non-TNBC Patients Research Articles

Targeted genotyping for recurring variants in cancer susceptibility genes in non-Ashkenazi Jewish patients with breast cancer diagnosed ≥ 50 years.

e12547 Background: Several recurring pathogenic variants (PVs) in BRCA1/BRCA2 and additional cancer susceptibility genes are described in ethnically diverse Israeli population. Since 2019 testing for these recurring PVs is reimbursed unselectively for all breast cancer (BC) patients in Israel, while extended multi-gene panel testing is reimbursed based on specific clinical criteria. We aimed to evaluate the yield of genotyping for these recurring PVs in non-Ashkenazi Jewish BC patients diagnosed ≥ 50 years. Methods: Clinical and genotyping data of all BC patients undergoing oncogenetic counseling at the Oncology institute at Sheba medical center from June 2017 to December 2023 were reviewed. Results: Of 2706 BC patients (mean age at diagnosis 54 years; range, 20-92 years) counseled, 515 patients of non-Ashkenazi Jewish (all 4 grandparents) descent, diagnosed ≥ 50 years of age were genotyped, 55 with triple-negative BC (TNBC) and 460 with non-TNBC. One of the recurring PVs in BRCA1/BRCA2 were detected in 12.7% (7/55) of TNBC patients and 0.65% (3/460) in non-TNBC. One patient with non-TNBC had PMS2 PV. Low-penetrance variants (not all in BC related genes) were found in 2.5% of genotyped TNBC and in 3.7% of non-TNBC patients, including CHEK2 c.499G>A (n=3), APC c.3920T>A (n=4), and heterozygous MUTYH c.1187G>A (n=5). Following first-pass genotyping, 146 patients performed multigene panel testing, none carried a BRCA1/BRCA2 PV, and only 5/127 non-TNBC (3.9%) harbored PVs in CHEK2 (n=2), ATM c.103C>T (n=2) and NBN (n=1). Conclusions: The observed low rates of PV detection in non-Ashkenazi Jewish non-TNBC cases older than 50 years at diagnosis, mostly for clinically insignificant variants, questions the justification of unselected genotyping in this subset of patients.

Abstract PO1-10-08: Building awareness of triple negative breast cancer: Results from the Canadian Breast Cancer Network national survey

Abstract Background: Assessing the education, information and support needs of Canadians diagnosed with breast cancer involves categorizing and tailoring topics and methods of delivery but, most importantly, it must be rooted in an understating of the patient. In 2022, the Canadian Breast Cancer Network (CBCN) initiated a project to identify the needs of the Canadian breast cancer population, determine differences between those diagnosed with triple negative breast cancer (TNBC) compared to non-TNBC patients and develop tailored, focused programs and materials as a result of the findings. Methods: CBCN conducted a series of 45-minute key informant interviews (7) with patients and oncologists to determine needs, gaps, programs, and materials for triple negative breast cancer patients in Canada. Five 90-minute patient focus groups (32 participants) were conducted to enhance the interviews. One group was specifically for metastatic patients. Findings from the interviews and focus groups were used to inform the questions for an online survey open to all Canadians diagnosed with breast cancer which was fielded May 1 to June 10, 2022. The data analysis began in September 2022 and is on-going. Results: While 47.9% of TNBC respondents (versus 51.3% of non-TNBC patients) said that they were aware of different types and subtypes of breast cancer, 70.6% of patients reported they were not aware of the term “triple-negative breast cancer” and only learned about at diagnosis. 69.9% of TNBC patients said that the person giving them their diagnosis used the term – triple-negative breast cancer. 54.5% reported being provided with specific details about their TNBC diagnosis. This included details about: the aggressive nature of TNBC (76.8%), treatments (67.6%), treatment goals (56.3%), and the urgency of beginning treatment (66.2%). TNBC patients reported that in retrospect, more information on clinical trials (41.7%), the long-term side effects of treatment (38.6%) and post-treatment follow-up (32.5%) should have been included in the discussion at diagnosis. Conclusions: Breast cancer is not a monolithic disease. TNBC impacts 10-20% of the breast cancer population. A majority of those diagnosed with TNBC in the survey were not even aware of this subtype. Building awareness of TNBC, its risk factors and different treatment needs in the public at large and among the breast cancer community could facilitate discussions with healthcare providers and assist researchers seeking new treatments and, most importantly, provide an informed voice for those with TNBC. Making the most current, evidence-based TNBC information and resources available to both patients and providers at diagnosis could build trust and understanding of the differences in treatment and follow up and instill confidence in the overall patient experience. Citation Format: Kathleen D. Swiger, Scott Richter, Bukun Adegbembo, Cathy Ammendolea. Building awareness of triple negative breast cancer: Results from the Canadian Breast Cancer Network national survey [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-10-08.

