Early Triple-negative Breast Cancer Research Articles

Efficacy and feasibility of neoadjuvant pembrolizumab plus chemotherapy for early-stage triple-negative and estrogen receptor low, HER2-negative breast cancer: a Japanese single-institution real-world study.

Neoadjuvant pembrolizumab plus chemotherapy and adjuvant pembrolizumab have been established as the optimal systemic therapies for patients with early stage triple-negative breast cancer (TNBC); however, their efficacy and feasibility in the Japanese population remain unexplored. This study included patients with early stage TNBC or low estrogen receptor (ER) positivity (1-9%) with human epidermal growth factor receptor type 2- (HER2-) negative breast cancer who received neoadjuvant pembrolizumab plus chemotherapy from October 2022 at Cancer Institute Hospital of Japanese Foundation for Cancer Research. Information regarding clinicopathological features, systemic therapy, treatment outcomes, and adverse events of patients who underwent surgery by February 2024 was retrospectively collected. Overall, 69 patients received neoadjuvant pembrolizumab plus carboplatin and paclitaxel therapy, and 46 underwent surgery by February 2024. The median age of the patients was 53.5years, and 80.4% and 19.6% had stage II and III disease, respectively. TNBC and ER-low HER2-negative breast cancer accounted for 82.6% and 17.4% cases, respectively. Overall pathological complete response rate was 56.5%, with 87.5% in patients with ER-low HER2-negative tumors. The completion rates for neoadjuvant pembrolizumab, chemotherapy, and pembrolizumab plus chemotherapy were 65.2%, 56.5%, and 52.2%, respectively. Furthermore, 80.4% and 15.2% of patients experienced grade 3 or higher treatment-related adverse events and immune-related adverse events, respectively, and 34% experienced unexpected hospitalization during neoadjuvant treatment. The efficacy and safety profiles of neoadjuvant pembrolizumab plus chemotherapy in the Japanese population are consistent with previous reports. This regimen may have therapeutic potential against ER-low HER2-negative tumors and TNBC.

Machine Learning-Based Prognostic Gene Signature for Early Triple Negative Breast Cancer.

This study aimed to develop a machine learning-based approach to identify prognostic gene signatures for early-stage Triple Negative Breast Cancer (TNBC) using next-generation sequencing data from Asian populations. We utilized next-generation sequencing data to analyze gene expression profiles and identify potential biomarkers. Our methodology involved integrating various machine learning techniques, including feature selection and model optimization. We employed logistic regression, Kaplan-Meier survival analysis, and receiver operating characteristic (ROC) curves to validate the identified gene signatures. We identified a gene signature significantly associated with relapse in TNBC patients. The predictive model demonstrated robustness and accuracy, with an area under the ROC curve (AUROC) of 0.9087, sensitivity of 0.8750, and specificity of 0.9231. The Kaplan-Meier survival analysis revealed a strong association between the gene signature and patient relapse, further validated by logistic regression analysis. This study presents a novel machine learning-based prognostic tool for TNBC, offering significant implications for early detection and personalized treatment. The identified gene signature provides a promising approach for improving the management of TNBC, contributing to the advancement of precision oncology.

Abstract B022: Investigating how monocytes impair NK cell cytotoxicity in lung metastasis of triple-negative breast cancer

