Extracellular matrix marker LAMC2 targets ZEB1 to promote TNBC malignancy via up-regulating CD44/STAT3 signaling pathway.

BACKGROUND: Triple negative breast cancer (TNBC) is a heterogeneous and aggressive disease characterized by a high risk of mortality and poor prognosis. It has been reported that Laminin γ2 (LAMC2) is highly expressed in a variety of tumors, and its high expression is correlated with cancer development and progression. However, the function and mechanism by which LAMC2 influences TNBC remain unclear. METHODS: Kaplan-Meier survival analysis and Immunohistochemical (IHC) staining were used to examine the expression level of LAMC2 in TNBC. Subsequently, cell viability assay, wound healing and transwell assay were performed to detect the function of LAMC2 in cell proliferation and migration. A xenograft mouse model was used to assess tumorigenic function of LAMC2 in vivo. Luciferase reporter assay and western blot were performed to unravel the underlying mechanism. RESULTS: In this study, we found that higher expression of LAMC2 significantly correlated with poor survival in the TNBC cohort. Functional characterization showed that LAMC2 promoted cell proliferation and migration capacity of TNBC cell lines via up-regulating CD44. Moreover, LAMC2 exerted oncogenic roles in TNBC through modulating the expression of epithelial-mesenchymal transition (EMT) markers. Luciferase reporter assay verified that LAMC2 targeted ZEB1 to promote its transcription. Interestingly, LAMC2 regulated cell migration in TNBC via STAT3 signaling pathway. CONCLUSION: LAMC2 targeted ZEB1 via activating CD44/STAT3 signaling pathway to promote TNBC proliferation and migration, suggesting that LAMC2 could be a potential therapeutic target in TNBC patients.

The prognostic marker KRT81 is involved in suppressing CD8 + T cells and predicts immunotherapy response for triple-negative breast cancer.

Triple-negative breast Cancer (TNBC) is an aggressive subtype lacking estrogen, progesterone, and HER2 receptors. Known for limited targeted therapies, it poses challenges and requires personalized treatment strategies. Differential analysis revealed a significant decrease in keratin 81 (KRT81) expression in non-TNBC samples and an increase in TNBC samples, lower KRT81 expression correlated with better TNBC patient outcomes. It emerged as an independent predictive factor for TNBC, with associations found between its expression and clinically relevant features. We further developed a nomogram for survival probability assessment based on Cox regression results, demonstrating its accuracy through calibration curves. Gene annotation analysis indicated that KRT81 is involved in immune-related pathways and tumor cell adhesion. KRT81 is associated with immune cell infiltration of Follicular helper T cells (Tfh) and CD8 + T cells, suggesting its potential impact on the immunological microenvironment. The study delved into KRT81's predictive value for immunotherapy responses, high expression of KRT81 was associated with greater potential for immune evasion. Single-cell RNA sequencing analysis pinpointed KRT81 expression within a specific malignant subtype which was a risk factor for TNBC. Furthermore, KRT81 promoted TNBC cell proliferation, migration, invasion, and adhesion was confirmed by gene knockout or overexpression assay. Co-culture experiments further indicated KRT81's potential role in inhibiting CD8 + T cells, and correlation analysis implied KRT81 was highly correlated with immune checkpoint CD276, providing insights into its involvement in the immune microenvironment via CD276. In conclusion, this comprehensive study positions KRT81 as a promising prognostic marker for predicting tumor progression and immunotherapy responses in TNBC.

CD163+ macrophages in the triple-negative breast tumor microenvironment are associated with improved survival in the Women's Circle of Health Study and the Women's Circle of Health Follow-Up Study.

BACKGROUND: Tumor-associated macrophages (TAMs) are a prominent immune subpopulation in the tumor microenvironment that could potentially serve as therapeutic targets for breast cancer. Thus, it is important to characterize this cell population across different tumor subtypes including patterns of association with demographic and prognostic factors, and breast cancer outcomes. METHODS: We investigated CD163+ macrophages in relation to clinicopathologic variables and breast cancer outcomes in the Women's Circle of Health Study and Women's Circle of Health Follow-up Study populations of predominantly Black women with breast cancer. We evaluated 611 invasive breast tumor samples (507 from Black women, 104 from White women) with immunohistochemical staining of tissue microarray slides followed by digital image analysis. Multivariable Cox proportional hazards models were used to estimate hazard ratios for overall survival (OS) and breast cancer-specific survival (BCSS) for 546 cases with available survival data (median follow-up time 9.68 years (IQR: 7.43-12.33). RESULTS: Women with triple-negative breast cancer showed significantly improved OS in relation to increased levels of tumor-infiltrating CD163+ macrophages in age-adjusted (Q3 vs. Q1: HR = 0.36; 95% CI 0.16-0.83) and fully adjusted models (Q3 vs. Q1: HR = 0.30; 95% CI 0.12-0.73). A similar, but non-statistically significant, association was observed for BCSS. Macrophage infiltration in luminal and HER2+ tumors was not associated with OS or BCSS. In a multivariate regression model that adjusted for age, subtype, grade, and tumor size, there was no significant difference in CD163+ macrophage density between Black and White women (RR = 0.88; 95% CI 0.71-1.10). CONCLUSIONS: In contrast to previous studies, we observed that higher densities of CD163+ macrophages are independently associated with improved OS and BCSS in women with invasive triple-negative breast cancer. Trial registration Not applicable.