LC-MS/MS platform-based serum untargeted screening reveals the diagnostic biomarker panel and molecular mechanism of breast cancer

BackgroundBreast cancer (BC), the most common form of malignant cancer affecting women worldwide, was characterized by heterogeneous metabolic disorder and lack of effective biomarkers for diagnosis. The purpose of this study is to search for reliable metabolite biomarkers of BC as well as triple-negative breast cancer (TNBC) using serum metabolomics approach. MethodsIn this study, an untargeted metabolomics technique based on ultra-high performance liquid chromatography combined with mass spectrometry (UHPLC-MS) was utilized to investigate the differences in serum metabolic profile between the BC group (n = 53) and non-BC group (n = 57), as well as between TNBC patients (n = 23) and non-TNBC subjects (n = 30). The multivariate data analysis, determination of the fold change and the Mann-Whitney U test were used to screen out the differential metabolites. Additionally, machine learning methods including receiver operating curve analysis and logistic regression analysis were conducted to establish diagnostic biomarker panels. ResultsThere were 36 metabolites found to be significantly different between BC and non-BC groups, and 12 metabolites discovered to be significantly different between TNBC and non-TNBC patients. Results also showed that four metabolites, including N-acetyl-D-tryptophan, 2-arachidonoylglycerol, pipecolic acid and oxoglutaric acid, were considered as vital biomarkers for the diagnosis of BC and non-BC with an area under the curve (AUC) of 0.995. Another two-metabolite panel of N-acetyl-D-tryptophan and 2-arachidonoylglycerol was discovered to discriminate TNBC from non-TNBC and produced an AUC of 0.965. ConclusionThis study demonstrated that serum metabolomics can be used to identify BC specifically and identified promising serum metabolic markers for TNBC diagnosis.

261P Dysregulation of immune checkpoint proteins in newly- diagnosed early breast cancer patients undergoing neoadjuvant chemotherapy: A comparison between TNBC and non-TNBC patients

261P Dysregulation of immune checkpoint proteins in newly- diagnosed early breast cancer patients undergoing neoadjuvant chemotherapy: A comparison between TNBC and non-TNBC patients

Clinical Value of cfDNA Content in Peripheral Blood of Patients with Triple-Negative Breast Cancer

Objective: To explore the value of circulating free (cfDNA) content in the clinical diagnosis and treatment of triple-negative breast cancer (TNBC). Methods: A total of 39 TNBC patients, 45 non-TNBC patients, and 50 healthy individuals admitted to the Baoding First Central Hospital during 2019–2022 were recruited. The clinical data, peripheral blood cfDNA concentration, and clinicopathological indicators of the patients were observed and analyzed. Results: The difference in clinical indicators such as age, age range, tumor size, clinical stage, and lymph node metastasis between patients with TNBC and non-TNBC was insignificant (P > 0.05). The cfDNA concentrations (ng/mL) of the TNBC group, non-TNBC group, and healthy group were 24.12 ± 4.98, 15.36 ± 4.12, and 3.12 ± 1.02, respectively, and they are statistically different (P < 0.05). The difference in cfDNA concentration was insignificant between TNBC patients with tumors ≤ 2 cm and > 2 cm (P > 0.05) but was significant between TNBC patients with clinical stages I+II and III+IV (P < 0.05). The cfDNA concentration in TNBC patients with lymph node metastasis was significantly higher than those without lymph node metastasis (P < 0.05). Conclusion: cfDNA has an important application value in the diagnosis and treatment of breast cancer. By detecting the cfDNA level and its gene variation, valuable information about the progress and treatment effects of breast cancer can be obtained. This non-invasive detection method has a wide range of applications and can be used for early screening, auxiliary diagnosis, efficacy evaluation, and recurrence monitoring of breast cancer.