Abstract Triple-negative breast cancer (TNBC) accounts for 20% of breast cancer (BC) cases worldwide, yet due to its aggressive phenotype and lack of targeted therapies it has the worst prognosis amongst BC subtypes. Up to 40% of TNBC patients will relapse after treatment and develop distant metastasis. Metastasis is the complex process by which disseminated tumor cells (DTCs) leave the primary tumor and grow at distal sites. Since most metastases occur within 3 years of diagnosis, the rapid onset and lack of effective treatments in metastatic TNBC (mTNBC) means less than 20% of patients survive after 4 years. Even though it is the most “immune-activated” BC subtype, and immune checkpoint blockade (ICB) has shown clinical benefits in early TNBC, there is a clear need for novel immunotherapeutic approaches for patients with mTNBC. Natural killer (NK) cells are innate lymphocytes that function as the body’s first line defense against metastatic cancer cells. NK cells eliminate DTCs in the blood or at distal sites via NK cell cytotoxicity (NKCC) and this process is known to be impaired in successful metastasis. We hypothesized that other cells within the tumor microenvironment (TME) can inhibit NKCC at the earliest stages of metastatic outgrowth. We have used Cherry-niche, an in vivo labelling tool, to characterize how TME cells change in early and established lung micro-metastases by single-cell RNA sequencing (scRNA-seq) and flow cytometry. Our initial analyses showed that monocytes are highly enriched, not only in the entire metastatic lung, but specifically in the established niche surrounding DTCs. Although we detected a slight increase in total NK cells, there was a shift in maturation status with fewer mature NK cells (CD27-CD11b+) and more immature NK cells (CD27+/-CD11b-) in the metastatic lung. Furthermore, NK cells were largely absent from the metastatic niche and those that were present displayed a dysfunctional phenotype. CellChat and NicheNet analyses of our scRNA-seq data predicted that several receptor-ligand interactions, including the cytokine macrophage migration inhibitory factor (MIF), can mediate the crosstalk between NK cells and monocytes. Next, we developed an in vitro 3D co-culture system to study the effect of blood-derived monocytes on human NKCC against mTNBC cells. We found that monocytes can suppress NKCC against MDA-MB-231 cells and decrease the viability of mature NK cells. Furthermore, recombinant MIF was able to directly inhibit NKCC, whilst a selective MIF antagonist was able to rescue monocyte-induced impairment of NKCC. These data implicate MIF as a critical monocyte-derived factor in the suppression of NK cell function against mTNBC cells. Future work will aim to identify the exact mechanism by which MIF inhibits NKCC, whilst also evaluate the effect of monocyte depletion and MIF inhibition on metastatic outgrowth and NK cell activation/maturation in vivo. This study will reveal novel inter-cellular dynamics occurring in the metastatic lung, as well as immunotherapeutic targets that may restore NKCC in mTNBC. Citation Format: Christos Ermogenous, Luigi Ombrato, Gordon Beattie. Investigating how monocytes impair NK cell cytotoxicity in lung metastasis of triple-negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B022.

Assessing the Prognostic Value of Cytoplasmic and Stromal Caveolin-1 in Early Triple-Negative Breast Cancer Undergoing Neoadjuvant Chemotherapy.

Triple-negative breast cancer (TNBC) is a highly aggressive subtype with limited therapeutic options, leading to higher relapse rates and mortality. Identifying prognostic biomarkers like caveolin-1 (CAV1) is crucial for personalized treatment. CAV1 influences tumor progression and chemotherapy response, particularly through its interaction with the tumor microenvironment (TME) and cancer metabolism. Understanding the prognostic value of CAV1 in different cellular compartments is essential for its clinical application in TNBC. In the methods section CAV1 gene expression in TNBC was evaluated using in silico analysis, followed by the immunohistochemical staining of tumor cytoplasm (cCAV1) and stromal cells (sCAV1) in 58 early-stage TNBC patients. Statistical analyses were performed to correlate CAV1 expression with clinicopathological features and survival. In the results section, in silico analysis revealed higher CAV1 expression in TNBC, correlating with shorter overall survival. In the patient samples, cCAV1 was observed in 10.3% of cases, and was associated with larger tumors, higher grades, and poorer prognoses. sCAV1 was detected in 42% of cases, associated with less proliferative and less aggressive tumors, but did not significantly impact prognoses. In conclusion, cCAV1 expression is a significant prognostic marker in early-stage TNBC, highlighting the importance of assessing CAV1 in different cellular compartments. Further research is needed to explore the mechanisms and clinical implications of cCAV1.

Abstract A053: Liquid biopsy-based detection of triple negative breast cancer using DNA methylation biomarkers

