Negative Breast Cancer Patients Research Articles

Evaluation of triple negative breast cancer with heterogeneous immune infiltration.

Tumor infiltrating lymphocytes (TILs) are known to be a prognostic and predictive biomarker in breast cancer, particularly in triple negative breast cancer (TNBC) patients. International guidelines have been proposed to evaluate them in the clinical setting as a continuous variable, without a clear defined cut-off. However, there are scenarios where the immune infiltration is heterogeneous that some areas of the patient's tumour have high numbers of TILs while other areas completely lack them. This spontaneous presentation of a heterogeneous immune infiltration could be a great opportunity to study why some tumours present TILs at diagnosis but others do not, while eliminating inter patient's differences. In this study, we haveidentifiedfive TNBC patients that showed great TIL heterogeneity, with areas of low (≤5%) and high (≥50%) numbers of TILs in their surgical specimens. To evaluate immune infiltration heterogeneity, we performed and analyzed bulk RNA-sequencing in three independent triplicates from the high and low TIL areas of each patient. Gene expression was homogeneous within the triplicates in each area but was remarkable different between TILs regions. These differences were not only due to the presence of TILs as there were other non-inflammatory genes and pathways differentially expressed between the two areas. This highlights the importance of intratumour heterogeneity driving the immune infiltration, and not patient's characteristics like the HLA phenotype, germline DNA or immune repertoire.

Triple Negatif Meme Kanseri Hastalarında Neoadjuvan Kemoterapiye Tam Yanıtı Etkileyen Faktörler

AIM: The triple negative breast cancer is a very aggressive type of breast cancer which constituting approximately 10-15% of all cases. Despite the administration of adjuvant chemotherapy, 5-year disease-free survival rates are lower than other types. Response to treatment may indicate patients' long-term outcome. Several studies are associated with pathological complete response , improved disease-free survival and overall survival . Residual disease after neoadjuvant chemotherapy shows the tumor resistance to treatment. The aim of this study is to explore the relationship between pathological complete response and tumor characteristics.
 MATERIAL AND METHOD: Data of 53 triple negative breast cancer patients who were operated at one center after neoadjuvant chemotherapy between 2015-2022 were retrospectively analyzed. The data analyzed with descriptive and inferential statistics using SPSS IBM version 25.
 RESULTS: In the evaluation of 53 patients between the ages of 28 and 81 (mean: 50.7), pathological complete response was obtained in 21 of the patients (39.6 %), while 32 (60.4 %) were found to have an incomplete response or no response. Absence of axillary lymph node metastasis before neoadjuvant chemotherapy, high Ki-67 proliferation index and absence of extracapsular invasion in metastatic LN were associated with pathological complete response; Other clinicopathologic parameters were found to have no effect on the results.
 DISCUSSION: Patients with a high Ki-67 proliferation index and no axillary involvement are more likely to have a pathological complete response after neoadjuvant chemotherapy.
 CONCLUSION: It can be predicted that the prognosis may be better in patients with high Ki-67 proliferastion index and no axillary involvement .

Kruppel-like factor 8 regulates triple negative breast cancer stem cell-like activity.

Breast tumor development is regulated by a sub-population of breast cancer cells, termed cancer stem-like cells (CSC), which are capable of self-renewing and differentiating, and are involved in promoting breast cancer invasion, metastasis, drug resistance and relapse. CSCs are highly adaptable, capable of reprogramming their own metabolism and signaling activity in response to stimuli within the tumor microenvironment. Recently, the nutrient sensor O-GlcNAc transferase (OGT) and O-GlcNAcylation was shown to be enriched in CSC populations, where it promotes the stemness and tumorigenesis of breast cancer cells in vitro and in vivo. This enrichment was associated with upregulation of the transcription factor Kruppel-like-factor 8 (KLF8) suggesting a potential role of KLF8 in regulating CSCs properties. Triple-negative breast cancer cells were genetically modified to generate KLF8 overexpressing or KLF8 knock-down cells. Cancer cells, control or with altered KLF8 expression were analyzed to assess mammosphere formation efficiency, CSCs frequency and expression of CSCs factors. Tumor growth in vivo of control or KLF8 knock-down cells was assessed by fat-pad injection of these cell in immunocompromised mice. Here, we show that KLF8 is required and sufficient for regulating CSC phenotypes and regulating transcription factors SOX2, NANOG, OCT4 and c-MYC. KLF8 levels are associated with chemoresistance in triple negative breast cancer patients and overexpression in breast cancer cells increased paclitaxel resistance. KLF8 and OGT co-regulate each other to form a feed-forward loop to promote CSCs phenotype and mammosphere formation of breast cancer cells. These results suggest a critical role of KLF8 and OGT in promoting CSCs and cancer progression, that may serve as potential targets for developing strategy to target CSCs specifically.

Incidence Rate and Clinical Characteristics of Triple Negative Breast Cancer Patients in Hasan Sadikin Hospital, for the Last Five Years

Breast cancer is the most common cancer in Indonesia and ranks as the first cause of cancer death. Data from the Global Cancer Observatory (GLOBOCAN) 2020 shows that as many as 16.6% of the total 396,914 new cases of cancer in Indonesia are breast cancer with a mortality rate of more than 22 million. This study took all data on breast cancer patients at Hasan Sadikin Hospital (RSHS) from 2015-2019. Where from all this data, then the inclusion criteria are patients who have TNBC from immunohistochemistry analysis. From all existing samples, the patient's age is then recorded and then grouped. This age mapping is to find out what age group TNBC occurs the most. Of the 4050 breast cancer patients who went to RSHS in 2015-2019, 628 patients showed supportive immunohistochemistry results towards a triple negative diagnosis. From all these data, it was then found that the age group that was most diagnosed with TNBC in RSHS was 41-50 years old, which was 237 people or about 37%. From all existing data, a recidivist incidence rate of 11 cases or around 1.7% was obtained. TNBC is a malignant and aggressive type of breast cancer because the immunohistochemistry (IHC) presentation does not have three receptors that can be found in other types of breast cancer, namely estrogen (ER), progesterone (PR), and a protein known as human epidermal growth factor (HER2). This research has limitations, namely that the data available is very minimal so that it is considered less representative. Research on a larger scale and longer time is needed to provide a more real and representative picture.

