TNBC is noted for its aggressive behavior and poor prognosis. Recently developed HER2 target agents have shown potential benefit even in HER2-low expressing breast cancers. This study retrospectively analyzed 2542 non-metastatic TNBC patients from 2008 to 2020, revealing that 26.0% were HER2-low. Data on demographics, tumor characteristics, pathologic complete response (pCR) rates and disease-free survival (DFS), distant metastasis-free survival (DMFS), overall survival (OS), and breast cancer-specific survival (BCSS) were analyzed. The HER2-low group, compared to the HER2-0 group, showed significantly better DFS, DMFS, OS, BCSS (p = 0.0072, p = 0.0096, p = 0.0180, and p = 0.0001, respectively) with older age and higher rates of postmenopausal status (p < 0.0001). No significant differences in pCR rates were observed. Multivariate analyses identified HER2 status as a significant prognostic factor for DFS (p = 0.048), DMFS (p = 0.018), OS (p = 0.049), and BCSS (p = 0.008). Subgroup analysis revealed that these effects varied with menopausal status, showing more pronounced benefits in postmenopausal women. Our findings suggest that HER2-low TNBC patients exhibit a distinct clinical profile and improved survival compared to HER2-0 TNBC patients, especially in postmenopausal patients. Further research on estrogen and HER2 interaction is needed.

Human epidermal growth factor receptor-2 (HER2), programmed death-ligand 1 (PD-L1), and microsatellite (MS) status are well-established biomarkers in gastroesophageal adenocarcinomas (GEAs). However, it is unclear how the combination of these biomarkers is associated with clinicopathological factors and prognosis. This retrospective study included baseline metastatic GEA patients who were tested for all three biomarkers (HER2, PD-L1, and MS status) at the MD Anderson Cancer Center between 2012 and 2022. Stratification was performed according to the combination of biomarker profiles: triple negative (TN), single positive (SP), and multiple positive (MP). Comparative analyses of clinicopathological factors and survival using combinations of biomarkers were performed. Among the 698 GEA patients analyzed, 251 (36.0%) were classified as TN, 334 (47.9%) as SP, and 113 (16.1%) as MP. The MP group showed a significant association with tumors located in the esophagus (p < .001), well to moderate differentiation (p < .001), and the absence of signet ring cells (p < .001). In the survival analysis, MP group had a significantly longer overall survival (OS) compared to the other groups (MP vs. TN, p < .001 and MP vs. SP, p < .001). Multivariate Cox regression analysis revealed that MP serves as an independent positive prognostic indicator for OS (hazard ratio = 0.63, p < .01). Our findings indicate that MP biomarkers are associated with a favorable prognosis in metastatic GEA. These results are reflective of clinical practice and offer valuable insights into how therapeutics and future biomarkers could influence therapy/prognosis.

The search for prognostic markers in breast cancer has bumped into a typical feature of these tumors, intra and intertumoral heterogeneity. Changes in the expression profile, localization of these proteins or shedding to the surrounding stroma can be useful in the search for new markers. In this context, classification by molecular subtypes can bring perspectives for both diagnosis and screening for appropriate treatments. However, the Triple Negative (TN) subtype, which is already the one with the worst prognosis, lacks appropriate and consistent molecular markers. In this work, we analyzed 346 human breast cancer samples in tissue microarrays (TMA) from cases diagnosed with invasive breast carcinoma to assess the expression and localization pattern of Maspin and their correlation with clinical parameters. To complement our findings, we also used TCGA data to analyze the mRNA levels of these respective genes. Our data suggests that the TN subtype demonstrates a higher level of cytoplasmic Maspin compared to the other subtypes. Maspin transcript levels follow the same trend. However, TN patients with lower Maspin expression tend to have worse overall survival and free-survival metastasis rates. Finally, we used Maspin expression data to verify possible relationships with the clinicopathological information of our cohort. Our univariate analyses indicate that Maspin is related to the expression of estrogen receptor (ER) and progesterone receptor (PR). Furthermore, Maspin expression levels also showed correlation with Scarff-Bloom-Richardson (SBR) parameter, and stromal Maspin showed a relationship with lymph node involvement. Our data is not consistently robust enough to categorize Maspin as a prognostic marker. However, it does indicate a change in the expression profile within the TN subtype.