Subcellular expression of MTA1, HIF1A and p53 in primary tumor predicts aggressive triple negative breast cancers: a meta-analysis based study.

BACKGROUND: The prevalence of TNBC in India is higher compared to western countries. There is a multitude of biomarkers associated with different clinical outcomes of TNBC with contradictory reports. Identification of a set of specific biomarkers from the very many number of proteins reported in the literature to predict prognosis of TNBC is an urgent clinical need. METHODOLOGY: A systematic review of key molecular biomarkers in cohort studies that have been investigated for their role in breast cancer prognosis was conducted. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology was followed. A meta-analysis was used to evaluate their pooled hazard ratio (HR) and the corresponding 95% confidence interval (95% CI) statistically. Immunohistochemical characterization of the meta-analyzed markers were performed in a cohort of 200 retrospective TNBC and 100 non TNBC patient tissues. Kaplan-Meier plot were used to evaluate disease free survival (DFS), and overall survival (OS). Cox regression models were used to evaluate predictors of DFS and OS. RESULTS: Using a meta-analytical approach, we consolidated the biomarker signatures associated with survival outcomes in breast cancers. The promising markers that emerged for the prediction of DFS and OS included E-Cadherin, Survivin, p53, MTA1, HIF1A, CD133, Vimentin and CK5/6. Evaluation of these markers in tumor tissue revealed that subcellular localization of p53, MTA1 and HIF1A had a significant association in predicting TNBC prognosis. Kaplan Meier plot revealed that p53 (OS p = 0.007, DFS p = 0.004), HIF 1 A (OS p = 0.054, DFS p = 0.009) and MTA1 (OS p = 0.043, DFS = p = 0.001) expression in the primary tumor tissue were found to be significantly correlated with poor OS and DFS, whereas expression of Survivin (DFS p = 0.024) and E Cadherin (DFS p = 0.027) correlated with DFS alone in TNBC. Univariate analysis revealed that p53, HIF1A and MTA1 could be independent prognostic markers. CONCLUSION: Our study suggests cytoplasmic over expression of HIF1A, nuclear over expression of MTA1 and mutated p53 in the primary tumor tissue of TNBC have significance as markers predicting survival of TNBC patients.

Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer.

Importance: The association of tumor-infiltrating lymphocyte (TIL) abundance in breast cancer tissue with cancer recurrence and death in patients with early-stage triple-negative breast cancer (TNBC) who are not treated with adjuvant or neoadjuvant chemotherapy is unclear. Objective: To study the association of TIL abundance in breast cancer tissue with survival among patients with early-stage TNBC who were treated with locoregional therapy but no chemotherapy. Design, Setting, and Participants: Retrospective pooled analysis of individual patient-level data from 13 participating centers in North America (Rochester, Minnesota; Vancouver, British Columbia, Canada), Europe (Paris, Lyon, and Villejuif, France; Amsterdam and Rotterdam, the Netherlands; Milan, Padova, and Genova, Italy; Gothenburg, Sweden), and Asia (Tokyo, Japan; Seoul, Korea), including 1966 participants diagnosed with TNBC between 1979 and 2017 (with follow-up until September 27, 2021) who received treatment with surgery with or without radiotherapy but no adjuvant or neoadjuvant chemotherapy. Exposure: TIL abundance in breast tissue from resected primary tumors. Main Outcomes and Measures: The primary outcome was invasive disease-free survival [iDFS]. Secondary outcomes were recurrence-free survival [RFS], survival free of distant recurrence [distant RFS, DRFS], and overall survival. Associations were assessed using a multivariable Cox model stratified by participating center. Results: This study included 1966 patients with TNBC (median age, 56 years [IQR, 39-71]; 55% had stage I TNBC). The median TIL level was 15% (IQR, 5%-40%). Four-hundred seventeen (21%) had a TIL level of 50% or more (median age, 41 years [IQR, 36-63]), and 1300 (66%) had a TIL level of less than 30% (median age, 59 years [IQR, 41-72]). Five-year DRFS for stage I TNBC was 94% (95% CI, 91%-96%) for patients with a TIL level of 50% or more, compared with 78% (95% CI, 75%-80%) for those with a TIL level of less than 30%; 5-year overall survival was 95% (95% CI, 92%-97%) for patients with a TIL level of 50% or more, compared with 82% (95% CI, 79%-84%) for those with a TIL level of less than 30%. At a median follow-up of 18 years, and after adjusting for age, tumor size, nodal status, histological grade, and receipt of radiotherapy, each 10% higher TIL increment was associated independently with improved iDFS (hazard ratio [HR], 0.92 [0.89-0.94]), RFS (HR, 0.90 [0.87-0.92]), DRFS (HR, 0.87 [0.84-0.90]), and overall survival (0.88 [0.85-0.91]) (likelihood ratio test, P < 10e-6). Conclusions and Relevance: In patients with early-stage TNBC who did not undergo adjuvant or neoadjuvant chemotherapy, breast cancer tissue with a higher abundance of TIL levels was associated with significantly better survival. These results suggest that breast tissue TIL abundance is a prognostic factor for patients with early-stage TNBC.