Ensemble learning model for identifying the hallmark genes of NFκB/TNF signaling pathway in cancers

BackgroundThe nuclear factor kappa B (NFκB) regulatory pathways downstream of tumor necrosis factor (TNF) play a critical role in carcinogenesis. However, the widespread influence of NFκB in cells can result in off-target effects, making it a challenging therapeutic target. Ensemble learning is a machine learning technique where multiple models are combined to improve the performance and robustness of the prediction. Accordingly, an ensemble learning model could uncover more precise targets within the NFκB/TNF signaling pathway for cancer therapy.MethodsIn this study, we trained an ensemble learning model on the transcriptome profiles from 16 cancer types in the TCGA database to identify a robust set of genes that are consistently associated with the NFκB/TNF pathway in cancer. Our model uses cancer patients as features to predict the genes involved in the NFκB/TNF signaling pathway and can be adapted to predict the genes for different cancer types by switching the cancer type of patients. We also performed functional analysis, survival analysis, and a case study of triple-negative breast cancer to demonstrate our model's potential in translational cancer medicine.ResultsOur model accurately identified genes regulated by NFκB in response to TNF in cancer patients. The downstream analysis showed that the identified genes are typically involved in the canonical NFκB-regulated pathways, particularly in adaptive immunity, anti-apoptosis, and cellular response to cytokine stimuli. These genes were found to have oncogenic properties and detrimental effects on patient survival. Our model also could distinguish patients with a specific cancer subtype, triple-negative breast cancer (TNBC), which is known to be influenced by NFκB-regulated pathways downstream of TNF. Furthermore, a functional module known as mononuclear cell differentiation was identified that accurately predicts TNBC patients and poor short-term survival in non-TNBC patients, providing a potential avenue for developing precision medicine for cancer subtypes.ConclusionsIn conclusion, our approach enables the discovery of genes in NFκB-regulated pathways in response to TNF and their relevance to carcinogenesis. We successfully categorized these genes into functional groups, providing valuable insights for discovering more precise and targeted cancer therapeutics.

Unraveling the Pivotal Network of Ultrasound and Somatic Mutations in Triple-Negative and Non-Triple-Negative Breast Cancer.

The emergence of genomic targeted therapy has improved the prospects of treatment for breast cancer (BC). However, genetic testing relies on invasive and sophisticated procedures. Here, we performed ultrasound (US) and target sequencing to unravel the possible association between US radiomics features and somatic mutations in TNBC (n=83) and non-TNBC (n=83) patients. Least absolute shrinkage and selection operator (Lasso) were utilized to perform radiomic feature selection. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was utilized to identify the signaling pathways associated with radiomic features. Thirteen differently represented radiomic features were identified in TNBC and non-TNBC, including tumor shape, textual, and intensity features. The US radiomic-gene pairs were differently exhibited between TNBC and non-TNBC. Further investigation with KEGG verified radiomic-pathway (ie, JAK-STAT, MAPK, Ras, Wnt, microRNAs in cancer, PI3K-Akt) associations in TNBC and non-TNBC. The pivotal network provided the connections of US radiogenomic signature and target sequencing for non-invasive genetic assessment of precise BC treatment.

Dysregulation of immune checkpoint proteins in patients with newly diagnosed early breast cancer undergoing neoadjuvant chemotherapy: A comparison between patients with triple negative breast cancer (TNBC) and non-TNBC.

e14546 Background: Checkpoint proteins regulate the immune system. Breast cancer is associated with up-regulation or down-regulation of these proteins to evade anti-tumor immune responses. Soluble forms of immune checkpoint molecules (sICMs) can be measured in human plasma. The study aimed to measure the systemic levels of a series of co-stimulatory and co-inhibitory ICMs at diagnosis, post-neo-adjuvant chemotherapy (NAC) and post-surgery in newly- diagnosed BC patients (pts) and compare the biological behaviour of these sICMs between TNBC and non-TNBC patients. Methods: Soluble ICMs were measured using multiplex bead array technology in plasma from 72 BC pts and 45 healthy controls. Data were prospectively obtained and levels were compared between pre-treatment, post-NAC, and post-surgery using non-parametric tests (Mann-Whitney & Kruskal-Wallis). Results: Following NAC, the plasma levels of six soluble co-stimulatory checkpoints (CD28, CD40, ICOS, CD27, CD80, GITR), all involved in the activation of CD8+ cytotoxic T cells, were significantly increased (p < 0.04-p < 0.00001). Four of the soluble co-inhibitory checkpoints (LAG-3, PDL1, TIM-3 and HVEM) increased significantly post-NAC, reaching levels significantly greater than those of the control group. PD-1 remained unchanged, while BTLA and CTLA-4 decreased significantly (p < 0.03 and p < 0.00001, respectively). Normalization of soluble co-stimulatory immune checkpoints seemingly indicates a reversal of systemic immune dysregulation following the administration of NAC in early BC. In contrast, recovery of immune homeostasis may explain the increased levels of several negative checkpoint proteins, albeit with the exceptions of CTLA-4 and PD-1. No significant differences were detected between the changes of 16 sICMs levels at pre-NAC, post-NAC and post-surgery when comparing the TNBC and non-TNBC patients. Conclusions: This study demonstrates low levels of co-stimulatory and co-inhibitory sICMs in newly-diagnosed, non-metastatic BC pts. Following treatment with NAC, the sICMs levels increase substantially, except CTLA-4. In the case of co-stimulatory sICMs, these novel findings are indicative of an immune-restorative mechanism. The pattern of co-inhibitory sICMs (elevated levels of PD-L1, LAG-3, TIM-3 and HVEM), might be indicative of immune-therapeutic resistance, underscoring the augmentative immune-therapeutic promise of targeting these molecules, either individually or in combination, to improve the outcome of pts with early BC. These differences were not significant between TNBC and non-TNBC patients.

