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Correlation of TROP-2 expression with clinical-pathological characteristics and outcome in triple-negative breast cancer.

ABSTRACT: Limited data exist regarding the associations between TROP-2 protein expression, clinical-pathological characteristics, and outcome in triple-negative breast cancer (TNBC). TROP-2 expression was determined for patients diagnosed with TNBC between 2000 and 2017 by immunohistochemistry (IHC) (ab227689, Abcam) on whole slide tumor sections, and assessed as continuous and categorical variables (H-score high, 201-300, medium 100-200 and low < 100). We investigated the prognostic value of TROP-2 expression for relapse and survival, associations between TROP-2 expression and baseline patient and tumor characteristics, stromal tumor-infiltrating lymphocytes (sTILs), androgen receptor (AR), standardized mitotic index (SMI) and pathological complete response (pCR, in patients with neoadjuvant chemotherapy) were assessed. We included 685 patients with a median age at diagnosis of 54 years (range 22-90 years). After median follow-up of 9.6 years, 17.5% of patients experienced distant relapse. TROP-2 expression was high, medium and low in 97 (16.5%), 149 (25.3%) and 343 (58.2%) of patients, respectively. The presence of LVI, associated DCIS, nodal involvement, apocrine histology and AR expression were correlated with higher TROP-2 levels. There were no associations between TROP-2 expression and sTILs, time-to-event outcomes, or pCR rate after neoadjuvant chemotherapy. TROP-2 expression is not associated with sTILs level and has no prognostic value in our cohort of stage 1-3 TNBC. However, an association with histotype and AR expression was found, suggesting a histotype specific TROP-2 expression pattern with highest expression in apocrine subtype, warranting further research.

SUBMITTER: Izci H

PROVIDER: S-EPMC9797547 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Correlation of TROP-2 expression with clinical-pathological characteristics and outcome in triple-negative breast cancer.

Izci Hava H Punie Kevin K Waumans Lise L Laenen Annouschka A Wildiers Hans H Verdoodt Freija F Desmedt Christine C Ardui Jan J Smeets Ann A Han Sileny N SN Nevelsteen Ines I Neven Patrick P Floris Giuseppe G

Scientific reports 20221228 1

Limited data exist regarding the associations between TROP-2 protein expression, clinical-pathological characteristics, and outcome in triple-negative breast cancer (TNBC). TROP-2 expression was determined for patients diagnosed with TNBC between 2000 and 2017 by immunohistochemistry (IHC) (ab227689, Abcam) on whole slide tumor sections, and assessed as continuous and categorical variables (H-score high, 201-300, medium 100-200 and low < 100). We investigated the prognostic value of TROP-2 expre ...[more]

PMID: 36577919

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Project description:IntroductionTriple-Negative Breast Cancer (TNBC) is an aggressive breast cancer subtype, in which targeting the Trophoblast cell-surface antigen-2 (Trop-2), using antibody-drug conjugates (ADC), results in significant clinical improvement. However, clinicopathological correlations with Trop-2 protein expression levels remain limited in TNBC patients.MethodsHere we assessed by immunohistochemistry (IHC) using the mouse monoclonal anti-Trop-2 antibody (Enzo, Cat. ENZ-ABS380) cell membrane Trop-2 expression levels and classified them in 3 H-Score classes, low (< 100), moderate (100-200), and strong (> 200). We also evaluated potential associations with clinicopathological variables including basal-like and molecular apocrine phenotypes, immune infiltrate characteristics, PTEN and PIK3CA alterations in a large retrospective series of 228 nonmetastatic TNBC patients.ResultsTrop-2 expression was evaluated as low, moderate and strong in 12.3%, 28.9%, and 58.8% of the cases respectively. Only 3 tumors showed no Trop-2 expression. Interestingly, Trop-2 expression was not associated with classical breast cancer clinicopathological variables, HER2 levels or molecular subtype, neither did we observe an association with relapse-free survival. Only a marginal association with pT1 tumors was observed, which tended to express increased levels of Trop-2 protein. In order to determine possible fluctuations of Trop-2 protein expression levels during the course of the disease, we studied a second independent cohort of 18 TNBC comprised of serial tissue samples (diagnostic biopsies, surgical resection specimens and corresponding patients-derived xenografts (PDX)). Trop-2 levels remained globally stable between cognate tumor samples with only one exception corresponding to a Trop-2-negative tumor giving rise to a Trop-2-positive PDX.ConclusionsAs Trop-2 expression appears nearly constant and independent of classical TNBC variables and outcome, association of anti-Trop-2 therapies with other targeted therapies can be evaluated without reducing the population in specific TNBC subgroups.