The relationship of changes in molecular subtypes with metastases and progression-free survival in breast cancer.

BACKGROUND: Molecular subtyping of breast cancer cells is increasingly being developed as an initial step in selecting therapy and predicting the prognosis of breast cancer patients. During breast cancer, the molecular subtype of cancer cells can change. This study aimed to analyze the relationship between changes in the intrinsic subtype of breast cancer with metastasis and progression-free survival in breast cancer patients. METHODS: This was a retrospective cohort study of patients diagnosed with breast cancer from 2016 to 2021. The molecular subtypes from the immunohistochemical examination results were recorded twice, and metastasis and progression-free survival (PFS) were recorded. The data were analyzed using the chi-square test and SPSS 26. RESULTS: Of the 44 patients, 19 (43.2%) experienced a change in molecular subtype, and 25 (56.8%) did not. No significant relationship existed between changes in molecular subtype and metastasis (p = 0.405). No significant relationship existed between changes in molecular subtype and PFS (p = 0.900). A significant relationship was found between changes in the molecular subtype and PFS in the patients with changes in the molecular subtype (p = 0.022). CONCLUSIONS: Changes in the intrinsic subtype were associated with PFS in breast cancer patients. Patients with an intrinsic subtype that changed to triple-negative showed worse PFS.

Improved outcomes for triple negative breast cancer brain metastases patients after stereotactic radiosurgery and new systemic approaches.

PURPOSE: Although ongoing studies are assessing the efficacy of new systemic therapies for patients with triple negative breast cancer (TNBC), the overwhelming majority have excluded patients with brain metastases (BM). Therefore, we aim to characterize systemic therapies and outcomes in a cohort of patients with TNBC and BM managed with stereotactic radiosurgery (SRS) and delineate predictors of increased survival. METHODS: We used our prospective patient registry to evaluate data from 2012 to 2023. We included patients who received SRS for TNBC-BM. A competing risk analysis was conducted to assess local and distant control. RESULTS: Forty-three patients with 262 tumors were included. The median overall survival (OS) was 16 months (95% CI 13-19 months). Predictors of increased OS after initial SRS include Breast GPA score > 1 (p < 0.001) and use of immunotherapy such as pembrolizumab (p = 0.011). The median time on immunotherapy was 8 months (IQR 4.4, 11.2). The median time to new CNS lesions after the first SRS treatment was 17 months (95% CI 12-22). The cumulative rate for development of new CNS metastases after initial SRS at 6 months, 1 year, and 2 years was 23%, 40%, and 70%, respectively. Thirty patients (70%) underwent multiple SRS treatments, with a median time of 5 months (95% CI 0.59-9.4 months) for the appearance of new CNS metastases after second SRS treatment. CONCLUSIONS: TNBC patients with BM can achieve longer survival than might have been previously anticipated with median survival now surpassing one year. The use of immunotherapy is associated with increased median OS of 23 months.

Tumor-Infiltrating Lymphocytes Refine Outcomes in Triple-Negative Breast Cancer Treated with Anthracycline-Free Neoadjuvant Chemotherapy.

