Negative Breast Cancer Research Articles

A Biosignature Integrating Immune and Metabolic Signaling Axes to Assess Limited Radiation Therapy Response in Early-Stage Breast Cancer from a Low-Risk Cohort

Radiation therapy (RT) post breast conserving surgery (BCS) reduces in-breast recurrence (IBR) rate in early-stage invasive breast cancer (BC) patients. The RT treatment recommendation is often driven by clinicopathological (CP) factors; however, CP factors alone have limited ability to identify which women significantly benefit from RT, or those with higher IBR risk after BCS plus RT. Biologic factors driving unique phenotypes, in addition to CP, may improve prediction of RT response. In this study we evaluated the role of immune and metabolic signaling axes in predicting RT response in hormone receptor positive, HER2 negative, early-stage BC patients. Biomarkers from immune and metabolic signaling axes were studied in a cohort of 939 women from Sweden, at a CLIA certified lab (Laguna Hills, CA). Formalin fixed paraffin embedded tissues were assayed for protein expression using multiplex immunofluorescence and multi-spectral imaging. Immune and metabolic axes were assessed using biomarkers combined with a non-linear model, adjusting for patient age. RT prediction by the model was assessed, along and adjusted for CP factors and also among patients over 50-yrs. The model defined patient risk groups that were analyzed for IBR rate using Kaplan Meier analyses and Cox proportional hazards to test for RT-risk group interaction. Within the cohort, 440 patients had hormone receptor positive, HER2 negative BC treated with BCS (negative margins) and +/- RT without chemotherapy, where 296 patients had complete biomarker data. CP factors individually were not predictive for RT benefit, but grade was prognostic for IBR rate (p = 0.02) after BCS without RT. In multivariable analysis, adjusting for CP factors (grade, palpability, continuous size and age), the model was predictive for RT benefit (p-interaction = 0.046), identifying patients (n = 129) with worse RT benefit (HR = 7.8) compared to baseline RT benefit. The model was not prognostic for IBR rate in patients treated with BCS without RT (16% 10-yr IBR rate) but identified patients with increased IBR rates after BCS plus RT (HR = 3.9, p<0.001), where corresponding 10-yr IBR rates increased from 3% to 15%. The model was also predictive for RT benefit in women over 50-yrs (p-interaction = 0.05). The model identified 28% of women over 50-yrs who had increased IBR rates after BCS plus RT (HR = 4.0, p = 0.004), where corresponding 10-yr IBR rates increased from 3% to 12%. The model incorporating metabolic and immune signaling axes assessed in the study was predictive for RT benefit among women with early-stage hormone receptor positive, HER2 negative BC. While CP factors were not predictive of RT benefit, the inclusion of metabolic and immune signaling axes improved identification of patients with high residual risk after BCS plus RT and can potentially aid in personalized treatment of early-stage breast cancer based on individualized risk.

Estimating the overall survival benefit of adjuvant chemo-endocrine therapy in women over age 50 with pT1-2N0 early stage breast cancer and 21-gene recurrence score ≥26: A National Cancer Database analysis.

Validation studies of the 21-gene recurrence score (RS) previously demonstrated that adjuvant chemotherapy plus endocrine therapy (CET) was associated with a significant survival benefit in women with node negative breast cancer (BC) and RS >31. However, the TAILORx trial, did not quantify the benefit of adjuvant CET in older women with node negative hormone receptor positive (HR+) BC with RS ≥26. We hypothesized that CET would be associated with improved overall survival (OS) compared to endocrine therapy (ET) in women >50 with HR+/HER2-node negative BC and RS ≥26. The National Cancer Database (NCDB) was queried to identify women >50 with RS ≥26 ER+/HER2-BC pT1-2N0M0. Chi-square and logistic regression analysis determined the difference between ET and CET. OS was analyzed using a multivariable Cox model. We included 16,745 women-4740 (28.3%) received ET and 12,005 (71.7%) received CET. Women who received CET had: moderately (OR = 1.853, p < 0.001) or poorly/undifferentiated tumors (OR = 3.875, p < 0.001), pT2 (OR = 1.356, p < 0.001), or lymph-vascular invasion (OR = 1.206, p = 0.001). After accounting for demographic and oncologic factors, 5-year OS rates were significantly superior in women receiving CET vs. ET alone (95.4% vs. 92.0%, Hazard Ratio = 0.680, p < 0.001). We observed that CET was associated with a clinically and statistically significant higher OS compared to ET alone in women >50 years of age with RS ≥26 pT1 and pT2 N0M0 HR+/HER2-breast cancer, and which suggests that cytotoxic chemotherapy has an impact on reducing mortality that is independent of induction of premature ovarian failure.

