Molecular characteristics and metastasis predictor genes of triple-negative breast cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1043-1043
Author(s):  
Wen-Hung Kuo ◽  
Yao-Yin Chang ◽  
Ming-Feng Hou ◽  
Eric Y Chuang ◽  
King-Jen Chang
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Early Stage ◽  
Gene Signature ◽  
Breast Cancers ◽  
Prognostic Signature ◽  
Characteristic Analysis ◽  
Disease Etiology ◽  
Breast Cancer Outcome

1043 Background: Triple-negative breast cancer(TNBC) 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. Methods: Clinicopathological 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 with oligonucleotide microarrays. A prognostic 45-gene signature for triple-negative breast cancer was identified using Student’s t test and receiver operating characteristic analysis. Results: Hierarchical clustering analysis revealed that the majority (94%) of triple-negative breast cancers were tightly clustered together carrying strong basal-like characteristics. A novel 45-gene signature giving 98% predictive accuracy in distant metastasis recurrence was identified in our triple-negative patient cohort. 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% CI 1.04-5.06, Cox P = 0.04), outperforming five other published breast cancer prognostic signatures. The prognostic signature was statistically predictive with the node-negative triple-negative patients in the validation cohort. Conclusions: The 45-gene prognostic signature identified in this study revealed that TGF-β signaling in immune/inflammatory regulation may be critically involved in distant metastatic invasion of TNBC. The 45-gene signature, if further validated, may be a clinically useful tool in risk assessment of metastasis recurrence for early-stage triple-negative patients.

scholarly journals Epigenetic Regulation of Immunotherapy Response in Triple-Negative Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4139
Author(s):  
Pere Llinàs-Arias ◽  
Sandra Íñiguez-Muñoz ◽  
Kelly McCann ◽  
Leonie Voorwerk ◽  
Javier I. J. Orozco ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Regulatory Elements ◽  
Her2 Overexpression ◽  
Breast Cancers ◽  
Cancer Subtypes

Triple-negative breast cancer (TNBC) is defined by the absence of estrogen receptor and progesterone receptor and human epidermal growth factor receptor 2 (HER2) overexpression. This malignancy, representing 15–20% of breast cancers, is a clinical challenge due to the lack of targeted treatments, higher intrinsic aggressiveness, and worse outcomes than other breast cancer subtypes. Immune checkpoint inhibitors have shown promising efficacy for early-stage and advanced TNBC, but this seems limited to a subgroup of patients. Understanding the underlying mechanisms that determine immunotherapy efficiency is essential to identifying which TNBC patients will respond to immunotherapy-based treatments and help to develop new therapeutic strategies. Emerging evidence supports that epigenetic alterations, including aberrant chromatin architecture conformation and the modulation of gene regulatory elements, are critical mechanisms for immune escape. These alterations are particularly interesting since they can be reverted through the inhibition of epigenetic regulators. For that reason, several recent studies suggest that the combination of epigenetic drugs and immunotherapeutic agents can boost anticancer immune responses. In this review, we focused on the contribution of epigenetics to the crosstalk between immune and cancer cells, its relevance on immunotherapy response in TNBC, and the potential benefits of combined treatments.

scholarly journals Practical Approach to Triple-Negative Breast Cancer

2017 ◽  
Vol 13 (5) ◽  
pp. 293-300 ◽  
Author(s):  
Vijayakrishna K. Gadi ◽  
Nancy E. Davidson
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Hormone Receptors ◽  
Triple Negative ◽  
Early Stage ◽  
Management Strategies ◽  
Growth Factor Receptor ◽  
Breast Cancers ◽  
Epidermal Growth ◽  
Proven Method

Triple negative is a term applied to breast cancers that do not meaningfully express the estrogen or progesterone hormone receptors or overexpress the human epidermal growth factor receptor 2 tyrosine kinase. At present, the only proven method for systemic management of triple-negative breast cancer for both early-stage and metastatic settings is cytotoxic chemotherapy. Here, we provide a comprehensive review of management strategies that are best supported by available data. We also review recent advances most likely to affect treatment of triple-negative breast cancer in the coming years with particular emphasis on targeted agents, biologics, and immunotherapy.