PURPOSE: Stromal tumor-infiltrating lymphocytes (sTIL) are associated with pathologic complete response (pCR) and long-term outcomes for triple-negative breast cancer (TNBC) in the setting of anthracycline-based chemotherapy. The impact of sTILs on refining outcomes beyond prognostic information provided by pCR in anthracycline-free neoadjuvant chemotherapy (NAC) is not known. EXPERIMENTAL DESIGN: This is a pooled analysis of two studies where patients with stage I (T>1 cm)-III TNBC received carboplatin (AUC 6) plus docetaxel (75 mg/m2; CbD) NAC. sTILs were evaluated centrally on pre-treatment hematoxylin and eosin slides using standard criteria. Cox regression analysis was used to examine the effect of variables on event-free survival (EFS) and overall survival (OS). RESULTS: Among 474 patients, 44% had node-positive disease. Median sTILs were 5% (range, 1%-95%), and 32% of patients had ≥30% sTILs. pCR rate was 51%. On multivariable analysis, T stage (OR, 2.08; P = 0.007), nodal status (OR, 1.64; P = 0.035), and sTILs (OR, 1.10; P = 0.011) were associated with pCR. On multivariate analysis, nodal status (HR, 0.46; P = 0.008), pCR (HR, 0.20; P < 0.001), and sTILs (HR, 0.95; P = 0.049) were associated with OS. At 30% cut-point, sTILs stratified outcomes in stage III disease, with 5-year OS 86% versus 57% in ≥30% versus <30% sTILs (HR, 0.29; P = 0.014), and numeric trend in stage II, with 5-year OS 93% versus 89% in ≥30% versus <30% sTILs (HR, 0.55; P = 0.179). Among stage II-III patients with pCR, EFS was better in those with ≥30% sTILs (HR, 0.16; P, 0.047). CONCLUSIONS: sTILs density was an independent predictor of OS beyond clinicopathologic features and pathologic response in patients with TNBC treated with anthracycline-free CbD chemotherapy. Notably, sTILs density stratified outcomes beyond tumor-node-metastasis (TNM) stage and pathologic response. These findings highlight the role of sTILs in patient selection and stratification for neo/adjuvant escalation and de-escalation strategies.

Two Hematological Markers Predicting the Efficacy and Prognosis of Neoadjuvant Chemotherapy Using Lobaplatin Against Triple-Negative Breast Cancer.

BACKGROUND: Our previous work indicated that the addition of lobaplatin to combined therapy with taxane and anthracycline can improve the pathological complete response rate of neoadjuvant therapy for triple-negative breast cancer (TNBC) and lengthen long-term survival significantly, but the therapeutic markers of this regimen are unclear. METHODS: Eighty-three patients who met the inclusion criteria were included in this post hoc analysis. We analyzed the association between platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) before neoadjuvant chemotherapy with the efficacy and prognosis after treatment with docetaxel, epirubicin, and lobaplatin neoadjuvant chemotherapy regimen. χ2 test and Cox regression were used to analyze the association between PLR and NLR with total pathologic complete response (tpCR), as well as the association between PLR and NLR with event-free survival (EFS) and overall survival (OS), respectively. RESULTS: The tpCR rate in the PLR- group was 49.0% (25/51), which was significantly higher than that in the PLR+ group (25.0% [8/32], P = .032). The tpCR rate in the NLR- group was 49.1% (26/53), which was significantly higher than that in the NLR+ group (23.3% [7/30], P = .024). The tpCR rate of the PLR-NLR- (PLR- and NLR-) group was 53.7% (22/41), which was significantly higher than that of the PLR+/NLR+ (PLR+ or/and NLR+) group (26.1% [11/42]; P = .012). EFS and OS in the NLR+ group were significantly shorter than those in the NLR- group (P = .028 for EFS; P = .047 for OS). Patients in the PLR-NLR- group had a longer EFS than those in the PLR+/NLR+ group (P = .002). CONCLUSION: PLR and NLR could be used to predict the efficacy of neoadjuvant therapy with the taxane, anthracycline, and lobaplatin regimen for patients with TNBC, as patients who had lower PLR and NLR values had a higher tpCR rate and a better long-term prognosis.

Racial/Ethnic Disparities in Pathologic Complete Response and Overall Survival in Patients With Triple-Negative Breast Cancer Treated With Neoadjuvant Chemotherapy.

PURPOSE: Black women have higher rates of death from triple-negative breast cancer (TNBC) than White women. We hypothesized that pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) and overall survival (OS) may vary by race/ethnicity in patients with TNBC. METHODS: We identified women 18 years and older with stage I-III TNBC who received NAC followed by surgery from the National Cancer Database (2010-2019). We excluded patients without race/ethnicity or pathology data. Primary outcomes were pCR rates and OS on the basis of race/ethnicity. RESULTS: Forty thousand eight hundred ninety women with TNBC met inclusion criteria (median age [IQR], 53 [44-61] years): 26,150 Non-Hispanic White (64%, NHW), 9,672 Non-Hispanic Black (23.7%, NHB), 3,267 Hispanic (8%), 1,368 Non-Hispanic Asian (3.3%, NHA), and 433 Non-Hispanic Other (1.1%, NHO) patients. Overall, 29.8% demonstrated pCR (NHW: 30.5%, NHB: 27%, Hispanic: 32.6%, NHA: 28.8%, NHO: 29.8%). Unadjusted OS was significantly higher for those with pCR compared with those with residual disease (5-year OS, 0.917 [95% CI, 0.911 to 0.923] v 0.667 [95% CI, 0.661 to 0.673], log-rank P < .001), and this association persisted after adjustment for demographic and tumor factors. The effect of achieving pCR on OS did not differ by race/ethnicity (interaction P = .10). However, NHB patients were less likely (odds ratio [OR], 0.89 [95% CI, 0.83 to 0.95], P = .001) and Hispanic patients were more likely (OR, 1.19 [95% CI, 1.08 to 1.31], P = .001) to achieve pCR than NHW patients. After adjustment for patient and disease factors, including achievement of pCR, Hispanic (hazard ratio [HR], 0.76 [95% CI, 0.69 to 0.85], P < .001) and NHA (HR, 0.64 [95% CI, 0.55 to 0.75], P < .001) race/ethnicity remained associated with OS. CONCLUSION: Odds of achieving pCR and OS in patients with TNBC appear to be associated with race/ethnicity. Additional research is necessary to understand how race/ethnicity is associated with rates of pCR and OS, whether related to socioeconomic factors or biologic variables, or both.