PRR15 deficiency facilitates malignant progression by mediating PI3K/Akt signaling and predicts clinical prognosis in triple-negative rather than non-triple-negative breast cancer

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast neoplasms with a higher risk of recurrence and metastasis than non-TNBC. Nevertheless, the factors responsible for the differences in the malignant behavior between TNBC and non-TNBC are not fully explored. Proline rich 15 (PRR15) is a protein involved in the progression of several tumor types, but its mechanisms are still controversial. Therefore, this study aimed to investigate the biological role and clinical applications of PRR15 on TNBC. PRR15 gene was differentially expressed between TNBC and non-TNBC patients, previously described as an oncogenic factor in breast cancer. However, our results showed a decreased expression of PRR15 that portended a favorable prognosis in TNBC rather than non-TNBC. PRR15 knockdown facilitated the proliferation, migration, and invasive ability of TNBC cells in vitro and in vivo, which was abolished by PRR15 restoration, without remarkable effects on non-TNBC. High-throughput drug sensitivity revealed that PI3K/Akt signaling was involved in the aggressive properties of PRR15 silencing, which was confirmed by the PI3K/Akt signaling activation in the tumors of PRR15Low patients, and PI3K inhibitor reversed the metastatic capacity of TNBC in mice. The reduced PRR15 expression in TNBC patients was positively correlated with more aggressive clinicopathological characteristics, enhanced metastasis, and poor disease-free survival. Collectively, PRR15 down-regulation promotes malignant progression through the PI3K/Akt signaling in TNBC rather than in non-TNBC, affects the response of TNBC cells to antitumor agents, and is a promising indicator of disease outcomes in TNBC.

YAP transduction drives triple-negative breast cancer aggressiveness through modulating the EGFR‒AKT axis in patient-derived xenograft cells.

Aside from the high prevalence of incidents of breast cancer, the high grade of heterogeneity and the dearth of standard treatment guidelines make triple-negative breast cancer (TNBC) the most refractory subtype. Though still in its infancy, the Hippo pathway has been known to play a critical role in tumorigenesis. However, the molecular mechanics through which the pathway exploits the breast cancer (BC) cell vulnerability are largely unexplored. In this study, we observed a relatively higher expression of the Hippo effector, yes-associated protein (YAP), in TNBC patients compared to non-TNBC patients. Thus, we sought to investigate the contribution of Hippo signaling in TNBC by focusing particularly on transducers of the pathway. Impeding YAP transactivation by means of RNA interference or pharmacological inhibition was carried out, followed by evaluation of the subsequent biological changes at the molecular level. We successfully translated the observed data into a TNBC patient-derived xenograft cell line (PDXC). We discovered that nuclear translocation of YAP was associated with TNBC aggressive characteristics and activated the EGFR-AKT axis. Here, we explored the putative role of the Hippo transducer in enhancing cancer hostility and observed that YAP transduction drives proliferation, migration, and survival of TNBC by preventing cellular apoptosis through mediating EGFR activation. These observations suggest that YAP represents a major vulnerability in TNBC cells that may be exploited therapeutically.

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.

Prognostic disparities in young patients based on breast cancer subtype: A population-based study from the SEER database.

