Therapy For Triple-negative Breast Cancer Research Articles

Di- and Triselenoesters—Promising Drug Candidates for the Future Therapy of Triple-Negative Breast Cancer

Breast cancer is a major malignancy among women, characterized by a high mortality rate. The available literature evidence indicates that selenium, as a trace element, has chemopreventive properties against many types of cancer; as such, compounds containing it in their structure may potentially exhibit anticancer activity. Accordingly, we have undertaken a study to evaluate the effects of novel selenoesters (EDAG-1, -7, -8, -10) on MCF-7 and MDA-MB-231 breast cancer cells. Our analysis included investigations of cell proliferation and viability as well as cytometric determinations of apoptosis/autophagy induction, changes in mitochondrial membrane polarity (ΔΨm), caspase 3/7, 8, and 9 activities, and Bax, Bcl-2, p53, Akt, AMPK, and LC3A/B proteins. The obtained data revealed that the tested derivatives are highly cytotoxic and inhibit cell proliferation even at nanomolar doses (0.41–0.79 µM). Importantly, their strong proapoptotic properties (↑ caspase 3/7) are attributable to the effects on both the extrinsic (↑ caspase 8) and intrinsic (↓ ΔΨm and Bcl-2, ↑ Bax, p53, and caspase 9) pathways of apoptosis. Moreover, the tested compounds are autophagy activators (↓ Akt, ↑ autophagosomes and autolysosomes, AMPK, LC3A/B). In summary, the potent anticancer activity suggests that the tested compounds may be promising drug candidates for future breast cancer therapy.

Multiparametric MRI–based radiomic models for early prediction of response to neoadjuvant systemic therapy in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is often treated with neoadjuvant systemic therapy (NAST). We investigated if radiomic models based on multiparametric Magnetic Resonance Imaging (MRI) obtained early during NAST predict pathologic complete response (pCR). We included 163 patients with stage I-III TNBC with multiparametric MRI at baseline and after 2 (C2) and 4 cycles of NAST. Seventy-eight patients (48%) had pCR, and 85 (52%) had non-pCR. Thirty-six multivariate models combining radiomic features from dynamic contrast-enhanced MRI and diffusion-weighted imaging had an area under the receiver operating characteristics curve (AUC) > 0.7. The top-performing model combined 35 radiomic features of relative difference between C2 and baseline; had an AUC = 0.905 in the training and AUC = 0.802 in the testing set. There was high inter-reader agreement and very similar AUC values of the pCR prediction models for the 2 readers. Our data supports multiparametric MRI-based radiomic models for early prediction of NAST response in TNBC.

Copper-Based Composites Nanoparticles Improve Triple-Negative Breast Cancer Treatment with Induction of Apoptosis-Cuproptosis and Immune Activation.

The synergistic effect of apoptosis and cuproptosis, along with the activation of the immune system, presents a promising approach to enhance the efficacy against triple-negative breast cancer (TNBC). Here, two prodrugs are synthesized: a reactive oxygen species (ROS)-responsive prodrug PEG-TK-DOX and a glutathione (GSH)-responsive prodrug PEG-DTPA-SS-CPT. These prodrugs are self-assembled and chelated Cu2+ to prepare nanoparticle PCD@Cu that simultaneously loaded doxorubicin (DOX), camptothecin (CPT), and Cu2+. The elevated levels of ROS and GSH in TNBC cells disrupted the PCD@Cu structure, leading to the release of Cu+, DOX, and CPT and the depletion of GSH. DOX and CPT triggered apoptosis with immunogenic cell death (ICD) in TNBC cells. Simultaneously, PCD@Cu downregulated the expression of copper transporting ATPase 2 (ATP7B), causing a significant accumulation of copper ions in TNBC cells. This further induced the aggregation of lipoylated dihydrolipoamide S-acetyltransferase (DLAT) and downregulation of iron-sulfur (Fe-S) cluster proteins, ultimately leading to cuproptosis and ICD in TNBC. In vitro and in vivo experiments confirmed that PCD@Cu induced apoptosis and cuproptosis in TNBC and activated the immune system, demonstrating strong anti-tumor capabilities. Moreover, PCD@Cu exhibited an excellent biosafety profile. Overall, this study provides a promising strategy for effective TNBC therapy.

