Triple Negative Breast Cancer

Combined paclitaxel/CKM regimen was safe, with desirable TME changes and preliminary indications of promising pCR+ypTmic of 66%, comparable to the combination of NAC with pembrolizumab.

Metformin (MET), a commonly used oral drug for type 2 diabetes, has played a vital role in fostering an immunostimulatory environment...Based on the function of MET, there is a marked increase in the infiltration of activated CD8+ T cells and NK cells, which subsequently augments ferroptosis to a greater extent. Taken together, Fe-PDA-MET NPs activate a ferroptotic positive-feedback loop for effectively control TNBC progression, which offers a promising therapeutic modality to enhance the immunogenicity and reshape the TIME.

In this study, we demonstrate that TRIM50 is downregulated in human breast cancer and that its overexpression closely correlates with diminished invasion capacity in breast cancer, suggesting that TRIM50 may serve as a diagnostic marker and therapeutic target. TRIM50 plays a key role in breast cancer proliferation and potentially serves as a prognostic and therapeutic target.

Based on the current literature, PSMA-targeted PET/CT cannot be suggested as a diagnostic tool to assess BC extent in any clinical scenario. However, based on the PSMA expression observed in triple-negative patients, it can be proposed as a tool to evaluate whether BC patients could benefit from PSMA-targeting radioligand therapy.

Physicians should make additional efforts to evaluate age-specific treatment efficacy and treatment-induced toxicities. Further efforts to enhance the representation of older patients in breast cancer trials are warranted.

Considering all these data, we can conclude that the expression of immunoregulatory genes depends on tumor phenotype and has potential clinical implications in BC patients.

Lastly, depletion of FOSL1 inhibits tumor spheroid growth and stemness properties of TNBC cells. Taken together, these findings uncover the key epigenetic role of FOSL1 and highlight the potential of targeting the FOSL1-TCOF1 axis for TNBC treatment.

HER2 and other tumor-associated antigens have served as valuable benchmarks for developing novel therapies, such as antibody engagers and CAR T-cells. However, further research is essential to identify and validate new target antigens that can enhance therapeutic efficacy and broaden the clinical applicability of these approaches.

Importantly, 10h induced immunogenic cell death (ICD), promoted dendritic cells (DCs) maturation, and activated T cells, thereby initiating antitumor immunity. In conclusion, compound 10h is a novel dual-target ROCK/HDAC inhibitor that represents a promising treatment strategy for TNBC.

Our study unravels AR-V7 as a marker for poor clinical outcomes, predicting breast cancer aggressiveness, and encourages consideration of AR-V7 as a probable target for therapeutic intervention.

Collectively, these findings suggest that CCTR offers superior predictive information compared to KI and MI alone with respect to long-term outcomes from adjuvant chemotherapy in patients with TNBC that may guide treatment decision making.

Molecularly, in MDA-MB-231, both inhibitors modulated metastasis and epithelial to mesenchymal transition (EMT) markers ROCK1, ROCK2, c-Myc, E-cadherin and N-cadherin, with EPI-001 downregulating NF-ĸB level as well. We concluded that ARv7 indicated poor prognosis in the studied cohorts and that blocking of AR/ARv7 abated metastasis and key regulators of EMT in MDA-MB-231, at least in part by targeting ROCK/NF-ĸB/c-Myc axis.

This review focuses on the topic of tumor-on-a-chip, microfluidic chip manufacturing, and drug screening for triple-negative breast cancer. Particular emphasis is placed on cancer biomarker diagnostics, 3D preclinical model development, and treatment strategies for triple-negative breast cancer.

In conclusion, following parameter optimization, LIPUS-MB was found to reduce the drug resistance of MDA-MB-231/DOX cells. The underlying mechanism may involve the downregulation of P-gp and ABCG2 proteins expression through the modulation of the JNK/c-Jun pathway by LIPUS-MB, thereby inhibiting cell proliferation activity and promoting apoptosis, and enhancing the in vivo anti-tumor effect of DOX, thus reversing multidrug resistance in triple-negative breast cancer.

Clinical analysis revealed that PKCα expression is positively correlated with T-cell function and the interferon-gamma signature in patients with breast cancer. This study demonstrated the antitumor capability of PKCα, identified potential therapeutic strategies to avoid tumor evasion via PKC-targeted therapies, and provided a proof of concept for targeting PKCα in combination with anti-PD-L1 mAb therapy as a potential therapeutic approach against breast cancer, especially TNBC.

Our findings demonstrate the utility of the anti-EGFR-MPB nanocomposite for both in vitro and in vivo photoacoustic image-guided PTT and PDT. The optimal treatment strategy for triple-negative breast cancer is found to be the use of 250 μg/ml of nanocomposite irradiated with 1.0 W/cm2 808-nm laser for 7 min.

Similar scaffold commercial drugs leucal (LEU), epirubicin (EPI), and lometrexol also displayed strong binding to the active site of MTHFD2...The interaction of breast cancer serum with high expression of MTHFD2 also showed an increase in binding of epirubicin in the presence of leucovorin...Further experimental studies are required to establish the potential mode of inhibition of the novel small ligands. Future in vivo trials may validate the effectiveness of the combinatorial therapy.

This review explores the mechanisms by which c-Met contributes to chemoresistance in breast cancer and current challenges in targeting c-Met for breast cancer therapy. It discusses strategies to optimize treatment outcomes, ultimately improving patient prognosis and reducing mortality rates associated with this devastating disease.

This effect appears to be mediated, in part, through its negative association with PLK1. Targeting the SAMD5/PLK1 axis offers a promising therapeutic strategy for addressing aggressive breast cancers.