Abstract Triple-negative breast cancer (TNBC) presents significant clinical challenges due to its aggressive phenotype, rapid progression, and limited targeted treatment options. TNBC often mimics benign lesions on ultrasound and metastatic features can be missed in routine mammography screening leading to misdiagnosis and delayed treatment. These limitations led us to investigate whether a blood-based liquid biopsy could provide a non-invasive, sensitive method for early TNBC detection, potentially overcoming the constraints of conventional imaging techniques. To discover biomarkers for TNBC, we performed targeted bisulfite sequencing on a cohort of 46 breast cancer solid tissue biopsy samples, comprising 19 TNBC and 27 non-TNBC cases. We identified 150 differentially methylated regions (mean length 703bp) separating TNBC and non-TNBC samples. Upon linking each region to its nearest gene, we observed several genes previously associated with prognosis and survival (HOXB3, PAX9, SOX9) substantiating the clinical relevance of these biomarkers. Using public TCGA data (369 breast cancer samples), we integrated expression and methylation data and observed directionally consistent changes. For example, HOXB3 showed increased methylation at its associated differential regions and decreased expression in TNBC cases. To ascertain whether these biomarkers could be useful in a liquid biopsy approach, we performed targeted bisulfite- sequencing on cell-free DNA samples derived from prospectively collected patients with breast cancer. All samples had independent tissue-based assessment of ER, PR and HER2 using immunohistochemistry or in situ hybridization. We then built a feed-forward neural network classifier with classes TNBC and non-TNBC that used transfer-learning and the identified biomarkers to learn methylation signatures in the biopsy samples and map them to cell-free DNA. To emulate clinical workflow, where subtyping follows cancer diagnosis and tissue of origin identification, we evaluated cfDNA samples correctly identified as breast cancer using two independent machine learning models trained using 2,393 prospectively collected multi- indication cancer and non-cancer samples (NCT05435066). Subsequent TNBC subtyping of breast cancer-positive cases (N=56) accurately identified 77% (10/13) of TNBC samples and 91% (39/43) of non-TNBC cases, with overall accuracy of 84%. The estimated tumor content range for correctly predicted TNBC samples was 0.5-33% with the three mis-classified samples all showing very low tumor content (0.22%, 0.28%, 0.59%). Non-TNBC cases showed a tumor content range of 0.07-36% for correct and 2.3-14% for misclassified samples. In conclusion, we identified novel methylation biomarkers that distinguish TNBC in the cell-free DNA of patients without needing invasive tissue biopsies. The high sensitivity of our assay at low tumor fractions has the potential to improve outcomes through earlier intervention and may enable earlier screening in high-risk groups, monitoring of minimal residual disease and longitudinal monitoring during treatment. Citation Format: Jocelyn Charlton, Shiva Farashahi, Kade Pettie, Elie Massaad, Josh Hubbell, Feras Hantash, Kieran I Chacko. Liquid biopsy-based detection of triple negative breast cancer using DNA methylation biomarkers [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A053.

Early Diagnosis of Triple-Negative Breast Cancer Based on Dual microRNA Detection Using a Well-Defined DNA Crown-Carbon Dots Structure as an Electrochemiluminescence Sensing Platform.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer (BC). Thus, early detection and accurate diagnosis of this cancer are crucial for improving the survival rate of patients. Specific microRNAs (miRNAs) have been implicated in the occurrence, proliferation, and metastasis of TNBC. Addressing this need, our study developed a biosensor platform for early and accurate TNBC diagnosis by integrating electrochemiluminescence (ECL) technology with a DNA sensing strategy. Specifically, synthesized positively charged carbon dots (CDs) were used to neutralize the electrostatic repulsion between DNA strands and facilitate the assembly of DNA triangular prisms (DNA TP-CDs). Hairpins were then incorporated into the DNA TP-CDs to form the final DNA crown structure. The early TNBC biomarker, microRNA-93-3p (miR-93-3p), allowed for the binding between the DNA Crown and the DNA track on the electrode and initiated the ECL signal. Subsequently, microRNA-210 (miR-210) unlocked the DNA tripedal walker, and its movement on the DNA Crown eventually quenched the ECL signal, enabling accurate TNBC diagnosis and tumor stage assessment. Our proposed biosensor had satisfactory sensing efficiency due to the ordered DNA track and rapid-moving DNA walker. The data revealed a good linear relationship between the ECL signals and the logarithm of miRNA concentrations, with miR-93-3p having a detection limit of 31.04 aM and miR-210 having a detection limit of 7.69 aM. The biosensor also showed satisfactory performance in serum samples and cells. Taken together, this study hopes to provide ideas and applications for clinical diagnosis as well as the personalized treatment of TNBC.

Intensive chemotherapy versus standard chemotherapy among patients with high risk, operable, triple negative breast cancer based on integrated mRNA-lncRNA signature (BCTOP-T-A01): randomised, multicentre, phase 3 trial

ObjectiveTo evaluate the feasibility of using a multigene signature to tailor individualised adjuvant therapy for patients with operable triple negative breast cancer.DesignRandomised, multicentre, open label, phase 3 trial.Setting7 cancer centres...