Triple-negative breast cancer (TNBC) is associated with younger age and worse long-term survival. However, the characteristics and prognosis of different subtypes of breast cancer (BC) in young (<40 years) patients have not yet been elucidated. The present population-based study explored the clinical and pathological characteristics of young TNBC patients and investigated their long-term survival. We enrolled patients from the Surveillance, Epidemiology, and End Results database younger than 40 years of age with primary BC. Cases were defined as patients with TNBC (hormone receptor [HR]-/human epidermal growth factor receptor 2 [HER2]-), and controls were patients with other subtypes of BC (HR-/HER2+, HR+/HER2-, and HR+/HER2+). Demographic, pathological, and radiotherapy, chemotherapy, and surgery data were extracted and the overall survival was the primary endpoint. We enrolled 14,234 young patients with BC in the present study, of whom 2798 (19.7%) had TNBC and 11,436 (80.3%) had another BC subtype. A higher proportion of TNBC patients than non-TNBC patients had a more advanced tumor-node-metastasis stage (II-IV 80.5% vs 73.1%, P < .001), and smaller proportions underwent radiotherapy (50.0% vs 53.3%, P = .002) and surgery (91.8% vs 92.9%, P < .001). TNBC was associated with significantly lower 5-year survival rates than other subtypes among patients with regional node positivity (0, 1-3, 4-9, ≥10: 54.2% vs 57.7%, 44.2% vs 55.9%, 31.0% vs 52.0%, and 27.7% vs 38.8%, P < .001) and those with different lymph node ratios (low, intermediate, high: 50.9% vs 56.0%, 34.6% vs 53.6%, and 24.8% vs 44.8%, P < .001). Our research is the first to investigate the relevant characteristics of young TNBC patients in comparison with those of young non-TNBC patients based on the surveillance, epidemiology, and end results database. We found that young TNBC patients have a higher pathological stage and worse long-term survival than young patients with other BC subtypes. These findings have implications in identifying young patients with TNBC for aggressive therapy and further investigations should be performed to explore new multimodal treatments for such patients.

Variable Landscape of PD-L1 Expression in Breast Carcinoma as Detected by the DAKO 22C3 Immunohistochemistry Assay.

In 2020, pembrolizumab was approved as a therapy for triple-negative breast cancer (TNBC) with the companion diagnostic DAKO 22C3 programmed death ligand-1 (PD-L1) immunohistochemistry assay. The study aimed to determine the landscape of PD-L1 expression as detected by the DAKO 22C3 PD-L1 assay in breast cancer subtypes and compare the clinicopathologic and genomic characteristics of PD-L1 positive and negative TNBC. PD-L1 expression using the DAKO 22C3 antibody was scored using a combined positive score (CPS) and positive status was defined as CPS ≥10. Comprehensive genomic profiling was performed using the FoundationOne CDx assay. Of the 396 BC patients stained with DAKO 22C3, the majority were HR+/HER2- and TNBC (42% and 36%, respectively). Median PD-L1 expression and frequency of CPS ≥10 was highest in TNBC cases (median: 7.5, 50% CPS ≥10) and lowest in the HR+/HER2- group (median: 1.0, 15.5% CPS ≥10) (P < .0001). A comparison of PD-L1 positive and PD-L1 negative TNBC demonstrated no significant differences in clinicopathologic or genomic characteristics. TNBC tissue samples from the breast did have an observed enrichment for PD-L1 positivity compared to TNBC tissue samples from a metastatic site (57% vs. 44%), but this was not statistically significant (P = .1766). In the HR+/HER2- group, genomic alterations in TP53, CREBBP, and CCNE1 were more prevalent and genomic loss of heterozygosity was higher in the PD-L1(+) group compared to the PD-L1(-) group. The subtypes of breast cancer have distinct patterns of PD-L1 expression, supporting that further research of immunotherapies may include specific evaluation of optimum cutoffs for non-TNBC patients. In TNBC, PD-L1 positivity is not associated with other clinicopathologic or genomic features and should be integrated into future studies of immunotherapy efficacy.

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 P3-03-19: Real-world data of clinical characteristics, risk factors and outcomes of Chilean triple-negative breast cancer patients