Oncologic efficacy of gonadotropin-releasing hormone agonist in hormone receptor-positive very young breast cancer patients treated with neoadjuvant chemotherapy.

Breast cancer in young women has been shown to have an aggressive behavior and poor prognosis. To evaluate the outcomes of young hormone receptor (HR)-positive patients with breast cancer treated with neoadjuvant chemotherapy (NAC), and the oncologic efficacy of gonadotropin-releasing hormone (GnRH) agonists. This retrospective study involved a prospectively enrolled cohort. We included patients diagnosed with invasive breast cancer who were treated with NAC followed by curative surgery at the Samsung Medical Center and Samsung Changwon Hospital between January 2006 and December 2017. Among patients with HR-positive and human epidermal grow factor 2 (HER2)-negative breast cancer, we analyzed the characteristics and oncology outcomes between the patients equal to or younger than 35 years and the patients older than 35 years. Among 431 patients with NAC and HR-positive/HER2-negative breast cancer, 78 were 35 years old or younger, and 353 patients were older than 35 years. The median follow-up was 71.0 months. There was no statistically significant difference in disease free survival (DFS, P = 0.565) and overall survival (P = 0.820) between the patients equal to or younger than 35 years and the patients older than 35 years. The two groups differed in that the GnRH agonist was used more frequently in the group of patients equal to or younger than 35 years than in the other group (52.4% vs 11.2%, P < 0.001). Interestingly, for the DFS according to the GnRH agonist in the group of patients equal to or younger than 35 years, patients treated with the GnRH agonist had better DFS (P = 0.037). Administration of GnRH agonists might improve the DFS rate of HR-positive/HER2-negative breast cancer in the equal to or younger than 35 years group of patients with NAC.

Elevated profiles of peripheral Th22, Th17, Th2 cells, and decreased percentage of Th1 cells in breast cancer patients.

Th22 subset is a particular type of CD4+ T helper cells subset. Our study aimed to explore the expression level of circulating Th22, Th17, Th1, and Th2 cells and the possible mechanism of these cells in breast cancer (BC) with different pathological features. Our study enrolled 43 newly diagnosed BC patients and 30 healthy controls. Frequencies of peripheral Th22, Th17, Th1, and Th2 cells were tested by flow cytometry. Concentrations of IL-22 cytokine in plasma were examined by enzyme-linked immunosorbent assay (ELISA). Real-time PCR was done to test aromatic hydrocarbon receptor (AHR) and RAR-associated orphan receptor C (RORC) gene expression. Frequencies of Th22, Th17, Th2 subsets, and the plasma IL-22 level was obviously higher in the BC patients. A positive correlation between Th22 frequency and IL-22 concentration in plasma was detected in BC patients. Furthermore, the percentage of Th22, Th2 subsets in peripheral blood of HER2 positive BC was higher than that in HER2 negative BC patients. A negative correlation between Th1 subset and Ki-67% as well as a positive correlation between Th2 subset and Ki-67% was found in BC patients. The proportion of Th1 cells in BC patients was significantly lower than that of the control group. Expression of AHR and RORC transcription factors were also observed to be upregulated in the BC patients. Furthermore, Th22 cells were positively correlated with BC tumor stage and clinical outcomes. The BC patients with a higher percentage of Th22, Th17, Th1 cells or a lower percentage of Th1 cells showed a decreased trend of survival rate. Th22, Th17, Th1, and Th2 subsets may play an essential role in BC patients. Th22, Th17, Th1, and Th2 cells may have potential significance to be used as clinical markers in BC patients with different molecular classification. Th22 cells may have potential value in BC patients' outcomes prediction, providing clinical value.

MEF2C and miR-194-5p: New Players in Triple Negative Breast Cancer Tumorigenesis.