Hainanenin-1, an oncolytic peptide, triggers immunogenic cell death via STING activation in triple-negative breast cancer

BackgroundIn triple-negative breast cancer (TNBC) therapy, insufficient tumor infiltration by lymphocytes significantly hinders the efficacy of immune checkpoint inhibitors. We have previously demonstrated that Hainanenin-1 (HN-1), a host defense peptide (HDP) identified from Hainan frog skin, induces breast cancer apoptosis and boots anti-tumor immunity via unknown mechanism.MethodsWe used in vitro experiments to observe immunogenic cell death (ICD) indicators in HN-1-treated TNBC cell lines, a mouse tumor model to verify HN-1 promotion of mice anti-tumor immune response, and an in vitro drug sensitivity test of patient-derived breast cancer cells to verify the inhibitory effect of HN-1.ResultsHN-1 induced ICD in TNBC in a process during which damage-associated molecular patterns (DAMPs) were released that could further increase the anti-tumor immune response. The secretion level of interleukin 2 (IL-2), IL-12, and interferon γ in the co-culture supernatant was increased, and dendritic cells (DCs) were activated via a co-culture with HN-1-pretreated TNBC cells. As a result, HN-1 increased the infiltration of anti-tumor immune cells (DCs and T lymphocytes) in the mouse model bearing both 4T1 and EMT6 tumors. Meanwhile, regulatory T cells and myeloid-derived suppressor cells were suppressed. In addition, HN-1 induced DNA damage, and double-strand DNA release in the cytosol was significantly enhanced, indicating that HN-1 might stimulate ICD via activation of STING pathway. The knockdown of STING inhibited HN-1-induced ICD. Of note, HN-1 exhibited inhibitory effects on patient-derived breast cancer cells under three-dimensional culture conditions.ConclusionsCollectively, our study demonstrated that HN-1 could be utilized as a potential compound that might augment immunotherapy effects in patients with TNBC.

Tanshinone I improves TNBC chemosensitivity by suppressing late-phase autophagy through AKT/p38 MAPK signaling pathway

The inhibition of autophagy is a potential therapeutic strategy to improve the chemosensitivity of triple-negative breast cancer (TNBC). In this study, we demonstrated that a natural terpenoid tanshinone I (TAN) enhanced the effectiveness of paclitaxel (PTX), at least in part, through an autophagy-dependent mechanism against TNBC. In vitro validation demonstrated that the combined therapy resulted in a synergistic decrease in the growth of TNBC cells. The chemosensitizing impact of TAN might be attributed to its inhibition of PTX-induced autophagy in the late phase by obstructing the fusion of autophagosomes and lysosomes, rather than by inhibiting lysosomal function. The findings from KEGG pathway analysis and molecular docking suggested that TAN might impact breast cancer chemoresistance primarily through the PI3K-Akt and MAPK signaling pathways. The non-canonical AKT/p38 MAPK signaling was further validated as the primary mechanism responsible for the inhibition of autophagy by TAN. In vivo study showed that the combined administration of TAN and PTX demonstrated a more significant suppression of tumor growth and autophagic activity compared to PTX monotherapy in the MDA-MB-231 xenograft nude mouse model. The safety evaluation of TAN in a zebrafish model, along with in vitro and in vivo validation, provided experimental and pre-clinical data supporting its potential as a natural adjunctive therapy in TNBC. Overall, this study suggests that the combination of TAN with PTX could provide an effective treatment option for advanced breast cancer, and targeting the AKT/p38 MAPK/late-autophagy signaling axis may be a promising approach for developing therapeutic interventions against TNBC.

Intermittent Fasting Attenuates Obesity-Induced Triple-Negative Breast Cancer Progression by Disrupting Cell Cycle, Epithelial-Mesenchymal Transition, Immune Contexture, and Proinflammatory Signature.

Obesity is associated with one-fifth of cancer deaths, and breast cancer is one of the obesity-related cancers. Triple-negative breast cancer (TNBC) lacks estrogen and progesterone receptors and human epidermal growth factor receptor 2, leading to the absence of these therapeutic targets, followed by poor overall survival. We investigated if obesity could hasten TNBC progression and intermittent fasting (IF) could attenuate the progression of obesity-related TNBC. Our meta-analysis of the TNBC outcomes literature showed that obesity led to poorer overall survival in TNBC patients. Fasting-mimicking media reduced cell proliferation disrupted the cell cycle, and decreased cell migration and invasion. IF decreased body weight in obese mice but no change in normal mice. Obese mice exhibited elevated plasma glucose and cholesterol levels, increased tumor volume and weight, and enhanced macrophage accumulation in tumors. The obesity-exacerbated TNBC progression was attenuated after IF, which decreased cyclin B1 and vimentin levels and reduced the proinflammatory signature in the obesity-associated tumor microenvironment. IF attenuated obesity-induced TNBC progression through reduced obesity and tumor burdens in cell and animal experiments, supporting the potential of a cost-effective adjuvant IF therapy for TNBC through lifestyle change. Further evidence is needed of these IF benefits in TNBC, including from human clinical trials.