The impact of germline BRCA pathogenic variants in locally advanced, triple negative breast cancer treated with platinum-based neoadjuvant chemotherapy.

BACKGROUND: Whether germline BRCA (gBRCA) pathogenic variants (PV) affect prognosis of women with triple negative breast cancer (TNBC) and whether it has implications for treatment decisions in the neoadjuvant setting is unclear. METHODS: This is a retrospective two-center cohort study comprising all women with early stage TNBC who have completed genetic testing and were treated with neoadjuvant dose-dense doxorubicin and cyclophosphamide followed by paclitaxel and carboplatin. All eligible patients treated between 10.2014 and 3.2020 were included. Data on clinico-pathological, pathological response, overall survival (OS) and disease-free survival (DFS) were evaluated. Differences in clinico-pathological features and outcomes were analyzed according to gBRCA status. RESULTS: Sixty-four women were included in the final analysis, of which 31 had gBRCA PV (gBRCA carriers) and 33 were gBRCA wild-type. Clinico-pathological characteristics were similar between both groups. The odds for pathological complete response (pCR) were significantly higher in gBRCA carriers (74.2%) compared to BRCA wild-type women (48.5%), p = 0.035. At a median follow-up of 30 months, gBRCA carriers had significantly favorable OS (HR = 8.64, 95% CI 1.08-69.21, p = 0.042). The difference in DFS did not reach statistical significance (HR = 7.4, 95% CI 0.91-60.27, p = 0.062). The favorable OS for gBRCA carriers remained significant in multivariate analysis (p = 0.029) and was noted regardless of pathological response (p = 0.018). CONCLUSION: Compared to wild-type, gBRCA carriers with locally advanced TNBC treated with neoadjuvant chemotherapy containing carboplatin had a higher pCR rate and better outcomes. These results strengthen the contention that gBRCA status should be considered when tailoring treatment decisions in women with locally advanced TNBC.

Event-free survival by residual cancer burden with pembrolizumab in early-stage TNBC: exploratory analysis from KEYNOTE-522.

BACKGROUND: KEYNOTE-522 demonstrated statistically significant improvements in pathological complete response (pCR) with neoadjuvant pembrolizumab plus chemotherapy and event-free survival (EFS) with neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab in patients with high-risk, early-stage triple-negative breast cancer (TNBC). Prior studies have shown the prognostic value of the residual cancer burden (RCB) index to quantify the extent of residual disease after neoadjuvant chemotherapy. In this preplanned exploratory analysis, we assessed RCB distribution and EFS within RCB categories by treatment group. PATIENTS AND METHODS: A total of 1174 patients with stage T1c/N1-2 or T2-4/N0-2 TNBC were randomized 2 : 1 to pembrolizumab 200 mg or placebo every 3 weeks given with four cycles of paclitaxel + carboplatin, followed by four cycles of doxorubicin or epirubicin + cyclophosphamide. After surgery, patients received pembrolizumab or placebo for nine cycles or until recurrence or unacceptable toxicity. Primary endpoints are pCR and EFS. RCB is a prespecified exploratory endpoint. The association between EFS and RCB was assessed using a Cox regression model. RESULTS: Pembrolizumab shifted patients into lower RCB categories across the entire spectrum compared with placebo. There were more patients in the pembrolizumab group with RCB-0 (pCR), and fewer patients in the pembrolizumab group with RCB-1, RCB-2, and RCB-3. The corresponding hazard ratios (95% confidence intervals) for EFS were 0.70 (0.38-1.31), 0.92 (0.39-2.20), 0.52 (0.32-0.82), and 1.24 (0.69-2.23). The most common first EFS events were distant recurrences, with fewer in the pembrolizumab group across all RCB categories. Among patients with RCB-0/1, more than half [21/38 (55.3%)] of all events were central nervous system recurrences, with 13/22 (59.1%) in the pembrolizumab group and 8/16 (50.0%) in the placebo group. CONCLUSIONS: Addition of pembrolizumab to chemotherapy resulted in fewer EFS events in the RCB-0, RCB-1, and RCB-2 categories, with the greatest benefit in RCB-2. These findings demonstrate that pembrolizumab not only increased pCR rates, but also improved EFS among most patients who do not have a pCR.