Among breast cancer (BC) subtypes, the most aggressive is triple negative BC (TNBC), which is prone to metastasis. We previously found that microRNA (miR)-194-5p is downregulated at the early stages of TNBC brain metastasis development. Additionally, the transcription factor myocyte enhancer factor 2 (MEF2)C, a bioinformatically predicted miR-194-5p target, was increasingly expressed throughout TNBC brain metastasis formation and disease severity. However, the contributions of these two players to malignant cells' features remain undetermined. This study aimed at disclosing the role of miR-194-5p and MEF2C in TNBC tumorigenesis. The transfection of 4T1 cells with a silencer for MEF2C or with a pre-miRNA for miR-194-5p was employed to study TNBC cells' phenotypic alterations regarding epithelial and mesenchymal markers, as well as migratory capability alterations. MEF2C-silenced cells presented a decline in both vimentin and cytokeratin expression, whereas the overexpression of miR-194-5p promoted an increase in cytokeratin and a reduction in vimentin, reflecting the acquisition of an epithelial phenotype. Both treatments reduced TNBC cells' migration. These results suggest that MEF2C may determine TNBC cells' invasive properties by partially determining the occurrence of epithelial-mesenchymal transition, while the overexpression of miR-194-5p promotes a decline in TNBC cells' aggressive behavior and reinforces this miRNA's role as a tumor suppressor in TNBC.

Survival After Development of Contralateral Breast Cancer in Korean Patients With Breast Cancer

Contralateral breast cancer (CBC) is the most frequently diagnosed primary cancer in patients with breast cancer. Although many studies have reported survival after the development of CBC, results have been inconsistent. To investigate whether the development of CBC is associated with survival among patients with breast cancer. This cohort study was conducted at the Asan Medical Center, Korea, among patients who were diagnosed with primary unilateral, nonmetastatic, stage 0 to III breast cancer between 1999 and 2013 and followed up through 2018. The median (IQR) follow-up was 107 (75-143) months. Patients were categorized into CBC and no-CBC groups by whether they developed CBC during the follow-up period. Data were analyzed from November 2021 to March 2023. Development of CBC. Survival rates of CBC and no-CBC groups were compared using a time-dependent Cox proportional hazard model in the entire study population and in subgroup analyses by interval of CBC development and subtype of the primary breast cancer. Among 16 251 patients with breast cancer (all Asian, specifically Korean; mean [SD] age, 48.61 [10.06] years), 418 patients developed CBC. There was no significant difference in overall survival between CBC and no-CBC groups (hazard ratio, 1.166; 95% CI, 0.820-1.657). Patients who developed CBC within 1.5 years after the surgery of the primary breast cancer had a higher risk for overall death during the study period (hazard ratio, 2.014; 95% CI, 1.044-3.886), and those who developed CBC after 1.5 years showed no significant difference in survival compared with the no-CBC group. Patients with hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (ERBB2, formerly HER2)-negative breast cancer had a higher risk for overall death in the CBC group (hazard ratio, 1.882; 95% CI, 1.143-3.098) compared with the no-CBC group. This study found that development of CBC in patients with breast cancer was not associated with survival but that early development of CBC after diagnosis of the primary breast cancer or development of CBC in patients with HR-positive/ERBB2-negative breast cancer was associated with survival. These results may provide valuable information for patients seeking advice on opting for contralateral prophylactic mastectomy.

Stratified endocrine therapy for advanced breast cancer: stratification guided, combination preferred

The endocrine therapy of hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative breast cancer has stepped into an era of targeted combination therapy. Many targeted agents, led by cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), have provided abundant treatment options for patients with HR-positive HER2-negative advanced breast cancer. To meet the needs of clinical practice in China and standardize the administration of targeted agents, the stratified endocrine strategy for advanced breast cancer has been proposed by Chinese Society of Clinical Oncology (CSCO) Breast Cancer guidelines based on medicine evidence and drug accessibility, offering scientific and organized decision-making guidance for clinical oncologists.