Antiplatelet drug ticagrelor suppresses triple negative breast cancer metastasis by targeting PI3K

Metastatic recurrence is still a major challenge in breast cancer treatment. Patients with triple negative breast cancer (TNBC) develop early recurrence and relapse more frequently. Due to the lack of specific therapeutic targets, new targeted therapies for TNBC are urgently needed. Phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway is one of the active pathways involved in chemoresistance and survival of TNBC, being considered as a potential target for TNBC treatment. Our present study identified ticagrelor, an anti-platelet drug, as a pan-PI3K inhibitor with potent inhibitory activity against four isoforms of class I PI3K. At doses normally used in clinic, ticagrelor showed weak cytotoxicity against a panel of breast cancer cells, but significantly inhibited the migration, invasion and the actin cytoskeleton organization of human TNBC MDA-MB-231 and SUM-159PT cells. Mechanistically, ticagrelor effectively inhibited PI3K downstream mTOR complex 1 (mTORC1) and mTORC2 signaling by targeting PI3K and decreased the protein expression of epithelial-mesenchymal transition (EMT) markers. In vivo, ticagrelor significantly suppressed tumor cells lung metastasis in 4T1 tumor bearing BALB/c mice model and experimental lung metastasis model which was established by tail vein injection of GFP-labeled MDA-MB-231 cells. The above data demonstrated that ticagrelor can inhibit the migration and invasion of TNBC both in vitro and in vivo by targeting PI3K, suggesting that ticagrelor, a pan-PI3K inhibitor, might represent a promising therapeutic agent for the treatment of metastatic TNBC.

Chemotherapy-induced high expression of IL23A enhances efficacy of anti-PD-1 therapy in TNBC by co-activating the PI3K-AKT signaling pathway of CTLs

Treatment of advanced triple-negative breast cancer (TNBC) is a great challenge in clinical practice. The immune checkpoints are a category of immunosuppressive molecules that cancer could hijack and impede anti-tumor immunity. Targeting immune checkpoints, such as anti-programmed cell death 1 (PD-1) therapy, is a promising therapeutic strategy in TNBC. The efficacy and safety of PD-1 monoclonal antibody (mAb) with chemotherapy have been validated in TNBC patients. However, the precise mechanisms underlying the synergistic effect of chemotherapy and anti-PD-1 therapy have not been elucidated, causing the TNBC patients that might benefit from this combination regimen not to be well selected. In the present work, we found that IL-23, an immunological cytokine, is significantly upregulated after chemotherapy in TNBC cells and plays a vital role in enhancing the anti-tumor immune response of cytotoxic T cells (CTLs), especially in combination with PD-1 mAb. In addition, the combination of IL-23 and PD-1 mAb could synergistically inhibit the expression of Phosphoinositide-3-Kinase Regulatory Subunit 1 (PIK3R1), which is a regulatory subunit of PI3K and inhibit p110 activity, and promote phosphorylation of AKT in TNBC-specific CTLs. Our findings might provide a molecular marker that could be used to predict the effects of combination chemotherapy therapy and PD-1 mAb in TNBC.

Emergence of Quantum Dots as Innovative Tools for Early Diagnosis and Advanced Treatment of Breast Cancer.

Quantum dots (QDs) semiconducting nanomaterials, have garnered attention due to their distinctive properties, including small size, high luminescence, and biocompatibility. In the context of triple-negative breast cancer (TNBC), notorious for its resistance to conventional treatments, QDs exhibit promising potential for enhancing diagnostic imaging and providing targeted therapies. This review underscores recent advancements in the utilization of QDs in imaging techniques, such as fluorescence tomography and magnetic resonance imaging, aiming at the early and precise detection of tumors. Emphasis is placed on the significance of QD design, synthesis and functionalization processes as well as their use in innovative strategies for targeted drug delivery, capitalizing on their ability to selectively deliver therapeutic agents to cancer cells. As the research in this field advances rapidly, this review covers a classification of QDs according to their composition, the characterization techniques than can be used to determine their properties and, subsequently, emphasizes recent findings in the field of TNBC-targeting, highlighting the imperative need to address challenges, like potential toxicity or methodologies standardization. Collectively, the findings explored thus far suggest that QDs could pave the way for early diagnosis and effective therapy of TNBC, representing a significant stride toward precise and personalized strategies in treating TNBC.

Peroxiporins in Triple-Negative Breast Cancer: Biomarker Potential and Therapeutic Perspectives.