Abstract 5821: Synergism of FAK and ROS1 inhibitors in the treatment of CDH1-deficient cancers mediated by FAK-YAP-TRX signaling

Abstract CDH1 deficiency is common in triple negative breast cancer and diffuse gastric cancer patients, both of which lack effective therapeutics. Although inhibiting ROS1 function results in synthetic lethality in CDH1-deficient cancers, adaptive resistance limits their potential clinical benefits. Hyperactive focal adhesion kinase (FAK) signaling contributes to adaptive drug resistance, and FAK inhibitors are partially effective against CDH1–deficient cancers. Thus, co-treatment with ROS1 and FAK inhibitors may provide stronger anti-cancer effects by targeting CDH1 deficiency and potentially overcome drug resistance. Here, we evaluated the effects and mechanisms of combined treatment with FAK inhibitor IN10018 and ROS1 inhibitors. Cell-based assays and in vivo animal experiments revealed that FAK and ROS1 inhibitor combination treatment showed stronger anti-cancer effects than either monotherapy. ROS1 inhibitors induced FAK-YAP-TRX signaling, decreasing oxidative stress–related DNA damage, and consequently reducing its anti-cancer effects. However, the combination treatment suppressed the aberrant FAK-YAP-TRX signaling, reinforcing the cytotoxicity of ROS1 inhibitor towards cancer cells. This mechanism of action was confirmed by inhibiting the activity of FAK-YAP-TRX downstream signaling molecules and by pretreatment with oxidative stress scavengers. These findings support the co-administration of FAK and ROS1 inhibitors as a therapeutic strategy in CDH1-deficient triple negative breast cancer and diffuse gastric cancer patients and support further clinical testing of this combination regimen. Citation Format: Jiaming Gao, Yunying Yao, Zaiqi Wang, Baoyuan Zhang, Ruibao Ren. Synergism of FAK and ROS1 inhibitors in the treatment of CDH1-deficient cancers mediated by FAK-YAP-TRX signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5821.

Abstract 6251: High expression level of GSK3β in basal triple negative breast cancer: Effects of the HDAC inhibitor, vorinostat

Abstract High expression levels of glycogen synthases kinase 3 beta (GSK3β) have been correlated with poor prognosis in triple negative breast cancer (TNBC) patients. GSK3β is a multifaceted kinase and is a key regulator of a number of cellular processes. It is known to function as a positive regulator of epithelial-mesenchymal transition (EMT). Usually, cells that undergo EMT are known to acquire stem cell properties and these cells have properties that are known to be resistant to chemotherapies. Inhibition of GSK3β has been shown to decrease markers of EMT and reduce cancer stem cells. High levels of GSK3β were found in the basal-2 subtype of triple negative breast cancer cells, HCC1806. Histone deacetylases (HDACs) are expressed at high levels in some cancers, including TNBC. In this study, vorinostat, a histone deacetylase inhibitor, was shown to down regulate GSK3 expression in HCC1806 cells at both the gene and protein level using qPCR and western blots. Furthermore, cancer stem cells (CSC) cell markers CD44/CD24 using flow cytometry and immunostaining were significantly decreased. Previous studies published from our laboratory have shown vorinostat’s ability to decrease TNBC cells invasion compacity, as well as cell growth. This study suggests that targeting GSK3β may be a potential therapeutic target for certain subtypes of TNBC. Triple negative breast cancer remains one of the most aggressive breast cancers, often having a high mortality rate in younger women. Citation Format: Beverly D. Lyn-Cook, Fatemeh Nouri Emamzaden, Beverly Word, George Hammons. High expression level of GSK3β in basal triple negative breast cancer: Effects of the HDAC inhibitor, vorinostat [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6251.

Abstract 3160: A rapid, non-invasive test to determine HER2-low status in triple negative breast cancer (TNBC) patients

Abstract Background: TNBC is defined as a HER2-negative disease, as assessed via immunohistochemistry (IHC). An IHC 3+ score is considered positive and 2+ (with a negative ISH), 1+, and zero scores are considered negative. Recently, HER2-low (1+, 2+) breast cancer has been proposed as a targetable disease distinct from TNBC. Indeed, use of an anti-HER2 antibody drug conjugate (ADC) in HER2-low metastatic patients resulted in improved progression free and overall survival (DESTINY-Breast04), and remarkably generated a response in HER2-zero cases. The potential to expand the current treatment for HER2-low and -zero patients, highlights the limitations of traditional HER2 assessment, including HER2 intra-tumoral heterogeneity, differential IHC pathology staining, and inter-reader variability. We therefore sought to address how to optimally identify HER2-low TNBC patients that may benefit from HER2 ADCs. Methods: We developed a rapid, non-invasive test to determine HER2-low status in TNBC tumors. Our test uses radiological imaging (DCE-MRIs) coupled with the biophysical simulation platform TumorScope and is informed by single cell RNA-sequencing data to connect molecular regulation to the tumor microenvironment in individual patients. We leveraged these relationships to design a rapid, non-invasive test, HER2Scope, that captures the fraction of each TNBC tumor likely to express significant levels of HER2 (a “HER2 score”). We then characterized the HER2 score in a cohort of TNBC patients from our Virtual Tumor Bank, leading us to identify 3 distinct cohorts: HER2-negative, -low, and -moderate tumors. Results: Using our platform, we identified that HER2 expression is associated with less proliferation and lower nutrient use. Interestingly, we found that there was significant overlap in HER2 expression between HER2+ and TNBC tumors. HER2Scope-identified HER2-low and- moderate tumors were associated with a lower likelihood of pCR in response to chemotherapy compared to HER2-zero tumors (25.3% in HER2-moderate vs. 40% in HER2-zero), suggesting a more aggressive and less drug-responsive phenotype in HER2-low and -moderate tumors. We then tested the expected rate of HER2-low and -moderate tumors within TNBC tumors using our Virtual Tumor Bank (n=264) and found a HER2-low and -moderate response rate of 56% (95% CI = 49-62%), which is strikingly similar to the TNBC response rate to trastuzumab deruxtecan (TDXd) reported in the DAISY trial (42%). HER2Scope may therefore be an effective test to identify TNBC patients for HER2 ADC therapies. Conclusion: We present a novel test to identify HER2-nonzero TNBC patients rapidly and non-invasively. HER2Scope relies on radiological imaging, and therefore does not depend on an inherently variable score derived from biopsy-driven pathologic staining. Additionally, by evaluating the entire tumor, it addresses the challenge of HER2 intra-tumoral heterogeneity. Citation Format: Daniel Cook, Snehal Patel, John Whitman, Nicole Hobbs, Dorys A. Lopez-Ramos, John Pfeiffer, Joseph Peterson, Tushar Pandey, Anuja K. Antony, John Cole. A rapid, non-invasive test to determine HER2-low status in triple negative breast cancer (TNBC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3160.