O.3.2-4 Sedentary time and the risk of breast cancer among Nigerian Women

Abstract Purpose The aim of this study was to determine if sedentary time is independently associated with BC risk in Nigeria. While the role of physical activity in breast cancer (BC) risk has been reported in a few available sub-Saharan African (SSA) studies, the independent role of sedentary behavior (prolonged sitting or reclining) hypothesized as differing from physical inactivity (the absence of health-enhancing PA) has not been investigated in SSA. Methods The study was a multisite hospital-based case-control design involving 379 histologically confirmed BC cases and 403 cancer-free controls. The participants ≥ 20 years were interviewed in-person using a pretested questionnaire. Data were collected on self-reported number of hours per week of sitting associated with occupation, religious activity, and television watching, as well as PA intensity scores (in metabolic equivalent hours per week) associated with each sedentary time domain. The results were stratified by estrogen receptor status (extracted from records) and body mass index (BMI). Data were analyzed using multivariable logistic regression based on Statistical Software for Social Sciences, adjusting for relevant confounders. Results Following full adjustment including total PA intensity, total sedentary time (OR [≥43.3 hrs./wk. vs &amp;lt; 28.30hrs/wk.] 1.78, 95% CI: 1.07, 2.94) was associated with an increased BC risk. Every additional hr./wk. of sitting was associated with a 2% (1.00,1.04, p for trend = 0.044) increased BC risk among women with estrogen receptor negative (ER-) BC, and 1% (95% CI: 1.00,1.03) increase in women with BMI&amp;gt; 25kg/m2. Similarly, every additional hr./wk. of sitting watching television was associated with a 5% (95% CI: 1%, 9%, p for trend = 0.023) increased BC risk especially among women &amp;lt; 50 years (OR 1.05, 95% CI:1.01, 1.09) and women with BMI &amp;gt; 25kg/m2 (OR 1.06, 95% CI:1.01,1.10) following full adjustments. Conclusion The findings suggest that the number of hours of sitting independently increased BC risk especially among women with ER- breast cancer and women with high BMI ≥25kg/m2. Health enhancing physical activity Intervention programs aimed at reducing sedentary time especially those associated with television watching will help reduce BC risk in Nigeria and SSA. Support/Funding source National Open University of Nigeria.

Ultrasensitive determination of surface proteins on tumor-derived small extracellular vesicles for breast cancer identification based on lanthanide-activated signal amplification strategy

Small extracellular vesicles (sEVs) carrying multiple tumor-associated proteins inherited from parental cells play crucial roles in noninvasive breast cancer (BC) diagnosis. However, it is challenging to assess the subtle variations of surface proteins on sEV membranes due to the highly heterogeneous BC. Therefore, a simple and ultrasensitive assay based on lanthanide (Ln3+)-activated luminescence signal amplification was developed to detect multiple surface proteins on BC-derived sEVs. Multiple protein biomarkers on sEVs can be well identified with high sensitivity and specificity through dissolution-amplified luminescence of the NaEuF4 nanoparticle-based nanoprobe. We employ linear discriminant analysis to successfully discriminate triple negative BC cell (MDA-MB-231 cell) derived sEVs from other breast cell lines (MCF-7, SK-BR-3, BT474 and MCF-10A cell). Furthermore, the strategy enables high accuracy for districting the progression stages of BC patients and healthy donors. The simple and sensitive signal amplification strategy exhibits great potential for early clinic diagnosis by precise protein profiling of sEVs.

Validation of PREDICT Version 2.2 in a Retrospective Cohort of Indian Women With Operable Breast Cancer.

Online prediction models that use known prognostic factors in breast cancer (BC) are routinely used to assist in decisions for adjuvant therapy. PREDICT Version 2.2 (P2.2) is one such online tool, which uses tumor size, lymph node involvement, grade, age, hormone receptor status, human epidermal growth factor receptor 2 (HER2) status, and Ki67. We performed an external validation in a retrospective cohort of patients treated at a tertiary center in India. Women with operable BC between 2008 and 2016 with nonmetastatic, T1-T2 invasive, and HER2 receptor-negative BC and with available 5-year overall survival (OS) data were selected. Median predicted 5-year OS rates were used to calculate predicted events for the whole cohort and subgroups. The chi-square test was used to evaluate the goodness of fit of the tool. Of 11,760 cases registered between 2008 and 2016, 2,783 (23.66%) eligible patients with a median age of 50 (26-70) years and a median pT size of 2.5 (0.1-5) cm, 2,037 (73.19%) with grade 3 tumors, 1,172 (42.11%) with node-positive disease, 817 (29.35%) with triple-negative breast cancer, and 1,966 (70.64%) with HR-positive BC were included in the analysis. The observed 5-year OS and predicted 5-year OS in the whole cohort were 94.8% and 90.00%, respectively, with an absolute difference of 4.8% (95% CI, 3.417 to 6.198, P < .001). The observed 5-year OS and predicted 5-year OS were also different in various subgroups. PREDICT version 2.2 overestimated the number of deaths, with lower predicted 5-year OS compared with the observed value, in this retrospective Indian cohort. The reasons for this discrepancy could be differing biologic characteristics and possible selection bias in our cohort. We recommend a prospective validation of PREDICT in Indian patients and advocate caution in its use until such validation is achieved.