Delivery of IL2RG mRNA via nanoparticles to enhance CD8+ T cell promotes anti-tumor effects against late-stage triple-negative breast cancer

BackgroundThe manipulation of CD8+ T cell functions through genetic modifications presents a novel approach to cancer immunotherapy. This study aimed to explore the effects of IL2RG-overexpressing CD8+ T cells and assess the efficacy of delivering IL2RG mRNA via nanoparticles (NPs) to the tumor microenvironment in triple-negative breast cancer (TNBC).MethodsSingle-cell RNA sequencing (scRNA-seq) was conducted on tissue from early and late-stage TNBC, followed by a meta-analysis of six breast cancer arrays from the GEO database to identify candidate genes. CRISPR/Cas9 was employed for gene knockout and overexpression in CD8+ T cells, which were then analyzed using flow cytometry, ELISA, immunofluorescence, and metabolic assays. A 3D cancer cell spheroid model was used for co-culture experiments. Lipid-coated calcium-phosphate (LCP)@IL2RG NPs were synthesized and injected into TNBC mouse models.ResultsIL2RG was identified as significantly associated with late-stage TNBC. Overexpression of IL2RG in CD8+ T cells led to increased cell activation, cytotoxicity, and glycolysis, while knockout reduced these effects. Overexpressing IL2RG in CD8+ T cells co-cultured with 3D cancer spheroids resulted in enhanced apoptosis and reduced cancer cell invasion. Injection of LCP@IL2RG NPs into TNBC mouse models significantly mitigated tumor growth.ConclusionsOverexpressing IL2RG in CD8+ T cells enhances tumor immunotherapy. Delivering IL2RG mRNA via NPs further amplifies this effect, offering a promising strategy for the treatment of late-stage TNBC.

Real-World Immune-Related Adverse Events in Patients With Early Triple-Negative Breast Cancer Who Received Pembrolizumab.

The addition of pembrolizumab to chemotherapy in high-risk early triple-negative breast cancer (TNBC) improves cancer outcomes. However, pembrolizumab induces varied immune-related adverse events (irAEs) where some can be severe or lifelong. This retrospective study describes real-world patterns of irAEs in patients with TNBC who received pembrolizumab. We evaluated irAEs in patients with TNBC from a comprehensive cancer center and a community hospital who received pembrolizumab with chemotherapy between 2021 and 2023, excluding those enrolled in clinical trials. We used national guidelines to grade toxicities. Logistic regression assessed the effect of clinicopathologic variables on irAEs adjusting for covariates. We identified 233 patients with a median age of 51 years, 62% had stage II TNBC, 35% had stage III TNBC, 25% were Hispanic, 21% were Black, and 42% were White. Eighty patients (34%) developed 100 separate irAEs. The most common irAEs were endocrinopathies (52%) and GI (23%); there were 26 grade ≥3 irAEs, which all resulted in hospitalization, the most common being GI (13 instances); 45 required systemic steroids, 16 required additional immunosuppressive therapy, and 32 patients discontinued pembrolizumab because of irAEs. Two patients who developed colitis eventually died due to complications. Most (67 instances) irAEs were unresolved at the time of last follow-up, but 55% (37/67) had improved to grade 1. No clinicopathologic factors were associated with the development or severity of irAEs. In this real-world diverse population, we observed rates of irAEs comparable with KEYNOTE-522, where endocrinopathies were the most prevalent, but GI irAEs were also prevalent and severe. This emphasizes a critical issue as pembrolizumab is increasingly being used in early TNBC and could have long-term survivorship implications.

The prognostic impact of Her2 status in early triple negative breast cancer: a Turkish Oncology Group (TOG) study