Abstract 6221: Support for targeted therapy selection in triple negative breast cancer patients using aberrant signal transduction pathway activity profiles

Abstract Introduction: Success of therapeutic interventions largely rely on the pathological and biological characteristics of the tumor and varies due to the heterogeneous nature of breast cancers. Triple negative breast cancers (TNBC) stain IHC negative for both hormone receptors (ER, PR) and HER-2. TNBC is usually treated with chemotherapy because of absence of any molecular target. This study is initiated to characterize TNBC based on a new methodology that measures and quantifies signal transduction pathways (STPs) activities to reveal potential tumor-driving STPs in TNBC and create new options for targeted therapy. Method: Using the mRNA-based OncoSIGNal pathway activity profiling PCR test (InnoSIGN) STP activities of 7 pathways (AR, ER, PI3K, MAPK, HH, TGFβ and Notch) in 39 samples from normal breast tissue and 12 TNBC patients were quantified and expressed on a scale from 0-100. Normal healthy breast tissue was obtained from breast reduction surgery and areas where epithelial cells content was at least 50% were annotated and harvested for mRNA isolation and STP analyses. The normal STP activity is representing the normal physiological activity and is used as reference value. Aberrant high pathway activity in a patient tumor sample was concluded when this score was higher than twice the standard deviation above the mean of normal breast tissue STP activity. Results: STP thresholds for interpretation of high aberrant activity were determined from 39 normal breast samples. Using these thresholds, STP activities in 12 TNBC samples were analyzed. In these TNBC samples, MAPK was in 75%, HH in 67%, PI3K in 58%, and AR, Notch and TGFβ were in 17% of the cases above the thresholds. In 50% of the cases a combination of MAPK and HH or a combination of PI3K and HH were found above thresholds. In 42% of the cases MAPK in combination with PI3K were above thresholds. Increased activity of AR was never observed in combination with increased HH activity. Conclusion: By using the OncoSIGNal test high aberrant STP activities could be determined in TNBC patient samples. Results show that different pathways are aberrantly active, depending on the patient sample, which opens the opportunity for personalized targeted treatment of individual TNBC patients. Next steps: The TNBC data set will be extended to further profile the STP activity in relation to different clinical outcomes and to investigate new opportunities for targeted therapies. Citation Format: Diederick M. Keizer, Yvonne J. Wesseling, Dianne A. van Strijp, Saskia M. Vermeer, Eveline C. den Biezen. Support for targeted therapy selection in triple negative breast cancer patients using aberrant signal transduction pathway activity profiles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6221.

Abstract 6781: Spatial omics using spatially-resolved laser-activated cell sorting for cancer biomarker discovery

Abstract Cancer is spatially heterogeneous in terms of genetic molecules. Revealing genomic, epigenomic, transcriptomic, and epitranscriptomic features that are unique to the malignant cell populations within cancer lead to cancer biomarker discoveries that can be translated into diagnostic or therapeutic tools. Here, we introduce spatially-resolved laser-activated cell sorting (SLACS) technology coupled to next generation sequencing and mass spectrometry that analyzes genetic molecules from regions of interest within spatial context. Specifically, we demonstrate application of SLACS in various cancers such as breast cancer, glioblastoma, glioma, meningioma, multiple myeloma, and leukemia. Examples of discovering cancer biomarker and their mechanism of action within spatial context are also provided. Specifically, we describe Select-seq which isolates the regions of interest as small as single cells from the immunofluorescence stained tissue and obtains the full-length transcriptome data. We demonstrated Select-seq on tumor tissue section from triple negative breast cancer patient who have received neoadjuvant chemotherapy. Select-seq produced full-length spatial transcriptome data, with which we analyzed the transcriptomic and epitranscriptomic features including alternative splicing variant, complementarity-determining region analysis of B cells, and even adenosine-to-inosine base editing. We were also able to analyze the immune- and stem-cell-like microniches, in which the complex mechanisms behind ferroptosis inhibition might suggest therapeutic options for the TNBC patients. Bridging spatial technologies to omics technologies, the discovery of specific markers within spatial context will provide insights into the next generation diagnostics and cancer therapeutics such as cancer vaccines. Citation Format: Amos C. Lee, Sumin Lee, Sunghoon Kwon. Spatial omics using spatially-resolved laser-activated cell sorting for cancer biomarker discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6781.

Abstract 2175: Gene signature predicts pathological complete response in triple negative breast cancer patients: NACATRINE trial