Abstract Background: triple-negative breast cancer (TNBC) is associated with hereditary and environmental risk factors plus an overall worse prognosis compared to other Breast Cancer (BC) subtypes. While TNBC risk factors, prevalence, clinical characteristics and prognosis may vary throughout different populations, limited data on Latin American patients forces clinical decisions to be based predominantly on data coming from non-Hispanic women. To obtain local epidemiological information, regarding risk factors and clinical outcomes, we analysed the largest Chilean BC registry. Methods: we conducted a retrospective population-cohort study involving females with any stage TNBC, treated at a community hospital (mid-low income) and at an academic private hospital (high income), between the years 2010 and 2021. Risk factors, reason for consultation, clinical and pathological characteristics and prognosis were separately analysed for both TNBC and non-TNBC subgroups. Univariate and multivariate analyses were performed to identify prognostic factors for survival on TNBC patients. Results: From 5,806 patients, 647 (11.2%) were identified as TNBC. Compared to non-TNBC patients, women were younger (median age 55.2 vs. 57.2, p=0.0001), with 15.8% of TNBC patients having been diagnosed before the age of 40 compared to 9.6% in non-TNBC (p= 0.0001). TNBC had a significantly lower screen-detected cancer rate (14.5% vs. 31.6% p= 0.0001) and worse stage at diagnosis. No differences were seen between patients seen at a community hospital and private centre, for both TNBC rate and stage. Other risk factors such as parity, age at first gestation, menarche, hormone therapy replacement and obesity showed no significant differences between TNBC and no-TNBC patients (table 1). With a median follow up of 57 months, 5-year overall survival (OS) and BC specific death were significantly shorter for TNBC compared to non-TNBC (76.4% vs 88.1% and 78.9% vs 91.2%, respectively; p=0.0001) (table 2). In the multivariate analysis, TN subtype (HR=2.3, p=0.0001), stage (HR=2.05 for stage II vs stage I, HR=7.04 for stage III vs. stage I, p=0.0001), lower income (HR= 1.64, p=0.0001), and non-screened detected BC (HR=1.32, p=0.03) were all associated with worse overall survival (table 3). Conclusion: This is the first study focusing on TNBC characteristics in Chilean BC patients and to our knowledge, the largest performed in a Latin American population. We identified a lower proportion of TNBC patients when compared with data reported from other LA groups and worldwide, a very low screen detected cancer rate and as expected significantly lower TNBC survival rate compared to non-TNBC women. While TNBC patients were younger compared to the non-TNBC group, this age difference was marginal compared to other reported studies. Community hospital patients (with mid-low income) were associated with lower survival rates for both all-cause mortality and BC specific survival, regardless of a similar stage distribution at diagnosis. Reflecting an underlying interaction between social and biological factors that needs to be addressed. Table 1. Patient characteristics: Triple-negative versus noN-triple negative breast cancer BMI: Body mass index; FH: Family history * Difference is statistically significant. Table 2. Survival comparison in triple-negative versus non-triple negative breast cancer * Difference is statistically significant. Table 3. Cox Regression Multivariate analysis * Difference is statistically significant. Citation Format: Benjamin Walbaum, FRANCISCO ACEVEDO, Catherine Bauerle, Mauricio Camus, Manuel Manzor, Raul Martinez, Paulina Veglia, Marisel Navarro, Constanza Guerra, Francisco Dominguez, Tomas Merino, Lidia Medina, CÉSAR SÁNCHEZ. Real-world data of clinical characteristics, risk factors and outcomes of Chilean 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 P3-03-19.

Abstract C009: Race- and TNBC-specific circulating biomarker profiles among breast cancer patients

Abstract Triple negative breast cancer (TNBC) is the most aggressive molecular subtype of BC, with no targeted therapeutics currently available and poor systemic treatment response among certain patient groups. Cytokines, chemokines and adipokines are cell signaling molecules that play significant roles in mediation of inflammation/immune response in tumorigenesis and cancer progression. Relative systemic levels of these molecules secreted from the BC tumor microenvironment may be developed as prognostic liquid biopsy biomarkers. At present, we have investigated race-specific and TNBC-specific differences in circulating biomarker profiles of AA (n = 65) and EA (n = 88) BC patients. The International Center for the Study of Breast Cancer Subtypes (ICSBCS) maintains a prospective cohort biorepository of African and US patients, including patients from Detroit, MI (Henry Ford Health System) and New York City, NY (NewYork Presbyterian Hospitals). Using a multiplexed bead-based ELISA platform (Luminex®) we quantified the relative plasma levels of 45 different biomarkers per manufacturer’s protocols. Normalization of plate/batch effect was completed using MDimnNormn, and statistical tests were completed with JMP Pro 16. There were no significant differences between groups across most clinicopathological variables; including, age (p = 0.86), tumor histology (p = 0.45), subtype (p = 0.4039) or stage (p = 0.20). However, BMI was significantly higher among AA patients compared to EA patients (AA mean 31.5, EA mean 28.7, p = 0.016), and multivariate analyses were adjusted for BMI. Histological subtypes and stage represented a cross section of the cohort, with the majority being invasive ductal (AA 70.8%, EA 71.6%), and early-stage (Stage I and II) disease (AA 83.1%, EA 80.7%). The predominant intrinsic subtype is LumA (AA 69.2%, EA 67%), with a relatively higher proportion of TNBC disease among AA (20%) compared to EA patients (10.2%) (p = 0.086). Our univariate/unadjusted SRR-association models identified four biomarkers: IFNg (p = 0.022), I-TAC/CXCL11 (p = 0.003), MDC/CCL22 (p = 0.041) and MIPa/CCL3 (p = 0.038), which were higher among AA compared to EA patients. After controlling for BMI as a covariate in our model, all markers retained significance, with IFNg, I-TAC/CXCL11 and MIPa/CCL3 being p &amp;lt; 0.05, and MDC/CCL22 with slightly lower significance (p = 0.054). To determine TNBC-specific profiles we compared biomarkers between TNBC (n = 22) and non-TNBC (n = 131) patients. The unadjusted/univariate analysis yielded no associations. However, after adjusting for BMI and SRR, 10 circulating biomarkers were significantly higher among patients with TNBC: IL16, MIF, TNFa, MPIF1/CCL23, IL1b, Gro-a/CXCL1, SCYB16/CXCL16, ENA-78/CXCL5, Fractalkine/CX3CL1 and Leptin (p &amp;lt; 0.05). Taken together, these findings highlight that there are distinct SRR- and TNBC- circulating biomarker profiles, that may elucidate functional distinctions across TNBC patients to provide biomarkers for novel prognostic or therapeutic opportunities for patients. Citation Format: Rachel Martini, Millicent Amankwah, Julie Sahler, Brian Stonaker, Mumina Sadullozoda, Peter Radzio, Avery August, Lisa Newman, Melissa Davis. Race- and TNBC-specific circulating biomarker profiles among breast cancer patients [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C009.