The studies evaluating the impact of Her2 levels in neoadjuvant setting have conflicting data. The aim of the study was to evaluate the prognostic impact of Her2 status in early triple negative breast cancer(TNBC). In the study TNBC patients who were treated with neoadjuvant chemotherapy (NAC) and surgery were analyzed retrospectively. The primary aim of the study was to analyze the impact of Her2 status(Her2-0 and Her2-low) on pathological complete response (pCR). The secondary objectives were disease free survival (DFS) and overall survival (OS). 620 female triple negative breast cancer patients were evaluated. 427 patients (68.9%) had Her2-0 and 193(31.1%) had her2-low pathology. The pCR rates were similar between Her2-0 and Her2-low patients (33.0% vs. 27.5%, p = 0.098). Although Her2-0 group has better DFS (106 vs. 50 months, p = 0.002), in multivariate analysis it had a HR of 0.74 (p = 0.06). In addition, OS was similar (131 vs. 105 months, p = 0.13) with a HR of 0.88 (p = 0.61). In multivariate analysis; presence of LVI (HR:2.2 (95% CI 1.1–3.5) p = 0.001), Clinical stage T1/T2 (HR:0.39 (95% CI 0.2–0.6) p < 0.001) and lymph node negativity (HR:0.35 (95% CI 0.1–0.9) p = 0.03) were independent factors for OS. Although there were pathological and clinical differences, the pCR, DFS and OS were similar between Her2-0 and Her2-low TNBC patients. The importance of Her2 status of TNBC in neoadjuvant setting should be further studied.

P87-9 Effect of pembrolizumab as neoadjuvant therapy in early triple-negative breast cancer: a systematic review

P87-9 Effect of pembrolizumab as neoadjuvant therapy in early triple-negative breast cancer: a systematic review

Prognostic and Predictive Markers for Early Stage Triple-Negative Breast Cancer Treated With Platinum-Based Neoadjuvant Chemotherapy.

Emerging evidence has indicated possible efficacy benefit of platinum-based chemotherapy as neoadjuvant treatment for invasive ductal carcinoma triple-negative breast cancer (TNBC). However, it has not been endorsed by current guidelines due to highly controversial results. Present study aims to investigate predictive and prognostic roles concerning single nucleotide polymorphisms (SNPs) in XRCC1 and BRCA1, BRCA2 genes for early stage TNBC patients that received platinum-based neoadjuvant treatment. We prospectively enrolled women with stage IIB-IIIB TNBC that had progressed on neoadjuvant taxane and anthracycline-based chemotherapy at Xinjiang Medical University Affiliated Cancer Hospital. Tumor response and pathological complete response (pCR) rate were assessed. Invasive disease-free survival (iDFS) and overall survival (OS) were analyzed. Patients' blood samples were subject to Sanger sequencing to genotype XRCC1 Arg194Trp and Arg399Gln, BRCA1 s1799949, and BRCA2 rs206115. Univariate and multivariate logistic regressions were employed to investigate associations between SNPs and clinical characteristics with treatment response and pCR. A total of 45 patients were enrolled. The cohort showcased ORR of 44.4%, pCR of 28.9%, median iDFS of 22 months, and a 3-year OS of 73.3%. The A/G and G/G genotypes of BRCA1 rs1799949, and the T/T genotype of BRCA2 rs206115 were associated with higher responsive rate. Histologic grade of III and Ki67 expression > 65% were associated with low responsive rate. Moreover, the A/G genotype of BRCA1 rs1799949 and T/T genotype of BRCA2 rs206115 correlated to high pCR. The histologic III and T4 stage correlated to inferior iDFS. Carrier of BRCA1 rs1799949 G/G had the most favorable OS, carriers of A/A showed the poorest OS, and those with A/G genotype showed an intermediate OS. Platinum-based chemotherapy might serve as a therapeutic option for TNBC patients who were resistant to anthracycline- and taxane-based neoadjuvant therapy. Our study identified several genetic and clinical features that might function as prognostic and predictive markers.

Neoadjuvant nivolumab or nivolumab plus ipilimumab in early-stage triple-negative breast cancer: a phase 2 adaptive trial

Immune checkpoint inhibition (ICI) with chemotherapy is now the standard of care for stage II–III triple-negative breast cancer; however, it is largely unknown for which patients ICI without chemotherapy could be an option and what the benefit of combination ICI could be. The adaptive BELLINI trial explored whether short combination ICI induces immune activation (primary end point, twofold increase in CD8+ T cells or IFNG), providing a rationale for neoadjuvant ICI without chemotherapy. Here, in window-of-opportunity cohorts A (4 weeks of anti-PD-1) and B (4 weeks of anti-PD-1 + anti-CTLA4), we observed immune activation in 53% (8 of 15) and 60% (9 of 15) of patients, respectively. High levels of tumor-infiltrating lymphocytes correlated with response. Single-cell RNA sequencing revealed that higher pretreatment tumor-reactive CD8+ T cells, follicular helper T cells and shorter distances between tumor and CD8+ T cells correlated with response. Higher levels of regulatory T cells after treatment were associated with nonresponse. Based on these data, we opened cohort C for patients with high levels of tumor-infiltrating lymphocytes (≥50%) who received 6 weeks of neoadjuvant anti-PD-1 + anti-CTLA4 followed by surgery (primary end point, pathological complete response). Overall, 53% (8 of 15) of patients had a major pathological response (<10% viable tumor) at resection, with 33% (5 of 15) having a pathological complete response. All cohorts met Simon’s two-stage threshold for expansion to stage II. We observed grade ≥3 adverse events for 17% of patients and a high rate (57%) of immune-mediated endocrinopathies. In conclusion, neoadjuvant immunotherapy without chemotherapy demonstrates potential efficacy and warrants further investigation in patients with early triple-negative breast cancer. ClinicalTrials.gov registration: NCT03815890.