Abstract In triple negative breast cancer (TNBC), achieving pathological complete response (pCR) is associated with improved survival outcomes. However, only one-third of patients receiving neoadjuvant chemotherapy (NAC) achieve pCR. Recognizing molecular markers that predict response to chemotherapy and selecting patients who can benefit from NAC in clinical practice has been a challenge in many studies. This exploratory analysis of the NACATRINE trial aimed to identify biomarkers that predict pCR TNBC patients receiving NAC. The NACATRINE trial is a Brazilian, phase II, single-center, randomized, open-label study that compared adding carboplatin to sequential neoadjuvant therapy based on anthracycline and taxane for TNBC. We evaluated gene expression in untreated samples to associate with the response to systemic therapy. RNA was extracted from the tissue biopsy, and the nCounter Breast Cancer panel analyzed gene expression. Gene counts were normalized by housekeeping. For statistical significance, the t-test was used with a p-value <0.05 and fold-change ≥2. Of the 66 patients included in the gene expression profile analysis, 24 (36.4%) had pCR, and 42 (63.6%) had residual disease. Thirty-seven genes were differentially expressed when associated with pCR in the carboplatin arm and twenty-seven in the non-carboplatin arm (p-value <0.001). We performed a linear regression model to evaluate gene performance, and the area under the curve (AUC) was calculated to assess the predictive value of differentially expressed genes. Eleven genes (KCNB1, FGF1, SNAI1, CXCL9, FGL2, HAS1, CXCL8, VEGFD, HEMK1, MS4A2, and NFKBIZ) in the carboplatin arm (AUC 0.938) and eight genes (ALDH1A1, FZD8, HIST1H3H, CXADR, WDR77, PRKACB, JUN, and CDK6) in the non-carboplatin arm (AUC 0.943) was associated with pCR. Overall survival (OS) was higher among patients who had downregulated KCNB1, FGF1, and SNAI1 (HR = 4.43, 95% CI 1.00 - 1.58; p=0.04; HR = 4.92, 95% CI 1.10 - 2.83; p= 0.03; HR = 4.86, 95% CI 1.38 - 1.11; p= 0.01) respectively. Similarly, upregulated of ALDH1A1, CXCL9 and FGL2 were associated with a better prognosis (HR = 0.17, 95% CI 0.05 - 0.50; p= 0.003; HR = 0.15, 95% CI 0.04 - 0.50; p = 0.004; HR = 0.21, 95% CI 0.07 - 0.60; p = 0.009), respectively. We identified potentially beneficial gene expression signatures (OS and pCR) for neoadjuvant chemotherapy, suggesting that these markers validated in a prospective study can be used in selecting patients for neoadjuvant chemotherapy in TNBC. Citation Format: Ana J. Freitas, Caroline R. Nunes, Rhafaela L. Causin, Iara V. Santana, Marco A. Oliveira, Stéphanie Calfa, Cristiano P. Souza, Márcia M. Marques. Gene signature predicts pathological complete response in triple negative breast cancer patients: NACATRINE trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2175.

Biomimetic nanoparticles drive the mechanism understanding of shear-wave elasticity stiffness in triple negative breast cancers to predict clinical treatment

In clinical practice, we noticed that triple negative breast cancer (TNBC) patients had higher shear-wave elasticity (SWE) stiffness than non-TNBC patients and a higher α-SMA expression was found in TNBC tissues than the non-TNBC tissues. Moreover, SWE stiffness also shows a clear correlation to neoadjuvant response efficiency. To elaborate this phenomenon, TNBC cell membrane-modified polylactide acid-glycolic acid (PLGA) nanoparticle was fabricated to specifically deliver artesunate to regulate SWE stiffness through inhibiting CAFs functional status. As tested in MDA-MB-231 and E0771 orthotopic tumor models, CAFs functional status inhibited by 231M-ARS@PLGA nanoparticles (231M-AP NPs) had reduced the SWE stiffness as well as attenuated hypoxia of tumor as tumor soil loosening agent which amplified the antitumor effects of paclitaxel and PD1 inhibitor. Single-cell sequencing indicated that the two main CAFs (extracellular matrix and wound healing CAFs) that produces extracellular matrix could influence the tumor SWE stiffness as well as the antitumor effect of drugs. Further, biomimetic nanoparticles inhibited CAFs function could attenuate tumor hypoxia by increasing proportion of inflammatory blood vessels and oxygen transport capacity. Therefore, our finding is fundamental for understanding the role of CAFs on affecting SWE stiffness and drugs antitumor effects, which can be further implied in the potential clinical theranostic predicting in neoadjuvant therapy efficacy through non-invasive analyzing of SWE imaging.

Immune Checkpoint and EMT-Related Molecules in Circulating Tumor Cells (CTCs) from Triple Negative Breast Cancer Patients and Their Clinical Impact

Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype. There are few targeted therapies for these patients, leading to an unmet need for new biomarkers. The present study aimed to investigate the expression of PD-L1, CTLA-4, GLU, and VIM in CTCs of TNBC patients. Ninety-five patients were enrolled in this study: sixty-four TNBC and thirty-one luminal. Of these patients, 60 were in the early stage, while 35 had metastatic disease. Protein expression was identified by immunofluorescence staining experiments and VyCAP analysis. All the examined proteins were upregulated in TNBC patients. The expression of the GLU+VIM+CK+ phenotype was higher (50%) in metastatic TNBC compared to early TNBC patients (17%) (p = 0.005). Among all the BC patients, a significant correlation was found between PD-L1+CD45-CK+ and CTLA-4+CD45-CK+ phenotypes (Spearman test, p = 0.024), implying an important role of dual inhibition in BC. Finally, the phenotypes GLU+VIM+CK+ and PD-L1+CD45-CK+ were associated with shorter OS in TNBC patients (OS: log-rank p = 0.048, HR = 2.9, OS: log-rank p < 0.001, HR = 8.7, respectively). Thus, PD-L1, CTLA-4, GLU, and VIM constitute significant biomarkers in TNBC associated with patients' outcome, providing new therapeutic targets for this difficult breast cancer subtype.

The role of the desmosomal protein desmocollin 2 in tumour progression in triple negative breast cancer patients

BackgroundThe disruption of epithelial features represents a critical step during breast cancer spread. In this context, the dysregulation of desmosomal proteins has been associated with malignant progression and metastasis formation. Curiously, both tumour suppressive and pro-metastatic roles have been attributed to desmosomal structures in different cancer entities. In the present study, we describe the pro-metastatic role of the desmosomal protein desmocollin 2 (DSC2) in breast cancer.MethodsWe analysed the prognostic role of DSC2 at mRNA and protein level using microarray data, western blot analysis and immunohistochemistry. Functional consequences of DSC2 overexpression and DSC2 knock down were investigated in the triple negative breast cancer (TNBC) cell line MDA-MB-231 and its brain-seeking subline MDA-MB-231-BR, respectively in vitro and in vivo.ResultsWe found a significantly higher DSC2 expression in the more aggressive molecular subtypes HER2-positive and TNBC than in luminal breast cancers, as well as a significant correlation between increased DSC2 expression and a shorter disease-free—also in multivariate analysis—and overall survival. Additionally, a significant association between DSC2 expression in the primary tumour and an increased frequency of cerebral and lung metastasis could be observed. In vitro, ectopic DSC2 expression or DSC2 down-regulation in MDA-MB-231 and MDA-MB-231-BR led to a significant tumour cell aggregation increase and decrease, respectively. Furthermore, tumour cells displaying higher DSC2 levels showed increased chemoresistance in 3D structures, but not 2D monolayer structures, suggesting the importance of cell aggregation as a means for reduced drug diffusion. In an in vivo brain dissemination xenograft mouse model, reduced expression of DSC2 in the brain-seeking TNBC cells led to a decreased amount of circulating tumour cells/clusters and, in turn, to fewer and smaller brain metastatic lesions.ConclusionWe conclude that high DSC2 expression in primary TNBC is associated with a poorer prognosis, firstly by increasing tumour cell aggregation, secondly by reducing the diffusion and effectiveness of chemotherapeutic agents, and, lastly, by promoting the circulation and survival of tumour cell clusters, each of which facilitates distant organ colonisation.