Project description:Necroptosis, a kind of programmed necrotic cell apoptosis, is the gatekeeper for the host to defend against the invasion of pathogens. It helps to regulate different biological processes regarding human cancer. Nevertheless, studies that determine the impact of death on triple-negative breast cancer (TNBC) are scarce. Therefore, this paper has comprehensively examined the expression as well as clinical significance of necroptosis in TNBC. ConsensusClusterPlus was used to establish a stable molecular classification that used the expression regarding the necroptosis-linked genes. The clinical and immune characteristics of different subclasses were evaluated. Then, the weighted gene coexpression network analysis (WGCNA) assisted in determining key modules, and we selected the genes exhibiting obvious association with necroptosis prognosis through the relationship with prognosis. The univariate Cox regression analysis together with least absolute shrinkage and selection operator (LASSO) techniques served for the construction of the necroptosis-related prognostic risk score (NPRS) model, and the pathway characteristics of NPRS model grouping were further studied. Finally, the NPRS, taking into account the clinicopathological features, used the decision tree model for enhancing the prognostic model as well as the survival prediction. First, two stable molecular subtypes with different prognosis and immune characteristics were identified using necroptosis marker genes. Then, the key modules were identified, and 10 genes significantly related to the prognosis of necroptosis were selected. Then, the clinical prognostic model of NPRS was developed considering the prognosis-linked necroptosis genes. Finally, the NPRS model, taking into account the clinicopathological features, adopted the decision tree model for enhancing the prognostic model as well as the survival prediction. Herein, two new molecular subgroups considering necroptosis-linked genes are proposed, and an NPRS model composed of 10 genes is developed, which maybe assist in the personalized treatment and clinical treatment guidance of TNBC patients.

Project description:BackgroundTriple-negative breast cancer is a subtype of breast cancer with aggressive tumor behavior and distinct disease etiology. Due to the lack of an effective targeted medicine, treatment options for triple-negative breast cancer are few and recurrence rates are high. Although various multi-gene prognostic markers have been proposed for the prediction of breast cancer outcome, most of them were proven clinically useful only for estrogen receptor-positive breast cancers. Reliable identification of triple-negative patients with a favorable prognosis is not yet possible.Methodology/principal findingsClinicopathological information and microarray data from 157 invasive breast carcinomas were collected at National Taiwan University Hospital from 1995 to 2008. Gene expression data of 51 triple-negative and 106 luminal breast cancers were generated by oligonucleotide microarrays. Hierarchical clustering analysis revealed that the majority (94%) of triple-negative breast cancers were tightly clustered together carrying strong basal-like characteristics. A 45-gene prognostic signature giving 98% predictive accuracy in distant recurrence of our triple-negative patients was determined using the receiver operating characteristic analysis and leave-one-out cross validation. External validation of the prognostic signature in an independent microarray dataset of 59 early-stage triple-negative patients also obtained statistical significance (hazard ratio 2.29, 95% confidence interval (CI) 1.04-5.06, Cox P=0.04), outperforming five other published breast cancer prognostic signatures. The 45-gene signature identified in this study revealed that TGF-? signaling of immune/inflammatory regulation may play an important role in distant metastatic invasion of triple-negative breast cancer.Conclusions/significanceGene expression data and recurrence information of triple-negative breast cancer were collected and analyzed in this study. A novel set of 45-gene signature was found to be statistically predictive in disease recurrence of triple-negative breast cancer. The 45-gene signature, if further validated, may be a clinically useful tool in risk assessment of distant recurrence for early-stage triple-negative patients.