Novel Association of IGF2BP2 Gene Variants With Altered Risk of Breast Cancer and as Potential Molecular Biomarker of Triple Negative Breast Cancer

BackgroundSeveral studies documented that insulin-like growth factor-2 mRNA-binding protein 2 (IGF2BP2) contributes to carcinogenesis, and 1 report documented the association of IGF2BP2 rs4402960 with increased risk of breast cancer (BC). This study investigated the association of rs4402960 and rs1470579 IGF2BP2 variants with BC and triple negative BC (TNBC). Materials and MethodsThis case-control study included 488 BC patients comprising 130 TNBC and 358 non-TNBC patients, and 476 cancer-free controls. Genomic DNA was obtained from peripheral venous blood, and genotyping was done by allelic exclusion method on real-time PCR. ResultsThe rs440960, but not rs1470579, minor allele was significantly associated with BC, and significantly higher rs4402960 T/T genotype frequency was noted in BC patients than controls; the distribution of rs1470579 genotypes were comparable between BC patients and controls. In contrast, significantly lower rs1470579 minor allele frequency, and reduced rs1470579 A/C and C/C, and rs4402960 T/T genotype frequencies were seen in TNBC cases. Among TNBC cases, rs4402960 and rs1470579 correlated with menses pattern, histological type, breastfeeding, oral contraceptive use and hormonotherapy. Among non-TNBC patients, and rs1470579 correlated significantly with breast feeding, oral contraceptive use, hormonotherapy, and nodal status; rs4402960 also correlated with menses pattern. Two-locus (rs440960-rs1470579) haplotype analysis confirmed the positive association of TC, and negative association of GC and TA haplotypes with BC, while TC and GC haplotypes were negatively associated with TNBC. ConclusionWhereas rs440960 was positively associated with BC, both rs4402960 and rs1470579 were negatively associated with TNBC, suggesting potential diagnostic/prognostic role in BC and its complications.

Clinical characteristics, risk factors, and outcomes in Chilean triple negative breast cancer patients: a real-world study.

Latin American (LA) studies on triple-negative breast cancer (TNBC) and their characteristics are scarce. This forces physicians to make clinical decisions based on data obtained from studies that include non-Hispanic patients. Our study sought to obtain local epidemiological data, including risk factors and clinical outcomes from a Chilean BC registry. This was a retrospective population-cohort study that included patients treated at a community hospital (mid-low income) or an academic private center (high income), in the 2010-2021 period. Univariate and multivariate analyses were performed to identify prognostic factors associated with survival. 647 out of 5,806 BC patients (11.1%) were TNBC. These patients were younger (p = 0.0001) and displayed lower rates of screening-detected cases (p = 0.0001) compared to non-TNBC counterparts. Among TNBC patients, lower income (i. e., receiving treatment at a community hospital) was associated with poorer overall survival (HR: 1.53; p = 0.0001) and poorer BC specific survival (HR: 1.29; p = 0.004). Other risk factors showed no significant differences between TNBC and non-TNBC. As expected, 5-year OS was significantly shorter on TNBC versus non-TNBC patients (p = 0.00001). In our multivariate analyses TNBC subtype (HR: 2.30), locally advanced stage (HR: 7.04 for stage III), lower income (HR: 1.64), or non-screening detected BC (HR: 1.32) were associated with poorer OS. To the best of our knowledge, this is the largest LA cohort of TNBC patients. Interestingly, the proportion of TNBC among Chileans was smaller compared to similar studies within LA. As expected, TNBC patients had poorer survival and higher risk for early recurrence versus non-TNBC. Other relevant findings include a higher proportion of premenopausal patients among TNBC. Also, mid/low-income patients that received medical attention at a community hospital displayed lower survival versus private health center counterparts.