SEER-Medicare study of early-stage triple-negative breast cancer: Real-world treatment patterns, survival, and expenditures 2010 to 2016.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e12512-e12512
Author(s):  
Jan Sieluk ◽  
Amin Haiderali ◽  
Min Huang ◽  
Lingfeng Yang ◽  
Konstantinos Tryfonidis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Radiation Therapy ◽  
Elderly Patients ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Early Stage ◽  
Patient Characteristics ◽  
Breast Cancers ◽  
The Us ◽  
Poor Outcomes

e12512 Background: In the US, triple-negative breast cancer (TNBC) represents about 10–20% of breast cancers. Current information about the clinical and economic burden of early-stage TNBC in elderly patients is lacking. Methods: We used the SEER-Medicare database to identify patients with continuous Medicare Parts A/B enrollment, ≥66 years old, newly diagnosed between 2010 - 2015 (followed until 2016) with stage II-III TNBC, who initiated systemic neoadjuvant and/or adjuvant (including chemotherapy and radiation) therapy. Overall survival (OS) and event-free survival (EFS) from diagnosis were estimated using Kaplan-Meier (KM). Healthcare costs were determined during neoadjuvant and adjuvant periods. Results: Of 1569 patients ( > 99% women), 94 (6%) received neoadjuvant therapy, 1162 (74%) received adjuvant therapy, and 313 (20%) received both (neo/adj; Table). Age and race/ethnicity distributions were comparable in the three cohorts. Primary tumor T stage was T1c/T2 for 43%, 83%, and 58% in neoadjuvant, adjuvant, and neo/adj, respectively, and T3 for 14%, 10%, and 15%, respectively. The most common systemic regimens in both neoadjuvant and adjuvant periods were a taxane +/- anthracycline; 21% and 67% of patients in adjuvant and neo/adj cohorts received radiation therapy after surgery. Most claims were for outpatient treatment; hospitalizations were uncommon. The total mean expenditures per patient per month were US$10,620 and $24,408 during neoadjuvant and adjuvant periods, respectively. Conclusions: This study provides insights into patient characteristics, as well as clinical and economic outcomes for elderly patients with early-stage TNBC, treated from 2010-2016 in the US, highlighting the high monetary burden of TNBC and poor outcomes associated with stage III patients. [Table: see text]

scholarly journals De-escalation of Systemic Therapy for Early-Stage, Node-Negative Her2+ and Triple-Negative Breast Cancer

2021 ◽  
Author(s):  
Lorena Gonzalez ◽  
Joanne Mortimer ◽  
Laura Kruper
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Systemic Therapy ◽  
Triple Negative ◽  
Early Stage ◽  
Cytotoxic Agents ◽  
Breast Cancers ◽  
Node Negative ◽  
Her2 Breast Cancer ◽  
Prospective Trials

Abstract Purpose of Review This review summarizes the most recent data on the management of small, node-negative Her2+ and triple-negative breast cancer. Recent Findings Both Her2+ and triple-negative breast cancers are characterized by high rates of recurrence and worse survival outcomes compared to hormone-positive cancers. De-escalation of systemic therapy in early-stage breast cancer is a recent national trend in clinical research. Recent prospective trials support the scaling back of cytotoxic agents and maximization of targeted therapy regimens. Similarly, large retrospective studies on small, node-negative triple-negative breast cancer report the omission of chemotherapy in women with T1a,N0 triple-negative cancers with favorable short term outcomes. Summary De-escalation of systemic therapy for Her2+ breast cancer is effective in the management of early-stage, node-negative disease. Future prospective studies on the omission of systemic therapy for triple-negative breast cancer are required to safely adopt into consensus guidelines.

scholarly journals Oncogene-mediated metabolic gene signature predicts breast cancer outcome

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Merve Aslan ◽  
En-Chi Hsu ◽  
Fernando J. Garcia-Marques ◽  
Abel Bermudez ◽  
Shiqin Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Gene Signature ◽  
The United States ◽  
Breast Cancer Patients ◽  
Metabolic Gene ◽  
Metabolic Signature ◽  
Breast Cancer Outcome ◽  
Cancer Outcome