Project description:BackgroundRanpirnase (Rap) is an amphibian ribonuclease with reported antitumor activity, minimal toxicity, and negligible immunogenicity in clinical studies, but the unfavorable pharmacokinetics and suboptimal efficacy hampered its further clinical development. To improve the potential of Rap-based therapeutics, we have used the DOCK-AND-LOCK™ (DNL™) method to construct a class of novel IgG-Rap immunoRNases. In the present study, a pair of these constructs, (Rap)2-E1-(Rap)2 and (Rap)2-E1*-(Rap)2, comprising four copies of Rap linked to the CH3 and CK termini of hRS7 (humanized anti-Trop-2), respectively, were evaluated as potential therapeutics for triple-negative breast cancer (TNBC).MethodsThe DNL-based immunoRNases, (Rap)2-E1-(Rap)2 and (Rap)2-E1*-(Rap)2, were characterized and tested for biological activities in vitro on a panel of breast cancer cell lines and in vivo in a MDA-MB-468 xenograft model.Results(Rap)2-E1-(Rap)2 was highly purified (>95%), exhibited specific cell binding and rapid internalization in MDA-MB-468, a Trop-2-expressing TNBC line, and displayed potent in vitro cytotoxicity (EC50???1 nM) against diverse breast cancer cell lines with moderate to high expression of Trop-2, including MDA-MB-468, BT-20, HCC1806, SKBR-3, and MCF-7. In comparison, structural counterparts of (Rap)2-E1-(Rap)2, generated by substituting hRS7 with selective non-Trop-2-binding antibodies, such as epratuzumab (anti-CD22), were at least 50-fold less potent than (Rap)2-E1-(Rap)2 in MDA-MB-468 and BT-20 cells, both lacking the expression of the cognate antigen. Moreover, (Rap)2-E1-(Rap)2 was less effective (EC50 > 50 nM) in MDA-MB-231 (low Trop-2) or HCC1395 (no Trop-2), and did not show any toxicity to human peripheral blood mononuclear cells. In a mouse TNBC model, a significant survival benefit was achieved with (Rap)2-E1*-(Rap)2 when given the maximal tolerated dose.ConclusionsA new class of immunoRNases was generated with enhanced potency for targeted therapy of cancer. The promising results from (Rap)2-E1-(Rap)2 and (Rap)2-E1*-(Rap)2 support their further investigation as a potential treatment option for TNBC and other Trop-2-expressing cancers.

Project description:Background and objectiveTriple negative breast cancer (TNBC) refers to a special subtype of breast cancer that is negative for the estrogen receptor, the progesterone receptors, and human epidermal growth factor receptor 2. As a group of diseases, it has strong heterogeneity. Refractory metastatic triple negative breast cancer (mTNBC) has even greater heterogeneity, more susceptibility to drug resistance, and faster progression, which makes it more difficult to treat effectively and significantly reduces a patient's overall survival. Therefore, in order to overcome this difficulty in clinical practice, we need to deeply understand the special subgroup by analyzing definition and prognostic factors of refractory mTNBC and describing the therapeutic status and future treatment directions.MethodsRecent domestic and foreign guidelines, as well as clinical studies related to refractory mTNBC on PubMed and the China National Knowledge Infrastructure (CNKI) databases were retrospectively analyzed. The six keywords we selected were used for literature search. Two authors performed database searches independently, and disagreements over the results were mediated by a third reviewer.Key content and findingsAccording to the guidelines, refractory mTNBC has not been clearly defined. Related studies indicated that tumor heterogeneity may be one of the main mechanisms of early relapse or drug resistance in refractory mTNBC. The clinical treatment options for refractory mTNBC are very limited. Although chemotherapy is the standard treatment, it is limited by poor efficacy and intolerance in the clinical stage. Therefore, in recent years, many studies have explored novel treatment options. Both immunotherapy and poly(ADP-ribose) polymerase (PARP) inhibitors have been selected as first-line treatment in clinical studies, but gained limited benefits. Indeed, clinical studies have shown good efficacy with novel ADCs, which may be promising in the clinical treatment of refractory mTNBC.ConclusionsCurrently, improving the survival time and quality of life of refractory mTNBC are major challenges for clinicians. Novel therapies including immunosuppressive agents, PARP inhibitors, and ADCs rather than chemotherapy alone have achieved good results in the exploration of first-line treatment for refractory TNBC patients, but this warrants further research and investigation.

Dataset Information

Correlation of TROP-2 expression with clinical-pathological characteristics and outcome in triple-negative breast cancer.

Publications

Correlation of TROP-2 expression with clinical-pathological characteristics and outcome in triple-negative breast cancer.

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