Measures of the spatial distributions of immune cells within the tumor microenvironment, in particular colocalization or close spatial proximity of PD-1+ T cells with PD-L1+ cells (immune and tumor cells), are significantly associated with response in the overall cohort as well as the in the triple negative (TN) and HR+HER2- subtypes. Our findings indicate that biomarkers associated with immune cell signaling, immune cell densities, and spatial metrics are predictive of neoadjuvant ICB efficacy in breast cancer.

Further, AXL/GAS6 signaling promotes angiogenesis through the activation of PI3K/AKT and NF-κB signaling pathways. Our results unveil role of AXL/GAS6 axis in the differentiation of TAMs, which governs malignant growth, and suggest that therapies that uncouple AXL/GAS6 axis may exhibit therapeutic opportunity for otherwise undruggable Triple Negative Breast Cancer (TNBC) patients.

Dose-dense chemotherapy regimens and the addition of carboplatin have been associated with an improvement in these response rates. Furthermore, immunotherapy, particularly pembrolizumab, has shown significant benefits in terms of recurrence-free survival...In conclusion, despite recent progress, TNBC remains a major clinical challenge. A better understanding of its biology and a personalized therapeutic approach are essential to improve clinical outcomes for patients with this aggressive form of breast cancer.

Pantoprazole (PPZ) administration at the most commonly used dose in the clinic notably increased the pondus hydrogenii (pH) of the TME, inhibited lysosomal activity, increased the membrane levels of the MSLN protein and improved the killing ability of MSLN-CAR-T cells both in vitro and in vivo. Similar results were obtained in non-small cell lung cancer (NSCLC) BMs. Hence, when administered in combination with CAR-T cells, PPZ, which increases the protein levels of target antigens, may constitute a new immunotherapeutic strategy for treating solid tumors with BMs.

However, despite these associations, PD-L1 expression did not significantly impact the 2-year survival rate in TNBC patients. These results emphasize the complexity of the immune microenvironment in TNBC and the necessity for further research to elucidate the precise role of PD-L1 in disease progression and patient outcomes.

Importantly, we found that OSU-T315 blocked the secretion of CCL17/CCL22 in tumor cells by inhibiting the ILK/NF-κB pathway, resulting in the apoptosis of Foxp3+-Tregs and decreased programmed cell death-1 (PD-1) expression. Therefore, our findings indicate a novel mechanism of OSU-T315 with potential therapeutic application in TNBC.

While TRPS1 remains a highly sensible immunohistochemical marker for confirming breast primary lesions, pathologists should be aware of its low specificity and incorporate complementary diagnostic methods in order to ensure accurate clinical management. Further research should focus on elucidating the molecular pathways regulating TRPS1 expression in various tumor types, which may better define its clinical utility.

The efficacy results showed a significantly greater clinical benefit with sacituzumab govitecan compared to standard chemotherapy in patients with triple-negative breast cancer. This drug will become a treatment of substantial impact in future treatment guidelines for this type of cancer.

RNA-Seq analysis identified critical pathways modulated by LIF/LIFR signaling in diet-induced obesity mouse models. These findings suggest that adiposity contributes to TNBC progression via the activation of the LIF/LIFR pathway, and LIFR inhibition with EC359 represents a promising therapeutic approach for obesity-associated TNBC.

Finally, public breast cancer database analyses demonstrated that ITGB4 correlates with PTPRZ1 and that high expression of ITGB4, UCHL1, HIF1A, and PTPRZ1 associated with decreased overall survival, distant metastasis free survival, post progression survival, and relapse-free survival. In summary, these findings provide a novel function of integrin α6β4 in promoting tumor invasive phenotypes through UCHL1-Hif-1α-mediated regulation of PTPRZ1.

P1, N=98, Active, not recruiting, Novartis Pharmaceuticals | Trial primary completion date: May 2025 --> Dec 2024

P2, N=180, Recruiting, MediLink Therapeutics (Suzhou) Co., Ltd. | Active, not recruiting --> Recruiting

Our findings showed that selective CB agonists and their combination suppressed breast cancer characteristics in MDA-MB-231 cells. The exposure of CB agonists also altered the proteomic profile of MDA-MB-231, which could lead to cell proliferation and motility suppression.

P1, N=42, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Nov 2024 --> Nov 2025 | Trial primary completion date: Nov 2024 --> Nov 2025

P1/2, N=316, Recruiting, Simcha IL-18, Inc. | Active, not recruiting --> Recruiting | Trial completion date: Jan 2025 --> Dec 2025 | Trial primary completion date: Sep 2024 --> Jun 2025

P2, N=45, Not yet recruiting, European Institute of Oncology

Our systematic review and meta-analysis confirmed that SG confers good clinical activity in certain solid tumor types and was tolerable with minimal adverse events. The potential utility of UGT1A1*28 genotyping in predicting clinical response and outcomes could not be determined due to the limited number of studies with available UGT1A1 genotype data.

P=N/A, N=14, Recruiting, Fudan University | Not yet recruiting --> Recruiting

P2, N=603, Completed, Merck Sharp & Dohme LLC | Active, not recruiting --> Completed

P2, N=20, Not yet recruiting, Cancer Institute and Hospital, Chinese Academy of Medical Sciences

In summary, this study highlights metabolic biomarkers that could potentially be used for the diagnosis and screening of TNBC. The comprehensive analysis of metabolomics and transcriptomics data offers a validated and in-depth understanding of TNBC metabolism.

P1, N=149, Recruiting, Phost'In Therapeutics | Trial primary completion date: Jul 2024 --> Nov 2024

The results showed that while proliferation rates, cell index values, mitotic index and bromodeoxyuridine labeling index decreased, caspase activity values increased. These results demonstrated that the combined application was more effective than the monotherapy application and could be used at lower concentrations than those drugs applied as monotherapy.