Racial and Ethnic Disparities in Locoregional Recurrence Among Patients With Hormone Receptor-Positive, Node-Negative Breast Cancer: A Post Hoc Analysis of the TAILORx Randomized Clinical Trial.

Importance: Whether racial and ethnic disparities in locoregional recurrence (LRR) exist among patients with similar access to care treated in randomized clinical trials is unknown. Objective: To examine racial and ethnic differences in LRR among patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (ERBB2 [formerly HER2 or HER2/neu])-negative, node-negative breast cancer enrolled in the Trial Assigning Individualized Options for Treatment (TAILORx). Design, Setting, and Participants: This unplanned retrospective post hoc analysis examined a prospective multicenter clinical trial population of women with breast cancer enrolled between 2006 and 2010, with 9 years of follow-up. The TAILORx investigators randomized patients to treatment based on their Oncotype DX recurrence score, including endocrine therapy alone (recurrence score <11), endocrine therapy alone vs chemotherapy followed by endocrine therapy (recurrence score 11-25), or chemotherapy followed by endocrine therapy (recurrence score >25). Patients with unknown race and ethnicity or lack of follow-up were excluded from this analysis. Data analysis was performed between December 2021 and March 2022. Main Outcome and Measures: Locoregional recurrence was defined as ipsilateral in breast, skin, chest wall, or regional nodal recurrence without concurrent distant recurrence, and was stratified by racial and ethnic group. Unadjusted Kaplan-Meier and adjusted Cox proportional hazards regression models were used for survival analyses. Results: Of the 10 273 women enrolled in TAILORx, this analysis included 9369 with T1-2N0 HR-positive, ERBB2-negative breast cancer. Of these patients, 428 (4.6%) were Asian, 886 (9.4%) were Hispanic, 676 (7.2%) were non-Hispanic Black (hereinafter Black), and 7406 (78.8%) were non-Hispanic White (hereinafter White). Assigned treatment receipt was high, with a 9.3% (n = 870) crossover of treatment groups and a median endocrine therapy duration of longer than 60 months, ranging from 61.1 to 65.9 months, across racial and ethnic groups. A total of 6818 patients (72.6%) received radiation (6474 [96.1%] after breast-conserving surgery and 344 [13.0%] after mastectomy). At a median follow-up of 94.8 months (range, 1-138 months), 8-year LRR rates were 3.6% (95% CI, 1.6%-5.6%) in Asian patients, 3.9% (95% CI, 2.2%-5.4%) in Black patients, 3.1% in Hispanic patients (95% CI, 1.7%-4.5%), and 1.8% (95% CI, 1.5%-2.3%) in White patients (P < .001). In survival analyses adjusted for patient, tumor, and treatment factors, Asian race (hazard ratio, 1.91 [95% CI, 1.12-3.29]) and Black race (1.78 [1.15-2.77]) were independently associated with LRR. In adjusted survival analyses for breast cancer mortality, LRR was independently associated with increased breast cancer mortality (hazard ratio, 5.71 [95% CI, 3.50-9.31]). Conclusions and Relevance: In this post hoc analysis, racial and ethnic differences in LRR were observed among patients with T1-2N0 HR-positive, ERBB2-negative breast cancer despite high rates of treatment receipt in this clinical trial population, with the highest LRR rates in Asian and Black patients. Further study is needed to understand whether failure to rescue after LRR may contribute to racial disparities in breast cancer mortality. Trial Registration: ClinicalTrials.gov Identifier: NCT00310180.

Survival differences between HER2-0 and HER2-low-expressing breast cancer - A meta-analysis of early breast cancer patients.

BACKGROUND: HER2-low (human epidermal growth factor receptor 2) breast cancer takes up 40-50% in all breast cancer subtypes. The survival difference between HER2-low and HER2-zero breast cancers remain uncertain. Therefore, the aim of this study was to compare survival outcome of the two subtypes and to explore the impact of hormone receptor status. METHODS: A comprehensive medical literature search was performed by searching PubMed, EMBASE, and the Cochrane Libraries up to August 2022. We included observational studies reporting hazard ratios (HRs) with corresponding 95% confidence intervals (CIs). The results of individual studies were pooled by random-effects models using Stata 16.0. Seventeen articles with a total of 78984 breast cancer patients were included in the meta-analysis. RESULTS: We observed a statistically significant association between low HER2 expression and better breast cancer survival outcomes (OS: HR: 0.83; 95% confidence interval: 0.75, 0.90; DFS/RFS: HR: 0.83; 95% confidence interval: 0.75, 0.91). In a subgroup analysis, we found that HER2-low patients had better survival outcomes relative to hormone receptor-positive breast cancer patients (OS: HR: 0.87; 95% confidence interval: 0.81, 0.93; DFS/RFS: HR: 0.91; 95% confidence interval: 0.85, 0.96). Similarly, in triple-negative breast cancer patients, we also observed a positive association between HER2 low expression and better survival (OS: HR: 0.85; 95% confidence interval: 0.71, 0.98; DFS/RFS: HR: 0.85; 95% confidence interval: 0.74, 0.95). CONCLUSIONS: Our study showed that HER2-low breast cancer had better survival outcomes compared to HER2 negative breast cancer in patients with early stage breast cancer, regardless of hormone receptor status. REGISTRATION: This meta-analysis was registered with PROSPERO (CRD42022335704) on June 10, 2022. AVAILABILITY OF DATA AND MATERIALS: All data generated or analysed during this study are included in this published article [and its supplementary information files].