Triple-negative breast cancer (TNBC) remains one of the most challenging subtypes since it is initially characterized by the absence of specific biomarkers and corresponding targeted therapies. Advances in methodology, translational informatics, genomics, and proteomics have significantly contributed to the identification of therapeutic targets. The development of innovative treatments, such as antibody-drug conjugates and immune checkpoint inhibitors, alongside chemotherapy, has now become the standard of care. However, the quest for biomarkers defining therapy outcomes is still ongoing. Peroxiporins, which comprise a subgroup of aquaporins, which are membrane pores facilitating the transport of water, glycerol, and hydrogen peroxide, have emerged as potential biomarkers for therapy response. Research on peroxiporins reveals their involvement beyond traditional channeling activities, which is also reflected in their cellular localization and roles in cellular signaling pathways. This research on peroxiporins provides fresh insights into the mechanisms of therapy resistance in tumors, offering potential avenues for predicting treatment outcomes and tailoring successful TNBC therapies.

Celecoxib Augments Paclitaxel-Induced Immunogenic Cell Death in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a highly aggressive malignancy that lacks effective targeted therapies. Inducing immunogenic cell death (ICD) in tumor cells represents a promising strategy to enhance therapeutic efficacy by promoting antitumor immunity. Paclitaxel (PTX), a commonly used chemotherapy drug for TNBC, can induce ICD; however, the resulting immunogenicity is limited. Thus, there is an urgent need to explore strategies that improve the effectiveness of ICD in TNBC by incorporating immunoregulatory agents. This study investigated the potential of celecoxib (CXB) to enhance PTX-induced ICD by blocking the biosynthesis of PGE2 in the tumor cells. We observed that the combination of CXB and PTX promoted the maturation of dendritic cells and primed a T cell-dependent immune response, leading to enhanced tumor rejection in a vaccination assay. To further optimize drug delivery in vivo, we developed cRGD-modified liposomes for the targeted codelivery of CXB and PTX. This delivery system significantly improved drug accumulation and triggered robust antitumor immunity in an orthotopic mouse model of TNBC. Moreover, it served as an in situ vaccine to inhibit tumor recurrence and lung metastasis. Overall, our findings provide in-depth insights into the therapeutic mechanism underlying the combination of CXB and PTX, highlighting their potential as effective immune-based therapies for TNBC.

Novel HLA-Ilo/HLA-IIhi phenotype and immune evasion in triple-negative breast cancer.

1095 Background: Immune checkpoint inhibitors (ICIs) are a therapeutic option for patients with triple-negative breast cancer (TNBC), however resistance and non-response remain an unmet clinical need. Human leukocyte antigens (HLAs) play an important role in induction and regulation of host immune responses. Downregulation of HLA class I expression is one mechanism by which cancer cells evade the immune control. HLA typing and understanding the role of HLAs can provide valuable insight into optimizing immunotherapy efficacy in TNBC. In this study, we evaluate the association of HLA I/II phenotypes with biomarkers of tumor immune interaction and overall survival (OS) in a real-world breast cancer cohort. Methods: A targeted RNA-seq assay was performed on 142 breast cancer samples. HLA I and HLA II expressions were estimated as average expression of HLA-A, HLA-B, HLA-C and HLA-DP, HLA-DQ, HLA-DR genes, respectively, by a percentile rank values [0-100]. Cohen D index was used to estimate ratio of HLA-I and II in each specimen. We particularly focused on the HLA-Ilow(lo)/HLA-IIhigh(hi) ratio given a proposed mechanism of immune escape by tumor cells (low expression of HLA-I) in response to a highly immune infiltrated state where there is increased expression of HLA-II by the immune cells. We studied the co-expression of HLA-Ilo/HLA-IIhi with other checkpoint targets using Spearman correlation(rs). The impact of HLA phenotypes on OS were analyzed using Kaplan-Meier analysis and Chi-squared assessed associations. Results: The cohort consisted of 106 non-TNBC (ER+/HER2- or HER2+) and 36 TNBC tumors. Most samples originated from metastatic visceral sites (96, 68%) followed by primary breast (33, 23%), and lymph nodes (13, 9%). Among TNBC, HLA-Ilo/HLA-IIhi phenotype displayed a significantly higher co-expression of immune checkpoint targets such as PD-1, PD-L1, TIM3 and LAG-3 than HLA-Ihi/HLA-IIlo phenotype (p<0.001). However, this difference was not observed between HLA-Ilo/HLA-IIhi and HLA-Ihi/HLA-IIlo phenotypes in non-TNBC tumors. In TNBC, there was no significant difference in OS between HLA-Ilo/HLA-IIhi when compared to HLA-Ihi/HLA-IIlo (43 vs. 37 months, p=0.21). Similarly, in non-TNBC, there were no significant differences in OS between HLA-Ilo/HLA-IIhi when compared to HLA-Ihi/HLA-IIlo (107 vs. 66 months, p=0.5). Conclusions: Concurrent loss of HLA I with increased HLA II expression was associated with co-expression of immune checkpoint molecules indicative of immune escape mechanism but not survival outcomes in TNBC. This same effect was not seen in non-TNBC with a more immunologically silent environment. Characterization of HLA phenotypes by immune profiling provides insight into the complex interplay of tumor immune microenvironment and offers an opportunity for developing novel approaches to overcome the immune evasion with cancer vaccines and adoptive cell therapies in TNBC.