Three-dimensional analysis of mitochondria in a patient-derived xenograft model of triple negative breast cancer reveals mitochondrial network remodeling following chemotherapy treatments.

Mitochondria are hubs of metabolism and signaling and play an important role in tumorigenesis, therapeutic resistance, and metastasis in many cancer types. Various laboratory models of cancer demonstrate the extraordinary dynamics of mitochondrial structure, but little is known about the role of mitochondrial structure in resistance to anticancer therapy. We previously demonstrated the importance of mitochondrial structure and oxidative phosphorylation in the survival of chemotherapy-refractory triple negative breast cancer (TNBC) cells. As TNBC is a highly aggressive breast cancer subtype with few targeted therapy options, conventional chemotherapies remain the backbone of early TNBC treatment. Unfortunately, approximately 45% of TNBC patients retain substantial residual tumor burden following chemotherapy, associated with abysmal prognoses. Using an orthotopic patient-derived xenograft mouse model of human TNBC, we compared mitochondrial structures between treatment-naïve tumors and residual tumors after conventional chemotherapeutics were administered singly or in combination. We reconstructed 1,750 mitochondria in three dimensions from serial block-face scanning electron micrographs, providing unprecedented insights into the complexity and intra-tumoral heterogeneity of mitochondria in TNBC. Following exposure to carboplatin or docetaxel given individually, residual tumor mitochondria exhibited significant increases in mitochondrial complexity index, area, volume, perimeter, width, and length relative to treatment-naïve tumor mitochondria. In contrast, residual tumors exposed to those chemotherapies given in combination exhibited diminished mitochondrial structure changes. Further, we document extensive intra-tumoral heterogeneity of mitochondrial structure, especially prior to chemotherapeutic exposure. These results highlight the potential for structure-based monitoring of chemotherapeutic responses and reveal potential molecular mechanisms that underlie chemotherapeutic resistance in TNBC.

Mass Spectrometry-Based Proteomics for Classification and Treatment Optimisation of Triple Negative Breast Cancer.

Triple-negative breast cancer (TNBC) presents a significant medical challenge due to its highly invasive nature, high rate of metastasis, and lack of drug-targetable receptors, which together lead to poor prognosis and limited treatment options. The traditional treatment guidelines for early TNBC are based on a multimodal approach integrating chemotherapy, surgery, and radiation and are associated with low overall survival and high relapse rates. Therefore, the approach to treating early TNBC has shifted towards neoadjuvant treatment (NAC), given to the patient before surgery and which aims to reduce tumour size, reduce the risk of recurrence, and improve the pathological complete response (pCR) rate. However, recent studies have shown that NAC is associated with only 30% of patients achieving pCR. Thus, novel predictive biomarkers are essential if treatment decisions are to be optimised and chemotherapy toxicities minimised. Given the heterogeneity of TNBC, mass spectrometry-based proteomics technologies offer valuable tools for the discovery of targetable biomarkers for prognosis and prediction of toxicity. These biomarkers can serve as critical targets for therapeutic intervention. This review aims to provide a comprehensive overview of TNBC diagnosis and treatment, highlighting the need for a new approach. Specifically, it highlights how mass spectrometry-based can address key unmet clinical needs by identifying novel protein biomarkers to distinguish and early prognostication between TNBC patient groups who are being treated with NAC. By integrating proteomic insights, we anticipate enhanced treatment personalisation, improved clinical outcomes, and ultimately, increased survival rates for TNBC patients.