P012 Survival outcomes and toxicities of adjuvant docetaxel-cyclophosphamide for four cycles in node negative triple negative and HER2 positive Chinese breast cancer patients: A 10 year follow up study

P012 Survival outcomes and toxicities of adjuvant docetaxel-cyclophosphamide for four cycles in node negative triple negative and HER2 positive Chinese breast cancer patients: A 10 year follow up study

Abstract P6-01-34: Longitudinal DCE-MRI Radiomic Models for Early Prediction of Response to Neoadjuvant Systemic Therapy (NAST) in Triple Negative Breast Cancer (TNBC) Patients

Abstract Background and Purpose Early prediction of neoadjuvant systemic therapy (NAST) response in triple negative breast cancer (TNBC) patients could potentially aid in the selection of alternative therapies and avoid unnecessary toxicity in patients unlikely to achieve pathologic complete response (pCR) with NAST. In this study, we investigated the radiomic features of the peritumoral and the tumoral regions from dynamic contrast enhanced (DCE) MRI acquired at different time points of NAST for early treatment response prediction in TNBC. Methods and Materials This study included 182 biopsy-confirmed stage I-III TNBC patients enrolled in an IRB approved prospective clinical trial (NCT02276433). All patients underwent DCE-MRI on a GE 3T MRI scanner at baseline (BL), after two (C2) and four (C4) cycles of doxorubicin/cyclophosphamide based chemotherapy and before surgery. The peritumoral and the tumoral regions were segmented manually by two fellowship-trained radiologists using early phase (2.5 min) DCE-MRI subtraction images. Ten first order radiomic features, 300 grey-level-co-occurrence matrix (GLCM) features along with their absolute and relative differences (C4/BL, C2/BL, C4/C2) between the 3 imaging time points were extracted from the peritumoral and the tumoral regions. Patients were randomly divided into training and testing sets in a 2:1 ratio. For univariate analysis, area under the receiver operating characteristics curve (AUC ROC) was measured to determine the features most predictive of pCR/non-pCR. Wilcoxon Rank Sum test was used to test the statistical significance of predictive performance. In multivariate analysis, radiomic models were established using logistic regression with elastic net regularization followed by 5-fold cross validation for performance assessment. Results Eighty-eight (48%) patients had pCR (59 training, 29 testing) and 94 (52%) patients had non-pCR (63 training, 31 testing). Twenty-five radiomic features (4 from peritumoral C4, 5 from tumoral C4, 4 from peritumoral C4/BL, 6 from tumoral C4/BL, 2 from peritumoral C4/C2 and 4 from tumoral C4/C2) were statistically significant with AUC ≥ 0.75 in both the training and the testing sets at the univariate analysis. The significant features at C4 had AUCs of 0.75-0.79 for the training set and 0.76-0.81 for the testing set. Changes measured between C4 and BL or C2 showed AUC of 0.76-0.84 in the training and 0.75-0.81 in the testing datasets. Eleven multivariate regression models comprised of radiomic features at BL, C2, C4 and their changes (C4/BL, C4/C2 and C2/BL) showed an AUC of 0.80-0.84 for cross validation and an AUC of 0.80-0.82 for independent testing. Conclusions Radiomic models using longitudinal DCE MRI parameters of peritumoral and tumoral regions during NAST have the potential to predict pCR in TNBC patients undergoing NAST. Citation Format: Bikash Panthi, Rania M. Mohamed, Beatriz Adrada, Rosalind Candelaria, Mary S. Guirguis, Wei Yang, Medine Boge, Miral Patel, Nabil Elshafeey, Sanaz Pashapoor, Zijian Zhou, Jong Bum Son, Ken-Pin Hwang, H. T. Carisa Le-Petross, Jessica Leung, Marion E. Scoggins, Gary J. Whitman, Zhan Xu, Deanna L. Lane, Tanya Moseley, Frances Perez, Jason White, Elizabeth Ravenberg, Alyson Clayborn, Mark Pagel, Huiqin Chen, Jia Sun, Peng Wei, Alastair M. Thompson, Stacy Moulder, Anil Korkut, Lei Huo, Kelly K. Hunt, Jennifer K. Litton, Vicente Valero, Debu Tripathy, Clinton Yam, Jingfei Ma, Gaiane Rauch. Longitudinal DCE-MRI Radiomic Models for Early Prediction of Response to Neoadjuvant Systemic Therapy (NAST) in Triple Negative Breast Cancer (TNBC) Patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-34.