Spatial transcriptomic and proteomic insight into Trop-2, HER2, and AR expression: A pathway to tailored therapies in triple-negative breast cancer.

e12576 Background: Triple-negative breast cancer’s (TNBC) dismal prognosis demands more effective therapy selection. Previously described molecular subtypes reveal its heterogeneity but lack spatial insight and are not currently used in clinical practice. Here, we aim to evaluate by immunohistochemistry (IHC) the expression of key biomarkers in TNBC and its correlation with spatial gene expression obtained by spatial transcriptomics (ST). Methods: We studied a retrospective cohort of 92 patients (pts) treated at the Institut Jules Bordet in Belgium with primary surgery for early TNBC. ST (Visium Spatial Gene Expression, 10X Genomics) was previously performed on fresh frozen surgical samples. Using serial sections of these samples, we performed duplex IHC staining for Trop-2/androgen receptor (AR) and HER2/Ki-67. IHC staining was scored using H-score (Trop-2), Allred score (AR), and current guidelines (Ki67/HER2), adding the ultra-low and null HER2 categories. Statistical analyses included descriptive statistics, Spearman correlation, Mann-Whitney test, and Kaplan-Meier with log-rank tests for estimating outcome distribution. Results: Of 92 pts included, 4 (4.3%), 25 (27.2%), 28 (30.4%), and 35 (38%) pts had HER2 2+, 1+, ultra-low, and null, respectively, tumors. Importantly, we observed a significant difference in tumor cell-derived ERBB2 gene expression of HER2 ultra-low versus HER2 null tumors ( p<0.0001), while there was no difference in ERBB2 expression between HER2 ultra-low and HER2 1+ tumors ( p=0.49). HER2 expression was not correlated with prognosis. Trop-2 expression by IHC was high, medium, and low in 67%, 23%, and 10% of pts, respectively. IHC expression correlated well with tumor-derived gene expression (r=0.54), with intrasample heterogeneity observed both in IHC and spatial gene expression. Trop-2 expression was prognostic, pts with high Trop-2 H-score tumors having significantly worse outcome ( p=0.021). In this cohort, 25%, 40.2%, and 34.8% of pts had AR Allred scores of 0-2, 3-5, and 6-8, respectively. Tumor AR gene expression was well correlated with IHC AR expression (67.7%). IHC AR expression was associated with the presence of adipose tissue in the stroma (r=0.23, p=0.025) but not with prognosis. Of note, we report for the first time, to our knowledge, for TNBC, AR expression both in tumor and stroma cells, both at the IHC and gene expression levels. Importantly, we could construct a classifier that identifies luminal androgen receptor tumors, using AR Allred score > 5 and Ki67 ≤ 40%, with a PPV of 93% and an NPV of 96%. Conclusions: ST data has the potential to improve easily accessible IHC classifiers, with the aim of refining patient selection for ADC and anti-AR therapies in TNBC.

Systemic inflammatory markers in neoadjuvant pembrolizumab therapy for triple-negative breast cancer: Prognostic insights and nomogram construction.

e12649 Background: Systemic inflammatory markers derived from peripheral blood cells, such as the neutrophils and lymphocytes ratio (NLR), derived neutrophil lymphocyte ratio (dNLR), platelet-lymphocyte ratio (PLR), and lymphocyte–monocyte ratio (LMR), have shown promise as prognostic markers. Currently, neoadjuvant treatment (NACT) for early triple-negative breast cancer (eTNBC) involves the addition of an immune therapy, and little is known about the variation of these markers in this specific context. Methods: This study evaluated two groups who received NACT for eTNBC in a single third-level cancer center. The first received NACT with EC X4 and a weekly paclitaxel regimen, the second pembrolizumab and NACT. A total of 70 patients were included, 37 patients in the pembrolizumab group. NLR was defined as the absolute blood neutrophil count (N) divided by the absolute lymphocyte count (L), dNLR was defined as the N divided by the derived L (absolute leukocyte count — N), PLR was defined as the absolute platelet count divided by the L, LMR was defined as the L divided by the absolute monocyte count. Association between systemic inflammatory markers and pathological complete response (pCR) was analyzed using statistical tests. Inflammatory markers were evaluated at the time of diagnosis, at the time of chemotherapy regimen change, and 1 week before surgery. The χ2 test or Fisher’s exact test was used for correlation and Student’s t-test to compare different groups. Results: The pCR rates were 60,6% in the standard therapy and 77,8% in the pembrolizumab. There were no significant differences in clinical characteristics between the two groups. NLR, dNLR, PLR and LMR at 6 months showed significant differences compared to baseline levels. dNLR in the immunotherapy group, at the end of therapy, showed statistical significance with the Welch Two Sample t-test with p-value = 0.001. Variables were weighted with respect to the type of treatment and the outcome was assessed as pCR. On the basis of these data, a nomogram was constructed to predict the likelihood of achieving pCR in patients undergoing neoadjuvant pembrolizumab therapy. Conclusions: This study highlights the potential of systemic inflammatory markers as prognostic indicators in patients with eTNBC undergoing NACT. dNLR is a novel biomarker associated with clinical outcome in solid tumors. In this study, for the first time, a correlation was found between the use of pembrolizumab and the change in dNLR and consequently its impact on pCR. A nomogram was constructed to predict the outcome of pCR. [Table: see text]