Can we counterbalance restricted access to innovation through specialized breast cancer care? The REAL-NOTE study

IntroductionThe KEYNOTE-522 (KN-522) trial showed that the addition of pembrolizumab to standard chemotherapy improved pathological complete response (pCR) and event-free survival (EFS) for patients with early triple negative breast cancer (TNBC). We analyzed results of a real-world cohort of patients treated in a certified Breast Unit, before the introduction of pembrolizumab, to see if high quality care can match outcomes brought by the addition of an innovative anticancer therapy. MethodsObservational, retrospective, single-center cohort study, with real-world data from an ongoing institutional database with prespecified variables. Inclusion criteria matched the ones from KN-522: previously untreated stage II or III TNBC, diagnosed between 2012 and 2022, who received neoadjuvant chemotherapy. The primary endpoints were pCR at the time of definitive surgery and EFS; overall survival (OS) was a secondary endpoint. ResultsTotal of 168 patients were included, median age 55 years, 55 % received neoadjuvant chemotherapy with dose dense anthracyclines and taxanes and 25 % carboplatin + paclitaxel, sequenced with dose dense anthracyclines. Most had Stage II disease (82.7 %), 47 % node + disease. pCR was achieved in 52.7 % cases. At 36 months, EFS was 83.3 % (95 % CI 75.1–89.0) and OS 89 % (95 % CI, 81.6 to 93.5). ConclusionsNotwithstanding the study limitations, outcomes of patients treated with chemotherapy without immunotherapy were numerically similar to the experimental arm of KN-522 trial. These data highlight that providing care by a specialized multidisciplinary team in a certified unit might be just as impactful as the incorporation of new technologies.

269P Her2-low/HRR proficient early triple negative breast cancer is characterized by good prognosis

269P Her2-low/HRR proficient early triple negative breast cancer is characterized by good prognosis

238MO PROMENADE: PembROlizuMab for early triple negative ER-low breast caNcer, reAl worlD frEnch cohort

238MO PROMENADE: PembROlizuMab for early triple negative ER-low breast caNcer, reAl worlD frEnch cohort

Towards targeting the breast cancer immune microenvironment.

The tumour immune microenvironment is shaped by the crosstalk between cancer cells, immune cells, fibroblasts, endothelial cells and other stromal components. Although the immune tumour microenvironment (TME) serves as a source of therapeutic targets, itis also considered a friend or foe to tumour-directed therapies. This is readily illustrated by the importance of T cells in triple-negative breast cancer (TNBC), culminating in the advent of immune checkpoint therapy in combination with cytotoxic chemotherapy as standard of care for both early and advanced-stage TNBC, as well as recent promising signs of efficacy in a subset of hormone receptor-positive disease. In this Review, we discuss the various components of the immune TME in breast cancer and therapies that target or impact the immune TME, as well as the complexity of host physiology.

Association between homologous recombination deficiency status and carboplatin treatment response in early triple-negative breast cancer.

The aim of this study was to assess homologous recombination deficiency (HRD) status and its correlation with carboplatin treatment response in early triple-negative breast cancer (TNBC) patients. Tumor tissues from 225 consecutive TNBC patients were evaluated with an HRD panel and homologous recombination-related (HRR) gene expression data. HRD positivity was defined as a high HRD score and/or BRCA1/2 pathogenic or likely pathogenic mutation. Clinicopathological factors, neoadjuvant treatment response, and prognosis were analyzed with respect to HRD status in these TNBC patients. HRD positivity was found in 53.3% of patients and was significantly related to high Ki67 levels (P = 0.001). In patients who received neoadjuvant chemotherapy, HRD positivity (P = 0.005) or a high HRD score (P = 0.003) was significantly associated with a greater pathological complete response (pCR) rate, especially in those treated with carboplatin-containing neoadjuvant regimens (HRD positivity vs. negativity: 50.00% vs. 17.65%, P = 0.040). HRD positivity was associated with favorable distant metastasis-free survival (hazard ratio HR 0.49, 95% confidence interval CI 0.26-0.90, P = 0.022) and overall survival (HR 0.45, 95% CI 0.20-0.99, P = 0.049), irrespective of carboplatin treatment. TNBC patients with high HRDs had high Ki67 levels and BRCA mutations. HRD-positive TNBC patients treated with carboplatin had a higher pCR rate. Patients with HRD positivity had a better prognosis, irrespective of carboplatin treatment, warranting further evaluation.