Abstract P3-05-10: Disease features, genomic profiles and outcomes of younger vs. older Chinese hormone receptor positive (HR+), HER2 negative (HER2-) metastatic breast cancer (MBC) patients

Abstract Background: Breast cancer in younger women has been characterized as a more aggressive disease with relatively poor outcomes compared to breast cancer in older women. This pattern has been attributed to a variety of clinicopathologic characteristics including the enrichment of aggressive HER2+ and TNBC subtypes in younger patients. However, similar to older breast cancer patients, the majority of young breast cancer patients are HR+/HER2-. Here we have evaluated the clinicopathologic characteristics and genomic profiles of real-world HR+/HER2- MBC patients to examine the determinants of outcome for younger vs. older patients in this subtype. Patients and Methods: This study included 65 Chinese patients presenting with HR+/HER2- MBC at the Peking University Cancer Hospital. Blood samples were collected upon metastatic disease diagnosis before treatment and profiled with the targeted 152-gene PredicineCARETM sequencing panel. Fourteen patients were &amp;lt; 40 years, 19 were 40-50 years, and 32 were &amp;gt; 50 years at the time of primary cancer diagnosis. Kaplan-Meier survival analysis was performed to analyze outcomes including overall survival (OS), disease free survival (DFS) and progression free survival (PFS) in association with clinicopathologic and genomic variables. OS was also evaluated in association with age in separate multivariate models using Cox proportional hazards regression. Results: Significant variation across age groups was observed for several clinicopathological features, including molecular subtype classification (p = 0.045), de novo Stage IV disease (p = 0.011), type of adjuvant endocrine therapy (p = 5.56E-06), resistance to adjuvant endocrine therapy (p = 0.015) and receipt of adjuvant chemotherapy (p = 0.042). Luminal B status was most frequent in patients &amp;lt; 40 years (92.31%), whereas de novo Stage IV disease was more prevalent in patients &amp;gt; 50 years (37.5%). Aromatase inhibitors (AIs) were administered as adjuvant endocrine therapy (ET) to 73.68% of women &amp;gt; 50 years vs. 16.67% and 0% of women aged 40-50 years and &amp;lt; 40 years, respectively. Resistance to adjuvant ET was observed in 23.08% of patients &amp;lt; 40 years but was not observed in the other age groups. Adjuvant chemotherapy was received by a higher proportion of patients in the 40-50 year age group (94.44%) compared to patients &amp;lt; 40 years (69.23%) and patients &amp;gt; 50 years (60%). No differences in somatic gene alteration frequencies were observed across age groups, menopausal status, germline mutation status or tumor grade. However, a higher frequency of FGFR1 alterations was observed in patients classified as Luminal B vs. A (p = 0.048). Comparison of profiles across women who received adjuvant ET revealed a higher prevalence of FGFR1 (p = 0.012), ATM (p = 0.047) and CCND2 (p = 0.04) alterations in patients treated with AIs vs. SERMS. In addition, a higher frequency of APC alterations was observed in patients with high (≥ 20%) vs. low (&amp;lt; 20%) Ki67 index (p = 0.035). At the univariate level OS was significantly associated with age (p = 0.039). OS was shortest in patients &amp;gt; 50 years, intermediate in patients &amp;lt; 40 years, and longest in patients 40-50 years. Across all patients, shorter OS was also associated with de novo Stage IV disease (p = 0.0001), Luminal B subtype (p = 0.008), adjuvant ET with AIs vs SERMS (p = 0.028) and the presence of an FGFR1 (p = 0.028) or CCND2 (p = 0.033) alteration. In multivariate analyses, OS remained significantly longer for patients aged 40-50 years after adjustment for de novo Stage IV disease, Luminal B subtype and FGFR1 status (all p &amp;lt; 0.05). Conclusions: In this group of real-world HR+/HER2- MBC breast cancer patients, younger age was not associated with worse outcomes. While current guidelines recommend treatment decisions based on tumor biology rather than age, young HR+ breast cancer patients are more likely to receive chemotherapy. Our findings support the development of biomarker-driven treatment strategies for these patients. Citation Format: Jinhao Wang, Yaxin Liu, Bin Shao, Hang Dong, Tiantian Zheng, Pan Du, Shidong Jia, Bonnie King, Jing Wang, Xiaoran Liu, Huiping Li. Disease features, genomic profiles and outcomes of younger vs. older Chinese hormone receptor positive (HR+), HER2 negative (HER2-) metastatic breast cancer (MBC) patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-10.

Abstract P4-01-13: A retrospective study of anlotinib in patients with HER-2 negative metastatic breast cancer after prior two or more lines treatment

Abstract Background: Anlotinib is a novel small molecule antiangiogenic drug that can inhibit multiple tyrosine kinase receptor activities. It has demonstrated antitumor activity in various cancers. This retrospective study explored the efficacy and safety of anlotinib combined chemotherapy in HER-2 negative metastatic breast cancer patients who have disease progressed after prior two or more lines of therapy. Methods: This retrospective study enrolled twenty-two HER-2 negative metastatic breast cancer patients including TNBC and HR+ subtypes. These patients pretreated with at least two lines of chemotherapy and/or endocrine drugs before receiving anlotinib. These patients received anlotinib combination with investigator-selected chemotherapy agents, including docetaxel, vinorelbine, gemcitabine, etoposide, alibrine and so on. Anlotinib was administered 12mg d1-d14 for a 21-day cycle. The primary end point of this study was progression free survival (PFS). Secondary end points included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and toxicity. The treatment continued until disease progression or intolerability or the patient withdraw informed consent. Results: The enrolled breast cancer patients received anlotinib with a median age of 52.5 (rang 30 to 73). The patients with multiple metastases were 59.1% (13/22). All patients were evaluated and the ORR was 50% (95% Cl 0.282-0.718), DCR 95.5% (95% Cl 0.772-0.999) and the mPFS was 8 months (95% Cl 5.15-10.85). We also analyzed the efficacy of anlotinib combination with chemotherapy in different subtypes. For HR+HER2- metastatic breast cancer patients, the ORR was 77.8% (95% Cl 0.4-0.972), DCR 100% (95% Cl 0.664-1.0) and the mPFS was 8.5 months (95% Cl 7.217-9.783). And for TNBC patients, the ORR was 30.8% (95% Cl 0.091-0.614), DCR 92.3% (95% Cl 0.640-0.998) and the mPFS was 6 months (95%Cl 4.405-7.595). The most common adverse events were grade 1/2 including fatigue, hand-foot syndrome and thrombocytopenia et.al., and no serious adverse events occurred. Conclusion: Anlotinib is safe and effective in patients with HER-2 negative metastatic breast cancer after prior two or more lines treatments, and it is well tolerated. Citation Format: Jing Sun, Yijun Tang, Xiaohui Liu, Jiangli Li, Jin Xia, Liang xu, Junlan Guo, Jing Wang, Shengnan Guo, Zhaojie Sheng, Yanfang Zhang, Yuan Yuan. A retrospective study of anlotinib in patients with HER-2 negative metastatic breast cancer after prior two or more lines treatment [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-13.