ER Negative Breast Cancer and miRNA: There Is More to Decipher Than What the Pathologist Can See!

Breast cancer (BC), the most prevalent cancer in women, is a heterogenous disease. Despite advancements in BC diagnosis, prognosis, and therapeutics, survival rates have drastically decreased in the metastatic setting. Therefore, BC still remains a medical challenge. The evolution of high-throughput technology has highlighted gaps in the classification system of BCs. Of particular interest is the notorious triple negative BC, which was recounted as being heterogenous itself and it overlaps with distinct subtypes, namely molecular apocrine (MA) and luminal androgen (LAR) BCs. These subtypes are, even today, still misdiagnosed and poorly treated. As such, researchers and clinicians have been looking for ways through which to refine BC classification in order to properly understand the initiation, development, progression, and the responses to the treatment of BCs. One tool is biomarkers and, specifically, microRNA (miRNA), which are highly reported as associated with BC carcinogenesis. In this review, the diverse roles of miRNA in estrogen receptor negative (ER-) and androgen receptor positive (AR+) BC are depicted. While highlighting their oncogenic and tumor suppressor functions in tumor progression, we will discuss their diagnostic, prognostic, and predictive biomarker potentials, as well as their drug sensitivity/resistance activity. The association of several miRNAs in the KEGG-reported pathways that are related to ER-BC carcinogenesis is presented. The identification and verification of accurate miRNA panels is a cornerstone for tackling BC classification setbacks, as is also the deciphering of the carcinogenesis regulators of ER - AR + BC.

A New Quinone-Based Inhibitor of Mitochondrial Complex I in D-Conformation, Producing Invasion Reduction and Sensitization to Venetoclax in Breast Cancer Cells.

Mitochondrial Complex I plays a crucial role in the proliferation, chemoresistance, and metastasis of breast cancer (BC) cells. This highlights it as an attractive target for anti-cancer drugs. Using submitochondrial particles, we identified FRV-1, an ortho-carbonyl quinone, which inhibits NADH:duroquinone activity in D-active conformation and reduces the 3ADP state respiration dependent on Complex I, causing mitochondrial depolarization, ATP drop, increased superoxide levels, and metabolic remodeling towards glycolysis in BC cells. Introducing methyl groups at FRV-1 structure produced analogs that acted as electron acceptors at the Complex I level or increased the inhibitory effect of FCCP-stimulated oxygen consumption rate, which correlated with their redox potential, but increased toxicity on RMF-621 human breast fibroblasts was observed. FRV-1 was inactive in the naphthoquinone oxidoreductase 1 (NOQ1)-positive BC cell line, MCF7, but the sensitivity was recovered by dicoumarol, a NOQ1 inhibitor, suggesting that FRV-1 is a NOQ1 substrate. Importantly, FRV-1 selectively inhibited the proliferation, migration, and invasion of NQO1 negative BC cell, MDA-MB-231, in an OXPHOS- and ROS-dependent manner and sensitized it to the BH3 mimetic drug venetoclax. Overall, FRV-1 is a novel Complex I inhibitor in D-active conformation, blocking possibly the re-activation to A-state, producing selective anti-cancer effects in NQO1-negative BC cell lines.

The immune microenvironment characterisation and dynamics in hormone receptor-positive breast cancer before and after neoadjuvant endocrine therapy.