BACKGROUND: Breast cancer, particularly triple-negative breast cancer (TNBC), poses a significant global health burden. Chemotherapy was the mainstay treatment for TNBC patients until immunotherapy was introduced. Studies indicate a noteworthy prevalence (0.2% to 18.6%) of mismatch repair protein (MMRP) deficiency in TNBC, with recent research highlighting the potential of immunotherapy for MMRP-deficient metastatic breast cancer. This study aims to identify MMRP deficiency in TNBC patients using immunohistochemistry.
METHODS: A retrospective cohort study design was used and included TNBC patients treated between 2015 and 2021 at King Hussein Cancer Center. Immunohistochemistry was conducted to assess MMRP expression.
RESULTS: Among 152 patients, 14 (9.2%) exhibited deficient MMR (dMMR). Loss of PMS2 expression was observed in 13 patients, 5 of whom showed loss of MLH1 expression. Loss of MSH6 and MSH2 expression was observed in one patient. The median follow-up duration was 44 (3-102) months. Despite the higher survival rate (80.8%, 5 years) of dMMR patients than of proficient MMR patients (62.3%), overall survival did not significantly differ between the two groups.
CONCLUSIONS: Approximately 9% of TNBC patients exhibit dMMR. dMMR could be used to predict outcomes and identify patients with TNBC who may benefit from immunotherapy.

BACKGROUND: Breast cancer (BC) is the second most common etiology of brain metastases (BrM). We aimed to examine the incidence of BrM among all BC patients presenting to a large tertiary cancer centre over one decade.
METHODS: We included all BC patients presenting consecutively between 2009 and 2019 and cross referenced that cohort to a radiotherapy database, identifying patients treated for BrM at any time following their initial presentation. Cumulative incidences (CI) of BrM diagnoses were calculated using death as a competing risk and compared using the Fine-Gray method. Overall survival was estimated using the Kaplan Meier method.
RESULTS: We identified 12,995 unique patients. The CI of BrM in patients who initially presented with Stage 0-4 disease was 2.1%, 3.7%, 9.4%, 10.6%, and 28.7%, respectively at 10 years. For 8,951 patients with available molecular subtype data, 6,470 (72%), 961 (11%), 1,023 (11%), and 497 (6%) had hormone-receptor (HR)-positive/ERBB2-, HR-negative/ERBB2-, HR-positive/ERBB2 + , and HR-negative/ERBB2 + disease, respectively; the CI of BrM in each was 7.6%, 25.3%, 24.1%, and 26.6%, at 10 years following BC diagnosis, respectively. Median overall survival (OS) following BC diagnosis and BrM diagnosis was 28 years 95% CI [25, 32] and 10 months 95% CI [9, 12], respectively.
CONCLUSIONS: From a large, registry-based study, we observed that patients with ERBB2 + and triple negative BC have the highest incidence of BrM. Our data supports prospective surveillance brain MRI studies. Given advancements in BrM treatment, clinicians should have a low threshold for brain imaging in BC patients with high risk subtypes.

暂无摘要。

OBJECTIVE: Neoadjuvant chemotherapy (NAC) for triple-negative (TN) and Her2-positive (HER2) breast cancers is supported by international guidelines as it can decrease extent of surgery, provide prognostic information, and allow response-driven adjuvant therapies. Our goal was to describe practice patterns for patients with TN and HER2-positive breast cancer and identify the factors associated with the receipt of NAC versus surgery as initial treatment.
METHODS: A retrospective population-based cohort study of adult women diagnosed with stage I-III TN or HER2-positive breast cancer (2012-2020) in Ontario was completed using linked administrative datasets. The primary outcome was NAC as first treatment. The association between NAC and patient, tumor, and practice-related factors was examined using multivariable logistic regression models.
RESULTS: Of 14,653 patients included, 23.9% (n = 3500) underwent NAC as first treatment. Patients who underwent NAC were more likely to be younger and have larger tumors, node-positive disease, and stage 3 disease. Of patients who underwent surgery first, 8.8% were seen by a medical oncologist prior to surgery. On multivariable analysis, increasing tumor size (T2 vs T1/T0: 2.75 (2.31-3.28)) and node-positive (N1 vs N0: OR 3.54 (2.92-4.30)) disease were both associated increased odds of receiving NAC.
CONCLUSIONS: A considerable proportion of patients with TN and HER2-positive breast cancer do not receive NAC as first treatment. Of those, most were not assessed by both a surgeon and medical oncologist prior to initiating therapy. This points toward potential gaps in multidisciplinary assessment and disparities in receipt of guideline-concordant care.

