also building a new paradigm. Particularly, ADCs targeting Trop-2 were approved for their efficacy in metastatic triple-negative breast cancer patients who received ≥2 prior systemic therapies and showed significant results in heavily pretreated hormone receptor-positive/HER2-negative breast cancer. In this brief review, we provide an overview of ongoing clinical trials of ADCs targeting Trop-2 in early breast cancer, specifically sacituzumab govitecan. • Antibody-drug conjugates (ADCs) are building a new paradigm in cancer treatment. • Sacituzumab govitecan (SG) and datopotamab deruxtecan (Dato-DXd) are ADCs targeting Trop-2. • SG and Dato-DXd showed improved efficacy in metastatic breast cancer treatment. • Several studies using SG are ongoing in the neoadjuvant/adjuvant setting for early breast cancer. [ABSTRACT FROM AUTHOR]

Objectives: Urothelial carcinomas (UCs) encompass a heterogeneous group of tumors. Several histopathologic features are associated with poor clinical outcomes and limited treatment options. With new rising therapeutic modalities, we aimed to determine the pattern of expression of Trop-2 and ephrin B2 in UC with aggressive subtype histology and/or divergent differentiation (SH/DD)., Methods: We performed a retrospective analysis of 113 UC samples with SH/DD at our institution from 2011 to 2021. Immunohistochemical staining for Trop-2 and ephrin B2 expression was performed on all cases. Expression was determined by the percentage of samples with a moderate or strong H-score., Results: Our results show Trop-2 expression was the highest in squamous cell carcinoma and UC with squamous differentiation, adenocarcinoma and UC with glandular differentiation, and plasmacytoid subtype, while ephrin B2 expression was highest in adenocarcinoma, UC with glandular differentiation, and small cell carcinoma., Conclusions: Expression of Trop-2 and ephrin B2 may demonstrate therapeutic possibilities for patients with SH/DD, who usually have limited treatment options, particularly in small cell carcinoma, in which few targets have been identified. Clinical trials to investigate the efficacy of these novel treatments are warranted., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Abstract: The therapeutic landscape of patients with breast cancer has changed significantly with the introduction of antibody-drug conjugates (ADCs). Although human epidermal growth factor receptor 2 (HER2) has been the centerpiece of ADC development, potentially any surface antigen with differential expression between tumor and normal cells may be suitable for targeting with ADCs. Exploration of new targets is critical to expand the fraction of patients who can benefit from ADCs. Sacituzumab govitecan, an anti-trophoblast cell surface antigen 2 ADC, is the only non-anti-HER2 ADC approved for breast cancer to date, with several novel ADCs directed against novel targets (e.g., HER3, LIV-1) at various stages of preclinical and clinical development. The aim of this review is to provide an overview of clinical trials investigating ADCs targeting novel antigens. We discuss the optimal characteristics of the target to be exploited in ADCs' design and potential future challenges in the evolving field of ADCs such as biomarker assessment, patient selection, and sequencing of ADCs. [ABSTRACT FROM AUTHOR]

Abstract: Antibody-drug conjugates (ADCs) have joined the armamentarium against urothelial cancer (UC) as an effective therapy option. Since 2019, the US Food and Drug Administration has approved 2 ADCs for advanced previously treated UC: enfortumab vedotin, which targets nectin-4 and sacituzumab govitecan, which targets trophoblast cell-surface antigen 2. These ADCs are now being tested in earlier disease settings and in previously untreated patients. Furthermore, novel ADCs (e.g., anti-HER-2) are being tested in the clinic and show promising clinical benefit. The next frontier is to understand the mechanisms of resistance and response, gaining experience with ADC-related adverse events and learning the best strategy to sequence and combine these agents with existing therapies. Here, we highlight the recent advances in the development of ADCs for treating localized and metastatic UC. [ABSTRACT FROM AUTHOR]

Background: Sacituzumab govitecan is an antibody–drug conjugate that delivers SN-38, an active metabolite of irinotecan, to the target molecule, trophoblast cell-surface antigen 2 (Trop-2). It is a promising drug for triple-negative breast cancer and is anticipated to be effective for luminal breast cancer. The efficacy of the agent relies on the expression of Trop-2 rather than its intracellular function. However, conditions that alter the Trop-2 expression have not been well investigated. Methods: We tested a range of clinically related treatments for their effect on Trop-2 expression in cultured breast cancer cell lines. Results: The expression level of Trop-2 differed among cell lines, independent of their subtypes, and was highly variable on treatment with kinase inhibitors, tamoxifen, irradiation, and chemotherapeutic agents including irinotecan. While inhibitors of AKT, RSK, and p38 MAPK suppressed the Trop-2 expression, tamoxifen treatment significantly increased Trop-2 expression in luminal cancer cell lines. Notably, luminal cancer cells with acquired resistance to tamoxifen also exhibited higher levels of Trop-2. We identified transcription factor EB (TFEB) as a possible mechanism underlying tamoxifen-induced elevation of Trop-2 expression. Tamoxifen triggers dephosphorylation of TFEB, an active form of TFEB, and the effect of tamoxifen on Trop-2 was prevented by depletion of TFEB. A luciferase reporter assay showed that Trop-2 induction by TFEB was dependent on a tandem E-box motif within the Trop-2 promoter region. Conclusions: Overall, these results suggest that the effectiveness of sacituzumab govitecan could be altered by concomitant treatment and that tamoxifen could be a favorable agent for combined therapy. [ABSTRACT FROM AUTHOR]

We recently reported that activation of Trop-2 through its cleavage at R87-T88 by ADAM10 underlies Trop-2–driven progression of colon cancer. However, the mechanism of action and pathological impact of Trop-2 in metastatic diffusion remain unexplored. Through searches for molecular determinants of cancer metastasis, we identified TROP2 as unique in its up-regulation across independent colon cancer metastasis models. Overexpression of wild-type Trop-2 in KM12SM human colon cancer cells increased liver metastasis rates in vivo in immunosuppressed mice. Metastatic growth was further enhanced by a tail-less, activated ΔcytoTrop-2 mutant, indicating the Trop-2 tail as a pivotal inhibitory signaling element. In primary tumors and metastases, transcriptome analysis showed no down-regulation of CDH1 by transcription factors for epithelial-to-mesenchymal transition, thus suggesting that the pro-metastatic activity of Trop-2 is through alternative mechanisms. Trop-2 can tightly interact with ADAM10. Here, Trop-2 bound E-cadherin and stimulated ADAM10-mediated proteolytic cleavage of E-cadherin intracellular domain. This induced detachment of E-cadherin from β-actin, and loss of cell-cell adhesion, acquisition of invasive capability, and membrane-driven activation of β-catenin signaling, which were further enhanced by the ΔcytoTrop-2 mutant. This Trop-2/E-cadherin/β-catenin program led to anti-apoptotic signaling, increased cell migration, and enhanced cancer-cell survival. In patients with colon cancer, activation of this Trop-2–centered program led to significantly reduced relapse-free and overall survival, indicating a major impact on progression to metastatic disease. Recently, the anti-Trop-2 mAb Sacituzumab govitecan-hziy was shown to be active against metastatic breast cancer. Our findings define the key relevance of Trop-2 as a target in metastatic colon cancer.