A proof-of-concept study of LXP5268 as an add-on neoadjuvant chemotherapy in patients with early-stage triple-negative breast cancer.

e12607 Background: Triple-negative breast cancer (TNBC) is a heterogeneous and aggressive subtype characterized by a high risk of mortality and a poor prognosis. The 2019 ASCO and St. Gallen International Consensus Guidelines strongly recommend neoadjuvant chemotherapy (NACT) for early-stage TNBC. Previous studies indicated that NACT improved overall and disease-free survival in early-stage TNBC. LXP5268, a drug in the 505(b)(2) category, has demonstrated efficacy in reducing tumor size in animal models. Our study aims to assess whether combining LXP5268 with NACT enhances anti-tumor efficacy and tumor shrinkage rates in early-stage TNBC patients. Methods: Enrolled patients had untreated stage II-III TNBC. NACT consisted of docetaxel every 3 weeks for four cycles, followed by epirubicin plus cyclophosphamide every 3 weeks for an additional four cycles (24 weeks total). In the LXP5268 add-on NACT (LXP5268+NACT) group, patients took LXP5268 orally once daily with NACT. After treatment, we analyzed tumor objective response rate (ORR), shrinkage rate by CT images, and adverse events (AEs) diagnosed by the principal investigator. Whole-exome sequencing (WES) was performed on 6 subjects in the LXP5268+NACT group, identifying potential germline variants and biomarkers, clinically interpreted following ACMG/AMP 2015 guidelines. Results: Both groups had similar baseline characteristics. LXP5268+NACT subjects (54.8 ± 7.2 years) and NACT subjects (59.3 ± 9.8 years) showed significant age differences ( p<0.001). The ORR was 100% in both the LXP5268+NACT group (3 pathological complete response, pCR and 4 pathological partial response, pPR) and NACT group (6 pPR). The tumor shrinkage rate was significantly higher in the LXP5268+NACT group at 77.3% ± 21.8 compared to 43.4% ± 12.8 in the NACT group ( p< 0.001). Moreover, subjects in the LXP5268+NACT group with a tumor reduction exceeding 50% surpassed those in the NACT group. AEs included neutropenia (85.7%), constipation (66.7%), and insomnia (66.7%), all grade 1. Interestingly, mutation in XIRP2 correlated with higher tumor shrinkage rate. Conclusions: LXP5268 combined with NACT was more effective than NACT alone for early-stage TNBC, without increasing AEs. These results highlight LXP5268's potential in TNBC therapy. Previous studies indicated XIRP2 mutations in metastatic breast cancer. LXP5268+NACT achieved pCR in XIRP2-mutated patients. Future clinical trials will expand to enhance result verification accuracy. Clinical trial information: CMUH106-REC3-145.

TBCRC 058: A randomized phase II study of enzalutamide, enzalutamide with mifepristone, and treatment of physician’s choice in patients with androgen receptor-positive metastatic triple-negative or estrogen receptor-low breast cancer (NCT06099769).