Neighborhood and racial influences on triple negative breast cancer: evidence from Northeast Ohio.

PURPOSE: Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer (BC) with higher recurrence rates and poorer prognoses and most prevalent among non-Hispanic Black women. Studies of multiple health conditions and care processes suggest that neighborhood socioeconomic position is a key driver of health disparities. We examined roles of patients' neighborhood-level characteristics and race on prevalence, stage at diagnosis, and mortality among patients diagnosed with BC at a large safety-net healthcare system in Northeast Ohio. METHODS: We used tumor registry to identify BC cases from 2007 to 2020 and electronic health records and American Community Survey for individual- and area-level factors. We performed multivariable regression analyses to estimate associations between neighborhood-level characteristics, measured by the Area Deprivation Index (ADI), race and comparative TNBC prevalence, stage at diagnosis, and total mortality. RESULTS: TNBC was more common among non-Hispanic Black (53.7%) vs. non-Hispanic white patients (46.4%). Race and ADI were individually significant predictors of TNBC prevalence, stage at diagnosis, and total mortality. Race remained significantly associated with TNBC subtype, adjusting for covariates. Accounting for TNBC status, a more disadvantaged neighborhood was significantly associated with a worse stage at diagnosis and higher death rates. CONCLUSION: Our findings suggest that both neighborhood socioeconomic position and race are strongly associated with TNBC vs. other BC subtypes. The burden of TNBC appears to be highest among Black women in the most socioeconomically disadvantaged neighborhoods. Our study suggests a complex interplay of social conditions and biological disease characteristics contributing to racial disparities in BC outcomes.

ZNF703 promotes triple-negative breast cancer cells through cell-cycle signaling and associated with poor prognosis.

BACKGROUND: The oncogenic drivers of triple-negative breast cancer (TNBC), which is characterized by worst prognosis compared with other subtypes, are poorly understood. Although next-generation sequencing technology has facilitated identifying potential targets, few of the findings have been translated into daily clinical practice. The present study is aimed to explore ZNF703 (Zinc finger 703) function and its underlying mechanism in TNBC. METHODS: ZNF703 expressions in tissue microarray were retrospectively examined by immunohistochemistry. The cell proliferation by SRB assay and colony formation assay, as well as cell cycle distribution by flow cytometry were assessed. The protein levels associated with possible underlying molecular mechanisms were evaluated by western blotting. Kaplan-Meier analysis was used to plot survival analysis. RESULTS: Our data suggest that ZNF703 expressed in 34.2% of triple-negative human breast tumors by immunohistochemistry. In vitro, ZNF703 knockdown had potent inhibitory effects on TNBC cell proliferation and cell cycle, with cyclin D1, CDK4, CDK6, and E2F1 downregulated, while Rb1 upregulated. Moreover, Kaplan-Meier analysis showed that high mRNA expression of ZNF703 was correlated to worse overall survival (HR for high expression was 3.04; 95% CI, 1.22 to 7.57, P = 0.017). CONCLUSIONS: Taken together, the results identified that targeting ZNF703 contributed to the anti-proliferative effects in TNBC cells, due to induced G1-phase arrest. This study is the first to identify ZNF703 as a potentially important protein that is involved in TNBC progression.

Breast cancer-specific mortality in early breast cancer as defined by high-risk clinical and pathologic characteristics.