AbstractBreast cancer remains the second most lethal cancer among women in the United States and triple-negative breast cancer is the most aggressive subtype with limited treatment options. Trop2, a cell membrane glycoprotein, is overexpressed in almost all epithelial cancers. In this study, we demonstrate that Trop2 is overexpressed in triple-negative breast cancer (TNBC), and downregulation of Trop2 delays TNBC cell and tumor growth supporting the oncogenic role of Trop2 in breast cancer. Through proteomic profiling, we discovered a metabolic signature comprised of TALDO1, GPI, LDHA, SHMT2, and ADK proteins that were downregulated in Trop2-depleted breast cancer tumors. The identified oncogene-mediated metabolic gene signature is significantly upregulated in TNBC patients across multiple RNA-expression clinical datasets. Our study further reveals that the metabolic gene signature reliably predicts poor survival of breast cancer patients with early stages of the disease. Taken together, our study identified a new five-gene metabolic signature as an accurate predictor of breast cancer outcome.

Dissecting the Heterogeneity of Triple-Negative Breast Cancer

2012 ◽  
Vol 30 (15) ◽  
pp. 1879-1887 ◽  
Author(s):  
Otto Metzger-Filho ◽  
Andrew Tutt ◽  
Evandro de Azambuja ◽  
Kamal S. Saini ◽  
Giuseppe Viale ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Early Stage ◽  
Parp Inhibitor ◽  
High Sensitivity ◽  
Phase Iii ◽  
Breast Cancers ◽  
Cancer Subtypes

Triple-negative breast cancer (TNBC) accounts for 15% to 20% of breast cancers. It is a heterogeneous disease, not only on the molecular level, but also on the pathologic and clinical levels. TNBC is associated with a significantly higher probability of relapse and poorer overall survival in the first few years after diagnosis when compared with other breast cancer subtypes. This is observed despite its usual high sensitivity to chemotherapy. In the advanced setting, responses observed with chemotherapy lack durability. Early-stage clinical studies suggested impressive potential when a poly (ADP-ribose) polymerase (PARP) inhibitor is given for the treatment of advanced TNBC with BRCA gene dysfunction. The molecular complexity of TNBC has led to proposed subclassifications, which will be of great value for the development of targeted therapies. In this review, we discuss the biology of TNBC at the pathologic and the molecular levels. We also elaborate on the role of systemic therapies and the results of the first phase III clinical trial evaluating the addition of iniparib, a novel investigational anticancer agent that does not possess characteristics typical of the PARP inhibitor class, in combination with chemotherapy in advanced TNBC.

scholarly journals The Early-Stage Triple-Negative Breast Cancer Landscape Derives a Novel Prognostic Signature and Therapeutic Target

2021 ◽  
Author(s):  
Yun-Song Yang ◽  
Yi-Xing Ren ◽  
Cheng-Lin Liu ◽  
Shuang Hao ◽  
Xiao-En Xu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Therapeutic Target ◽  
Prognostic Value ◽  
Triple Negative ◽  
Cox Regression ◽  
Early Stage ◽  
Cancer Center ◽  
Transcriptome Data ◽  
Prognostic Signature

Abstract Purpose: Triple-negative breast cancer (TNBC) is a highly heterogeneous disease. Patients with early-stage TNBCs have distinct likelihood of distant recurrence. Current therapeutic guidance is still limited.Methods: We extracted transcriptome data for 189 pathologically confirmed pT1-2N0M0 TNBC patients at Fudan University Shanghai Cancer Center. Candidate mRNAs were filtered, which was followed by differential expressed mRNAs analysis, survival analysis, and LASSO Cox regression model. All-subsets regression program was used for constructing a multi-mRNA signature in the training set (n=159); the accuracy and prognostic value were then validated using an independent validation set (n=158). Results: Here, we profiled the transcriptome data from 189 early-stage TNBC patients along with 50 paired normal tissues. Early-stage TNBCs are featured of basal-like and immune-suppressed subtype and homologous recombination ability deficiency. We developed a prognostic signature contained seven mRNAs from transcriptome data (ACAN, KRT5, TMEM101, LCA5, RPP40, LAGE3, CDKL2). In both the training (n=159) and validation cohorts (n=158), the signature could identify patients with relatively high recurrence risks and serve as an independent prognostic factor. The signature had better prognostic value than traditional clinicopathological features in both sets. Among the seven mRNAs, TMEM101 is highly expressed in TNBC and represents a potential therapeutic target. Inhibition of TMEM101 impaired tumor progression.Conclusions: Our 7-mRNA signature could accurately predict recurrence risks of early-stage TNBCs. Clinical and genomic low risk TNBC patients may have the opportunity to avoid adjuvant chemotherapy