TPS1138 Background: Triple-negative breast cancer (TNBC) refers to a heterogenous group of breast cancers that lack expression of ER, PR, and HER2. Despite recent advances with immunotherapy (IO) and antibody-drug conjugates (ADCs), TNBC remains the most aggressive subtype, characterized by a high risk of recurrence and a short overall survival in the metastatic setting. Breast tumors with low levels of ER and PR expression (1-10%) clinically behave like TNBC, and clinical management follows the TNBC treatment (tx) paradigm. We and others have identified a subset of ER/PR/HER2 negative breast cancers (BC) that express the androgen receptor (AR). Enzalutamide (enza), an AR-antagonist, has demonstrated activity in AR+ metastatic TNBC (Traina et al, JCO 2018). Activation of the glucocorticoid receptor (GR) has been implicated as a mechanism of resistance to AR inhibition in prostate and BCs (Kach et al, Sci Transl Med 2015). Effective therapies for advanced TNBC remain an unmet need, particularly in patients who are ineligible for or progress following a checkpoint inhibitor. This randomized study will evaluate the efficacy of enzalutamide or enzalutamide plus the GR antagonist mifepristone (mif) as compared to physician’s choice chemotherapy (TPC). Methods: This is a randomized phase II trial; 201 patients (pts) will be randomized in a 1:1:1 fashion to enza, enza with mif, or TPC (carboplatin, paclitaxel, eribulin, or capecitabine). The primary endpoint (endpt) is progression free survival (PFS), and the trial is designed to test the hypothesis that PFS in the pooled enzalutamide arms is superior to TPC; there is 80% power to detect a hazard ratio (HR) of 0.70, corresponding to increase in PFS from 3.5 months (mos) with TPC to 5.0 mos with enza-based tx. Secondary endpts include comparisons of PFS among 3 arms and evaluation of response rate, clinical benefit rate, duration of response, overall survival, safety/toxicity, and patient-reported outcomes by arm. Exploratory endpts include correlation of tumor and circulating markers (constitutively active AR variants in circulating tumor cells and circulating tumor cell DNA) with tx response. Eligible pts must have: ECOG 0-2, metastatic ER/PR low or negative, HER2 negative breast cancer (BC), measurable or evaluable disease (dz), < 2 prior lines of chemotx, any # prior endocrine txs, no prior anti-AR tx, no prior mif, concurrent CYP17 inhibitors prohibited. Pts with PD-L1+ BC must have received prior IO if not contraindicated. Tumors must have AR ≥10%, normal organ function, no history of brain mets. As of 1/15/2024, 2 of 201 pts have begun protocol-specified tx. Clinical trial information: NCT06099769 .

Use of chemotherapy and loco-regional therapy for stage IA triple-negative breast cancer and their association with oncologic outcomes: A cancer registry study.

524 Background: We aimed to evaluate the role of adjuvant chemotherapy and loco-regional therapy for stage IA (pT1, pN0) triple-negative breast cancer (TNBC) in a real-world setting. Methods: We identified patients with pT1, pN0 TNBC diagnosed between 2009 and 2021 within the clinical cancer registry of Baden-Wuerttemberg, Germany. Overall survival (OS) was assessed using Kaplan-Meier statistics and multivariate Cox regression models (adjusted for age, use of chemotherapy, local therapy (breast conserving therapy [breast conserving surgery + radiotherapy] vs. mastectomy), and tumor histologic subtype). Results: A total of 1191 patients with a median follow-up of 43.8 months were identified: 0.9% (11 of 1191) with pT1mi stage, 10.0% (119 of 1191) with pT1a, 24.0% (286 of 1191) with pT1b, and 65.0% (775 of 1191) with pT1c. Use of adjuvant chemotherapy was 9.1% (1 of 11) in pT1mi stage, 41.2% (49 of 119) in pT1a, 66.8% (191 of 286) in pT1b, and 69.8% (541 of 775) in pT1c. Multivariate Cox regression analysis revealed no significant influence for the use of adjuvant chemotherapy on OS in pT1a and pT1b patients (for pT1a HR 1.27, 95% CI 0.19 to 8.50, for pT1b HR 1.07, 95% CI 0.50 to 2.30) but for patient age in the pT1b group (HR 4.71, 95% CI 2.26 to 9.8, for age ≥70 vs. <70 years). For pT1c patients, there was significant influence for the use of adjuvant chemotherapy on OS (HR 0.55, 95% CI 0.38 to 0.8), for local therapy (HR 0.41, 95% 0.25 to 0.69, for breast conserving therapy vs. mastectomy only), and patient age (HR 2.33, 95% CI 1.61 to 3.39 for age ≥70 vs. <70 years). Notably, for pT1c patients aged <70years, local therapy (HR 0.32, 95% CI 0.15-0.69), in favor of breast conserving therapy) but not use of chemotherapy (HR 1.11, 95% CI 0.56-2.19) was associated with OS. Conclusions: This data suggests that OS in stage IA TNBC is strongly influenced by local therapy and patient age, but not use of chemotherapy. Larger studies with longer-term follow-up are welcomed to fully inform this discussion.