New targeted treatments are urgently needed to improve triple-negative breast cancer (TNBC) patient survival. Previously, we identified the cell surface protein A Disintegrin And Metalloprotease 8 (ADAM8) as a driver of TNBC tumor growth and spread via its metalloproteinase and disintegrin (MP and DI) domains. In proof-of-concept studies, we demonstrated that a monoclonal antibody (mAb) that simultaneously inhibits both domains represents a promising therapeutic approach. Here, we screened a hybridoma library using a multistep selection strategy, including flow cytometry for Ab binding to native conformation protein and in vitro cell-based functional assays to isolate a novel panel of highly specific human ADAM8 dual MP and DI inhibitory mAbs, called ADPs. The screening of four top candidates for in vivo anti-cancer activity in an orthotopic MDA-MB-231 TNBC model of ADAM8-driven primary growth identified two lead mAbs, ADP2 and ADP13. Flow cytometry, hydrogen/deuterium exchange-mass spectrometry (HDX-MS) and alanine (ALA) scanning mutagenesis revealed that dual MP and DI inhibition was mediated via binding to the DI. Further testing in mice showed ADP2 and ADP13 reduce aggressive TNBC characteristics, including locoregional regrowth and metastasis, and improve survival, demonstrating strong therapeutic potential. The continued development of these mAbs into an ADAM8-targeted therapy could revolutionize TNBC treatment.

Triple negative breast cancer (TNBC) is known for its heterogeneous nature and aggressive onset. The unresponsiveness to hormone therapies and immunotherapy and the toxicity of chemotherapeutics account for the limited treatment options for TNBC. Ion channels have emerged as possible therapeutic candidates for cancer therapy, but little is known about how ligand gated ion channels, specifically, GABA type A ligand-gated ion channel receptors (GABAAR), affect cancer pathogenesis. Our results show that the GABAA β3 subunit is expressed at higher levels in TNBC cell lines than non-tumorigenic cells, therefore contributing to the idea that limiting the GABAAR via knockdown of the GABAA β3 subunit is a potential strategy for decreasing the proliferation and migration of TNBC cells. We employed pharmacological and genetic approaches to investigate the role of the GABAA β3 subunit in TNBC proliferation, migration, and cell cycle progression. The results suggest that pharmacological antagonism or genetic knockdown of GABAA β3 subunit decreases TNBC proliferation and migration. In addition, GABAA β3 subunit knockdown causes cell cycle arrest in TNBC cell lines via decreased cyclin D1 and increased p21 expression. Our findings suggest that membrane bound GABAA receptors containing the β3 subunit can be further developed as a potential novel target for the treatment of TNBC.

BACKGROUND: There are multiple neoadjuvant regimens, including platinum agents for triple-negative breast cancer (TNBC), each with a different safety profile, outcome, and pathologic complete response rate (pCR%). We performed a systematic review and network meta-analysis to compare the efficacy and safety of different platinum-based neoadjuvant CT treatments for TNBC.
METHODS: Bibliographic databases (PubMed, Embase, and Cochrane Library) were searched from their inception to October 31, 2022. Eligible studies were randomized clinical trials that evaluated the addition of carboplatin or cisplatin to standard neoadjuvant CT for TNBC. The primary endpoints were pCR rates and DFS/EFS, while the secondary endpoints were grade (G)3-4 hematological toxicity and OS.
RESULTS: Thirteen trials involving 3154 patients comparing six treatments (carboplatin AUC 5, carboplatin AUC 6, carboplatin AUC 2, carboplatin AUC 1.5, cisplatin 75 mg/m2, and standard anthracycline-and/or taxane-based CT) were identified. Based on the most effective treatments added to neoadjuvant CT, carboplatin AUC 2 was associated with the least improvement in pCR% (RR, 1.49; 95%CI, 1.23, 1.8), carboplatin AUC 6 was associated with similar improvement in pCR% (RR 1.58, 95%CI, 1.35, 1.84) and carboplatin AUC 5 with the highest improvement in pCR% (RR 2.23, 95%CI, 1.6,32). The treatment associated with the most considerable improvement in DFS when added to neoadjuvant CT was carboplatin AUC 5 (HR 0.36, 95%CI 0.18, 0.73). It was also better than AUC 6 and AUC 2 (HR= 0.45, 95%CI 0.21-0.96 and HR=0.48, 95%CI 0.23-0.98). All schedules exhibited similar outcomes in terms of OS; however, only AUC 2 demonstrated a significant improvement compared to the no-platinum arms. Neutropenia, thrombocytopenia, and anemia G3-4 were significantly increased by carboplatin AUC 6.
CONCLUSIONS: Based on this network meta-analysis, carboplatin AUC 5 added to standard neoadjuvant CT may provide substantial pCR and DFS benefits with a low toxicity risk compared to other carboplatin doses.