321 Phase I clinical trial assessing the combination of systemic chemokine modulatory regimen targeting TLR3 with neoadjuvant chemotherapy in triple negative breast cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A347-A347
Author(s):  
Shipra Gandhi ◽  
Mateusz Opyrchal ◽  
Cayla Ford ◽  
Victoria Fitzpatrick ◽  
Melissa Grimm ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Phase I ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Early Stage ◽  
Standard Dose ◽  
Surrogate Marker ◽  
Comprehensive Cancer Center ◽  
Cancer Center

BackgroundNeoadjuvant chemotherapy (NAC) with taxanes is the standard of care in triple negative breast cancer (TNBC). Intratumoral prevalence of CD8+ cytotoxic T-lymphocytes (CTLs) is associated with an improvement in relapse-free survival (RFS) and overall survival (OS), while regulatory T-cells (Treg) and myeloid derived suppressor cells (MDSC) are associated with poor survival. Higher ratio of CTL/Treg is associated with higher probability of obtaining pathological complete response (pCR), a surrogate marker for RFS. Intratumoral production of CCL5, CXCL9, CXCL10 and CXCL11 is critical for local infiltration with CTLs, while CCL22 is responsible for Treg attraction. Previous studies have shown that CXCL9 expression in the pre-treatment breast tissue is associated with a three-fold higher rate of achieving pCR. Our preclinical data show that Chemokine modulating (CKM) regimen, combining rintatolimod (TLR3 agonist), interferon (IFN)-α2b, and celecoxib (COX-2 inhibitor) increases CTL-attracting, and decreases MDSC-, Treg-favoring chemokines, increasing CTL/Treg ratio in tumor microenvironment, with preferential tumor tissue activation than adjacent healthy tissues. We hypothesize that the combination of CKM with paclitaxel will result in infiltration of TNBC with CTLs, and along with doxorubicin/cyclophosphamide (AC), result in higher pCR, translating into improved RFS and OS.MethodsIn this phase I study NCT04081389, eligibility includes age ≥18 years, confirmed resectable TNBC, radiographically measurable disease ≥1 cm, ECOG PS ≤ 2, adequate organ and marrow function. Patients with autoimmune disease, serious mood disorders, invasive carcinoma within 3 years, history of peptic ulcers or hypersensitivity to NSAIDs will be excluded. We plan to treat three patients with early stage TNBC with paclitaxel 80 mg/m2 IV weekly for 12 weeks, rintatolimod 200 mg IV, celecoxib 200 mg oral twice daily, and accelerated titration of IFN-α2b at doses 0, 5, or 10 million units (MU)/m2 [Dose Levels (DL) 1, 2 and 3 respectively] on days 1–3 (no intra-patient dose escalation) in weeks 1–3. Dose-limiting toxicity (DLT) is defined as grade 3 or higher toxicities within the first 3 weeks. Any DLT will mandate recruitment per the 3+3 model. If no DLT, three patients will be enrolled at DL 4 at 20 MU/m2 IFN- α2b. This will be followed by standard dose-dense AC, and then surgery. The primary endpoint is safety and tolerability of combination and to identify the appropriate DL of CKM and paclitaxel for extended efficacy study. The secondary endpoints include investigation of efficacy (pCR and breast MRI response), along with RFS and OS. Intratumoral biomarkers will be analyzed in an exploratory manner.ResultsN/AConclusionsN/ATrial RegistrationNCT04081389Ethics ApprovalThe study was approved by Roswell Park Comprehensive Cancer Center Institution’s Ethics Board, approval number I-73718.

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