Real world outcomes of 2,339 patients with early-stage triple-negative breast cancer (TNBC) treated in British Columbia.

e23274 Background: TNBC represents 15-20% of all breast cancers, and tends to exhibit more aggressive features, more frequent distant metastasis and overall worse prognosis than other breast cancer subtypes. The treatment landscape for early-stage TNBC has changed considerably in the last decade, with new additions to neoadjuvant therapy (NAT) aimed at improving pathologic responses and outcomes. In this study, we assess real world data regarding treatment and outcomes in those with early-stage TNBC. Methods: The BC Cancer Breast Cancer Outcomes Unit database contains prospectively collected data on patients residing in British Columbia and diagnosed with breast cancer since 1989. This retrospective study evaluated patients diagnosed with stage I-III TNBC from 2010 to 2019. During this era, regimens containing anthracyclines and taxanes were routinely used. TNBC was defined as per ASCO-CAP guidelines as ER≤1%, PR≤1% and negative HER 2 (0, 1+ by immunohistochemistry, or 2+ ISH negative). Outcomes of interest included event free survival (EFS), overall survival (OS), and pathologic complete response (pCR). Results: 2,339 patients withstage I-III TNBC were identified with a mean follow up of 6.5 years. OS was 87% (95% CI 85-88%) at 3-years and 79% (95% CI 77-80%) at 5-years. The presenting stage was a significant prognostic factor, with 5-year EFS of 89%, 81% and 51%- and 5-year OS of 90%, 80%, and 53% for stages I, II, and III, respectively. There was an increase in NAT use in 2019 (n = 82/230,35.7%) when compared to 2010 (n = 20/227, 8.8%). The most common neoadjuvant regimens used included anthracycline and taxane chemotherapies (n = 343,81.4%), with only a small number receiving neoadjuvant platinum chemotherapy (n = 52, 12.4%). Pathological complete response (pCR) was achieved in 24.5% (103/421) of patients who received NAT. Patients with pCR had improved 5- year EFS (91% vs. 57%, HR 0.26 [95% CI 0.15-0.45]) and 5-year OS (90% vs. 59%, HR 0.26 [95% CI 0.15-0.45]) compared to those with residual disease. The subgroup that received salvage capecitabine had a poor 3-year EFS at 22% but was enriched for patients with residual nodal disease after NAT (n = 77/130, 59.2%). Conclusions: This real-world study of TNBC in the era prior to routine immunotherapy (IO), highlights the poor prognosis of TNBC, particularly patients with locally advanced disease and those who did not achieve pCR, despite adjuvant capecitabine. This stresses the need for advances in NAT and salvage therapies for TNBC with residual disease at high risk of recurrence. [Table: see text]

Advancements and challenges in triple-negative breast cancer: a comprehensive review of therapeutic and diagnostic strategies.

Triple-negative breast cancer (TNBC) poses significant challenges in oncology due to its aggressive nature, limited treatment options, and poorer prognosis compared to other breast cancer subtypes. This comprehensive review examines the therapeutic and diagnostic landscape of TNBC, highlighting current strategies, emerging therapies, and future directions. Targeted therapies, including PARP inhibitors, immune checkpoint inhibitors, and EGFR inhibitors, hold promise for personalized treatment approaches. Challenges in identifying novel targets, exploring combination therapies, and developing predictive biomarkers must be addressed to optimize targeted therapy in TNBC. Immunotherapy represents a transformative approach in TNBC treatment, yet challenges in biomarker identification, combination strategies, and overcoming resistance persist. Precision medicine approaches offer opportunities for tailored treatment based on tumor biology, but integration of multi-omics data and clinical implementation present challenges requiring innovative solutions. Despite these challenges, ongoing research efforts and collaborative initiatives offer hope for improving outcomes and advancing treatment strategies in TNBC. By addressing the complexities of TNBC biology and developing effective therapeutic approaches, personalized treatments can be realized, ultimately enhancing the lives of TNBC patients. Continued research, clinical trials, and interdisciplinary collaborations are essential for realizing this vision and making meaningful progress in TNBC management.

Recent Developments in Combination Immunotherapy with Other Therapies and Nanoparticle-Based Therapy for Triple-Negative Breast Cancer (TNBC).

Triple-negative breast cancer (TNBC), lacking specific receptors found in other breast cancer subtypes, poses significant treatment challenges due to limited therapeutic options. Therefore, it is necessary to develop novel treatment approaches for TNBC. In the last few decades, many attempts have been reported for alternative tools for TNBC treatment: immunotherapy, radiotherapy, targeted therapy, combination therapy, and nanotechnology-based therapy. Among them, combination therapy and nanotechnology-based therapy show the most promise for TNBC treatment. This review outlines recent advancements in these areas, highlighting the efficacy of combination therapy (immunotherapy paired with chemotherapy, targeted therapy, or radiotherapy) in both preclinical and clinical stages and nanotechnology-based therapies utilizing various nanoparticles loaded with anticancer agents, nucleic acids, immunotherapeutics, or CRISPRs in preclinical stages for TNBC treatment.