Abstract P3-05-45: Circulating tumor cells, immunohistochemical subtypes, and genes mutation as prognostic markers in HER2 negative metastatic breast cancer patients candidates to chemotherapy

Abstract Background: In the era of targeted therapies, chemotherapy (CT) is still a valuable treatment option for patients (pts) with HER2 negative metastatic breast cancer (MBC). The identification of predictive and prognostic markers might improve treatment response and survival. Here we investigated the role of tumor subtypes, circulating tumor cells (CTCs), and mutations in genes or pathways of interest, in predicting response to CT and prognosis of HER2 negative MBC pts within AARES trial. Methods: AARES is an open label multicentric randomised phase 2 trial comparing a DNA-damaging (arm A: cisplatin 25 mg/m2/day, day 1-3 + cyclophosphamide 600 mg/m2 day 1) versus (vs) a non-DNA-damaging (arm B: capecitabine 1000 mg/m2 bid/day, day 1-14 + vinorelbine 60 mg/m2/day, day 1,8) CT regimen in pts with HER2 negative MBC. Archival tumor tissue samples and blood samples were collected at baseline. The Cell SearchTM system was used for CTCs isolation and enumeration and a cut-off of 5 CTC/7,5 ml was used. Tumor subtypes were based on locally assessed hormone receptors and HER2 status. The luminal-like subtype (Lum) was defined by ER or PR positivity, while the triple negative subtype (TN) by ER, PR, and HER2 negativity. Tissue samples were used for DNA extraction and next generation sequencing analysis using a target enrichment panel of 170 genes (TruSight 170, Illumina). Primary endpoint was objective response rate (ORR) assessed for the two treatment arms. Progression free survival (PFS) and overall survival (OS) were evaluated as secondary endpoints, and estimated with the Kaplan-Meier method. ORR, PFS and OS were correlated with CTC counts, tumor subtypes, and mutational status of genes/pathway of interest (PIK3CA, TP53, BRCA1, BRCA2, PI3K/AKT pathway (PI3K/AKT)). Results: AARES enrolled 102 pts from 2011 to 2016 across 9 Italian centers. Of these, 77 pts were evaluable for ORR. Median follow up was 32 months. Overall, median age was 57. The majority of pts had Lum tumors (73%), while 27% had TN. 86% of pts had visceral metastases, and 52% had 3 or more metastatic sites. 48% of pts received the study treatment as 1st line, 32% as 2nd line, and 19% as 3rd line. Out of the 77 pts with ORR data, 41 (53%) were CTC- and 36 (47%) CTC+. A larger proportion of pts with Lum tumors were CTC+ (54% n=30), while TN tumors were mainly CTC- (71% n=15). 49 pts had adequate tumor tissue for sequencing analysis. TP53 mutations (mut) were found in 33% of pts, BRCA1/2 mut in 14%, PIK3CA mut in 35%, and PI3K/AKT mut in 47%. ORR was 24% and 37% in arm A vs arm B, respectively (p= 0.2), and no difference in ORR was observed by tumor subtypes (Lum vs TN), and CTCs count (+ vs -). PFS and OS were assessable on the whole population (n=102) and did not significantly differ by treatment arms. Median OS (mOS) was higher in Lum pts compared to TN (24 months (mo) vs 15.4 mo, p=0.048) while median PFS (mPFS) did not differ according to tumor subtypes (p=0.28). Overall, CTCs count was not significantly associated with mPFS or OS however in pts with TN tumors and CTC-, mPFS and mOS were significantly longer (mPFS: 4.44 mo vs 2.56 mo in CTC- and CTC+ subgroups, respectively, p=0.00087 and mOS: 22.07 mo vs 3.57 mo in CTC- and CTC+ subgroups, respectively, p&amp;lt; 0.0001). On the other hand, no differences were observed in Lum pts categorized according to CTC status (p=0.83 for mPFS, p=0.54 for mOS). Finally, pts with PI3K/AKT mut had a significantly worse PFS compared to wild type in the overall population (p=0.0091) as well as in Lum (p=0.034) and TN pts (p=0.0052). Conclusions: CTCs and tumor subtypes were not predictive of response to CT regimens in HER2 negative MBC pts. A number of CTC &amp;gt;5 in TN MBC, and mutations in the PI3K/AKT pathway, identified a subgroup of pts with worse prognosis, potentially candidates for alternative treatments. Further studies are needed to confirm these results in a larger population. Citation Format: Emanuela Risi, Marta Pestrin, Chiara Biagioni, Dario Romagnoli, Ilenia Migliaccio, Francesca Galardi, Francesca De Luca, Matteo Benelli, Erica Moretti, Giuseppina Sanna, Luca Livraghi, Silvia Cappadona, Roberta Di Marsico, Domenico Amoroso, Angelo Martignetti, Angela S. Ribecco, Elena Rota Caremoli, Luigi Coltelli, Fabio Puglisi, Luca Malorni, Laura Biganzoli. Circulating tumor cells, immunohistochemical subtypes, and genes mutation as prognostic markers in HER2 negative metastatic breast cancer patients candidates to chemotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-45.

Abstract P2-13-05: Triple Negative Breast Cancer (TNBC) patients are more likely to digitally explore clinical trial options and prior to receiving treatment for advanced disease compared to non-TNBC patients