OBJECTIVES: To investigate breast cancer-specific mortality by early breast cancer (EBC; Stages I-IIIC) subtype; incidence of high-risk indicators for recurrence (defined in monarchE trial); and mortality risk difference by those who did/did not meet these criteria. MATERIALS AND METHODS: Analyses included patients with initial EBC diagnosis between 2010-2015 from Surveillance, Epidemiology, and End Results (SEER) data (n = 342,149). Cox proportional hazards models and Kaplan-Meier estimates examined mortality among 228,031 patients, by subtype (hormone receptor [HR]-positive [+], human epidermal growth factor receptor-2 [HER2] negative [-]; triple negative [TNBC]; HR+, HER2+; HR-, HER2+). Incidence and mortality among patients who did/did not meet monarchE clinicopathological high-risk criteria were examined. RESULTS: Among patients with HR+, HER2- EBC, histologic Grade 3 (vs. Grade 1) was the most influential factor on mortality (hazard ratio, 3.61; 95%CI, 3.27, 3.98). Among patients with TNBC, ≥4 ipsilateral axillary positive nodes (vs. node negative) was the most influential factor on mortality (hazard ratio, 3.46; 95%CI, 2.87, 4.17). For patients with HR-, HER2+ or HR+, HER2+ EBC, tumor size ≥5 cm (vs. <1 cm) and ≥4 ipsilateral axillary positive nodes were the most influential factors on mortality. The 60-month mortality rate for the 12% of patients within the HR+, HER2- EBC group meeting monarchE clinicopathological high-risk criteria was 16.5%, versus 7.0% (Stage II-III and node positive) and 2.8% (Stage I or node negative) for those not meeting criteria. The 60-month mortality rate for patients with TNBC was 18.5%. CONCLUSION: Mortality risk and the relative importance of risk factors varied by subtype. monarchE clinicopathological high-risk criteria were associated with increased mortality risk among patients with HR+, HER2- EBC. Patients with HR+, HER2- EBC, and monarchE clinicopathological high-risk criteria experienced risk of mortality similar to patients with early TNBC. These data highlight a high unmet need in this select patient population who may benefit most from therapy escalation.

Impact of BRCA mutation on the survival and risk of contralateral breast cancer in Asian breast cancer patients.

PURPOSE: Breast cancer is increasing around the globe, including Asia. We aimed to examine the survival and risk of contralateral breast cancer (CBC) in Asian breast cancer patients with BRCA mutations. METHODS: A total of 128 breast cancer patients with germline BRCA mutations and 4,754 control breast cancer patients were enrolled. Data on clinical-pathologic characteristics, survival, and CBC were collected from the medical record. The rates of survival and CBC were estimated by Kaplan-Meier method. RESULTS: The mean age of onset in BRCA mutation carriers was significantly younger than control patients (BRCA vs. Non-BRCA: 43.9 vs. 53.2 years old). BRCA mutation carriers had a higher proportion of triple-negative breast cancer (TNBC) (52%) than control patients (12%, p < 0.001). The risk of CBC was significantly higher in BRCA mutation patients than in control cases (hazard ratio (HR) = 3.95, 95% CI 2.71-5.75); when stratified by genotype, the HRs (95%CI) were 4.84 (3.00-7.82) for BRCA1 and 3.13 (1.78-5.49) for BRCA2 carriers, respectively. Moreover, BRCA1 mutation patients with triple-negative breast cancer (TNBC) as their first breast cancer had the highest risk of CBC (HR = 5.55, 95% CI 3.29-9.34). However, we did not observe any differences in relapse-free survival and overall survival between mutation carriers and control patients. CONCLUSION: Our study suggest that BRCA patients had a significantly higher risk of developing CBC, particularly for BRCA1 mutation carriers with TNBC as the first breast cancer.

Proteomic analysis of archival breast cancer clinical specimens identifies biological subtypes with distinct survival outcomes.

Despite advances in genomic classification of breast cancer, current clinical tests and treatment decisions are commonly based on protein level information. Formalin-fixed paraffin-embedded (FFPE) tissue specimens with extended clinical outcomes are widely available. Here, we perform comprehensive proteomic profiling of 300 FFPE breast cancer surgical specimens, 75 of each PAM50 subtype, from patients diagnosed in 2008-2013 (n = 178) and 1986-1992 (n = 122) with linked clinical outcomes. These two cohorts are analyzed separately, and we quantify 4214 proteins across all 300 samples. Within the aggressive PAM50-classified basal-like cases, proteomic profiling reveals two groups with one having characteristic immune hot expression features and highly favorable survival. Her2-Enriched cases separate into heterogeneous groups differing by extracellular matrix, lipid metabolism, and immune-response features. Within 88 triple-negative breast cancers, four proteomic clusters display features of basal-immune hot, basal-immune cold, mesenchymal, and luminal with disparate survival outcomes. Our proteomic analysis characterizes the heterogeneity of breast cancer in a clinically-applicable manner, identifies potential biomarkers and therapeutic targets, and provides a resource for clinical breast cancer classification.

Developing an immune signature for triple-negative breast cancer to predict prognosis and immune checkpoint inhibitor response.

Aim: We aimed to develop a new signature based on immune-related genes to predict prognosis and response to immune checkpoint inhibitors in patients with triple-negative breast cancer (TNBC). Materials & methods: Single-sample gene set enrichment was used to develop an immune-based prognostic signature (IPRS) for TNBC patients. We conducted multivariate Cox analysis to evaluate the prognosis value of the IPRS. Result: An IPRS based on 66 prognostic genes was developed. Multivariate Cox analysis indicated that the IPRS was an independent factor for prognosis. PD-1, PD-L1, PD-L2 and CTLA4 gene expression was higher in the low-risk group, suggesting IPRS could predict the response to immune checkpoint inhibitors. Conclusion: The IPRS might be a reliable signature to predict TNBC patients' prognosis and response to immune checkpoint inhibitors, but needs prospective validation.