Unique ESR1 and ESR2 estrogen receptor gene variants associated with altered risk of triple-negative breast cancer: A case-control study

BackgroundWe previously reported on the association between ESR1 and ESR2 gene variants and heightened risk of breast cancer (BC). Here we investigated the association of common ESR1 and ESR2 gene variants with triple negative BC (TNBC). MethodsThis retrospective case-control study involved 488 BC patients (130 TNBC, 358 non-TNBC patients). ESR1 (rs2234693, rs9340799, rs3020314, rs3798577) and ESR2 (rs928554, rs944459, rs4986938, rs1256049, rs1256030, rs1271572) genotyping was done by real-time PCR. ResultsWhile minor allele frequencies (MAF) of ESR1 variants were comparable between TNBC and non-TNBC subjects, significantly higher ESR2 rs1256049 MAF was seen in TNBC patients. Significantly higher frequency of ESR1 rs3798577 T/C and C/C genotypes were noted in TNBC cases, and significant differences were seen in ESR2 rs928554, rs1256049, and rs1271572 genotype distribution. Increased TNBC risk was associated with ESR1 rs3798577 T/C and C/C genotypes according to codominant and dominant models, while positive association of ESR2 rs928554 with TNBC was seen according to codominant and recessive models, and positive association of ESR2 rs1256049 with TNBC was seen according to codominant and dominant models. Positive interactions were noted between ESR2 rs1271572-ESR1 rs3020314, ESR2 rs1271572-ESR1 rs9340799, and ESR2 rs1271572-ESR1 rs2234693, ESR2 rs4986938-ESR1 rs2234693, and ESR2 rs928554-ESR1 rs9340799. Haplotype analysis confirmed the positive association of ESR1 CATT with TNBC, while ACGGCTC and ACGGTT ESR2 haplotypes were positively associated with TNBC. ConclusionResults of this study confirmed the association of unique ESR1 and ESR2 genetic variants with altered risk of TNBC. This suggests possible diagnostic and prognostic role of these variants with TNBC independent of their association with BC.

Expression characteristics of the yes-associated protein in breast cancer: A meta-analysis.

Background:The yes-associated protein (YAP) gene plays an important role in many malignant tumors, but its clinical significance in breast cancer remains unclear. This study aimed to explore the significance of YAP expression in breast cancer using meta-analysis.Methods:Seven databases will be searched to collect the case–control studies published on the association between YAP expression and clinical pathogenic features in breast cancer until December 2021: PubMed, EMBASE, Web of Science, China National Knowledge Infrastructure, Chinese Scientific Journal Database, Wan Fang Database, and the Chinese Biomedical Literature Database. To perform meta-analysis, STATA 14.0 and RevMan5 software were used with odds ratio (OR) and 95% confidence interval (95% CI) as the effect index, and publication bias and sensitivity analysis were subsequently tested.Results:Form a total of 10 articles used in this study, 8 studies consisted of nontriple negative breast cancer (non-TNBC) and the other 2 of TNBC. Meta-analysis indicated a positive expression rate of YAP in non-TNBC tissues that was lower than in normal breast tissue (OR = 0.15, 95% CI = 0.10–0.21, P < .001). In contrast, the positive rate of YAP expression in TNBC was significantly higher than that in normal breast tissue (OR = 18.23, 95% CI = 8.20–40.52, P < .001). Furthermore, the positive expression rate was higher in the patients with lymph node metastasis, higher tumor node metastasis stage and histologic grade, and larger diameter in TNBC. However, there was no statistical difference in the positive expression rate of YAP between non-TNBC patients and lymph node metastasis, tumor node metastasis stage, histologic grade, and tumor size.Conclusions:YAP may participate in the occurrence and development of non-TNBC as a tumor suppressor gene; however, it may also be a carcinogenic factor in TNBC and may be a potential therapeutic target for TNBC.