Abstract Introduction: Triple-negative breast cancer (TNBC), an aggressive form of breast cancer (BC) that is associated with poor prognosis, accounts for 10-15% of all BCs. Chemotherapy remains the standard of care (SOC) for advanced disease, with limited clinical benefit. Oncology clinical trials (CTs) are globally recommended and encouraged as the preferred treatment (tx) option for any cancer patient (pt). ‘TrialJectory’ (TJ) is an artificial intelligence (AI)-based technology that matches pts to oncology CTs. Here, we identified distinct characteristics of TNBC pts who signed up to the TJ platform compared to non-TNBC pts. Methods: Using AI and an unsupervised natural language processing approach, the TJ platform clinically matches pts to CTs. Matching is achieved by pt response to an online dynamic questionnaire (www.trialjectory.com) that collects detailed clinical data including clinico-pathologic characteristics, tx history, general health, and comorbidities. Those are compared to the eligibility criteria of available CTs to yield a high-quality actionable matched-trial list. Results: Between 1/2020 and 12/2021, out of 9796 BC pts that signed up, 2688 were TNBC pts (27%). There was no significant difference in age at sign-up between TNBC and non-TNBC patients (median age of 57 years vs 58 years, respectively). Consistently with Non-hispanic black (NHB) race prevalence in the different molecular subtypes in the general US population, NHB race had higher signup rate in TNBC compared to non-TNBC (9.95% vs 5.76%, respectively). TNBC pts signed up at a later disease stage compared to non-TNBC pts (19% of TNBC reported having a stage 1 disease compared to 27% of non-TNBC pts, p&amp;lt; 0.001).A significantly higher percentage of pts with advanced/metastatic TNBC signed up to the TJ platform before starting tx compared to non-TNBC patients (34% vs 22%, respectively, p&amp;lt; 0.001). Furthermore, there was a significant difference in the willingness to travel any distance within the US for a matched clinical trial between TNBC and non-TNBC pts (39% vs 34%, respectively, p&amp;lt; 0.001). Conclusions: In this study, we found significant differences in the characteristics of TNBC vs non-TNBC pts that have signed up to the TJ platform. There was an up to 2-fold enrichment of TNBC on the TJ platform pts compared to their frequency in the general population. While previous studies do not show a difference in stage distribution between different subtypes, TNBC patients initiated their search for CTs at a higher stage. In addition, advanced TNBC patients started their search earlier in their journey, before starting chemotherapy. This may reflect the lack of effective SOC and possibly, the motivation to avoid the use of chemotherapy. This is also supported by the willingness of TNBC patients to travel farther in order to identify and enroll in a CT compared to non-TNBC pts. Importantly, the motivation of TNBC pts to travel any distance has not been reduced despite the COVID-19 pandemic, reflecting a strong drive of this pt population to enroll in CTs. It also demonstrates that with the right access, diverse patient populations are willing to participate in clinical trials. In sum, TNBC pts are more likely to explore CT options, in the advanced stage setting, earlier in their journey. This study demonstrates the power of TJ platform for clinico-pathologic characterization and diverse pt groups, including their drivers and behavioral choices during their battle with cancer. Citation Format: Michal Safran, Yelena Lapidot, Tzvia Bader, Avital Gaziel. Triple Negative Breast Cancer (TNBC) patients are more likely to digitally explore clinical trial options and prior to receiving treatment for advanced disease compared to non-TNBC patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-13-05.

Abstract P2-11-19: Inflammatory indexes as prognostic biomarkers in advanced triple negative breast cancer patients

Abstract Background The identification of treatment selection biomarkers for advanced triple negative breast cancer (aTNBC) patients remains an unmet need. The immune system is known to be involved in the microenvironment of triple negative breast cancer (TNBC). Immune ratios like the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), the monocyte-lymphocyte ratio (MLR) and the systemic immune-inflammation index (SII) may reflect the immune system functional status in these patients and the involvement of circulating immune cells in cancer progression. In particular MLR showed to predict overall survival (OS) in aTNBC and to contribute to migration of circulating tumor cells [1]. Methods A retrospective-prospective, observational multicenter study from the GIM-14 experience was performed to investigate the association between inflammatory indexes (NLR, MLR, PLR and SII), as measured at baseline and at progression, and clinical and survival aspects in patients with aTNBC in first line setting. The optimal cutoff values between low and high expression of inflammatory indexes were established on the basis of cut-off values determined in a previously conducted study in order to validate them[1], and was used to predict progression-free survival (PFS) and OS. Time-to-event variables (PFS; OS) were calculated using Kaplan-Meier method, while Cox regression model was used to estimate HRs and their 95% CI. Results 105 consecutive patients with a diagnosis of aTNBC were fully evaluated for the final analysis. The median age at diagnosis was 55 years (33-86). Of them, 80 patients received a neo/adjuvant treatment after diagnosis. At first progression the majority of patients (n= 97) received chemotherapy, while only 8 patients were treated with chemo-immunotherapy due to the programmed death ligand 1 (PD-L1) expression in the immunohistochemical analyses. At a median follow-up of 54 months, median PFS in the whole patients population was 13 months (95% CI 9,4-16,5), while median OS was 17.3 OS (95% CI 13-22,2). All high inflammation based scores evaluated at diagnosis of metastatic disease were significantly associated with lower PFS, in particular high NLR (≥3) and high MLR (≥0.34) (p = 0.0006 and p = 0.011, respectively). Similarly, all high indexes appeared significantly associated with a lower OS, especially NLR (&amp;gt;3), SII (≥836) and MLR (≥0.34) (p &amp;lt; 0.0001, p = 0.0005, p=001 respectively). In particular also NLR and SII evaluated at disease progression after first line treatment were significantly associated with a worse OS (p=0.0006 and p=0.001 respectively). In multivariable analysis for predictors of overall survival, the number of metastatic sites, NLR, SII and MLR remained significant (p&amp;lt; 0.0001, p=0.006, p=0.005 respectively). Conclusions NLR, SII and MLR are predictors of OS in aTNBC. Although our results need validation with larger studies, we suggest that inflammatory ratios could be used as feasible biomarkers of prognosis and treatment efficacy in aTNBC. Further research about HER-2 low categorized patients will be updated and presented at the final meeting. 1. De Giorgi U, Mego M, Scarpi E, Giordano A, Giuliano M, Valero V, Alvarez RH, Ueno NT, Cristofanilli M, Reuben JM. Association between circulating tumor cells and peripheral blood monocytes in metastatic breast cancer. Ther Adv Med Oncol. 2019 Aug 14;11:1758835919866065. doi: 10.1177/1758835919866065. PMID: 31452692; PMCID: PMC6696837. Citation Format: Caterina Gianni, Michela Palleschi, Emanuela Scarpi, Filippo Merloni, Eva Blondeaux, Fabio Puglisi, Elena Collovà, Palma Pugliese, Francesco Cognetti, Irene Giannubilo, Tommaso Ruelle, Claudia Bighin, Lucia Del Mastro, Ugo De Giorgi. Inflammatory indexes as prognostic biomarkers in advanced triple negative breast cancer patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-19.