Oestrogen receptor positive (ER+)/HER-2 negative breast cancer (BC) is considered to be an immunologically cold tumour compared to triple negative breast cancer. Therefore, the tumour microenvironment (TME) of ER+/HER-2 negative BC is understudied. The aim of this project is to investigate the TME and the immune response during neoadjuvant endocrine therapy (NET) and to correlate this with the treatment response in a real life setting. Expression of immune checkpoint receptors and immune cells was examined immunohistochemically, pre- and post-NET in a cohort of 56 ER+/HER-2 negative BC patients. They were treated with tamoxifen (n = 16), an aromatase inhibitor (n = 40) or a combination of an aromatase inhibitor with a PI3K inhibitor (n = 11) for a median duration of 6 months (range 1-32 months). Immunohistochemical staining with monoclonal antibodies for PDL-1, PD-1, TIM-3, LAG-3, CTLA-4, CD4, CD68 and FOXP3 were performed. All staining procedures were done according to validated protocols, and scoring was done by a pathologist specialized in breast cancer. Positivity was defined as staining >1% on TILs. Response to NET was evaluated according to tumour size change on imaging and Ki-67 change. The median age was 61.02 (37-90) years. Diameter of tumour size decreased with a mean of 8.1 mm (-16 mm to 45 mm) (p < 0.001) during NET and the value of Ki-67 value decreased with a median of 9 after NET (p < 0.001). An increase in PD-L1 expression after NET showed a trend towards significant (p = 0.088) and CD-4+ T cells significantly increased after NET (p = 0.03). A good response to NET defined as a decrease in tumour size and/or decrease of Ki-67 was found to be associated with a longer duration of NET, a change of CD4+ T-cells and a higher number of CD68+ tumour-associated macrophages before the start of NET. The immune microenvironment plays an important role in ER+/HER-2 negative BC. NET influences the composition and functional state of the infiltrating immune cells. Furthermore, changes in the immune microenvironment are also associated with treatment response.

Diabetes and incidence of breast cancer and its molecular subtypes: A systematic review and meta-analysis.

Diabetes mellitus (DM) has been proposed to be positively associated with breast cancer (BCa) risk due to shared risk factors, metabolic dysfunction, and the use of antidiabetic medications. We conducted a systematic review and meta-analysis to evaluate the association between DM and BCa risk. We searched PubMed, Embase, and Web of Science for cohort and case-control studies assessing the association between DM and BCa published before 10 December 2021. Two reviewers independently screened the studies for inclusion, abstracted article data, and rated study quality. Random effects models were used to estimate summary risk ratios (RRs) and 95% confidence intervals (CIs). From 8396 articles identified in the initial search, 70 independent studies were included in the meta-analysis. DM was associated with an overall increased risk of BCa (RR=1.20, 95% CI: 1.11-1.29). The 24 case-control studies demonstrated a stronger association (RR=1.26, 95% CI: 1.13-1.40) than the 46 cohort studies (RR=1.15, 95% CI: 1.05-1.27). Studies reporting risk by menopausal status found that postmenopausal women had an elevated risk of developing BCa (RR=1.12, 95% CI: 1.07-1.17). No association between DM and BCa risk was observed among premenopausal women (RR=0.95, 95% CI: 0.85-1.05). In addition, DM was associated with significantly increased risks of oestrogen receptor (ER)+ (RR=1.09, 95% CI: 1.00-1.20), ER- (RR=1.16, 95% CI: 1.04-1.30), and triple negative BCa (RR=1.41, 95% CI: 1.01-1.96). The association estimate for human epidermal growth factor 2-positive BCa was also positive (RR=1.21, 95% CI: 0.52-2.82), but the CI was wide and crossed the null. Our meta-analysis confirms a modest positive association between DM and BCa risk. In addition, our results suggest that the association between DM and BCa may be modified by menopausal status, and that DM may be differentially associated with BCa subtypes defined by receptor status. Additional studies are warranted to investigate the mechanisms underlying these associations and any influence of DM on BCa receptor expression.

The effect of adjuvant radiotherapy after breast-conserving surgery in elderly women with T1-2N0 estrogen receptor-negative breast cancer.

To evaluate whether adjuvant radiotherapy (RT) following breast-conserving surgery (BCS) results in better survival among women ≥ 70 years with T1-2N0 estrogen receptor (ER)-negative breast cancer. In this retrospective cohort study, we included patients who met the inclusion criteria between 2010 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) program. Univariate and Multivariate Cox proportional analysis were used to identify the risk factors for overall survival (OS) and breast cancer-specific survival (BCSS). Kaplan-Meier survival analysis was used to compare the prognosis of patients with or without adjuvant RT. Propensity score matching (PSM) was applied to perform a 1:1 matched case-control analysis. A total of 4201 women were included in this study, with a median follow-up time of 64 months (range: 0-107 months). Of these patients, 2811 (66.9%) received adjuvant RT, while 1390 (33.1%) did not. Patients who did not receive adjuvant RT were more likely to be aged ≥ 80 years old, have a single marital status, larger tumors, and HER2-positive status (p < 0.05). Multivariate Cox proportional analysis indicated that receiving adjuvant RT was an independent factor associated with better OS and BCSS before and after PSM (P < 0.001). The survival curves before and after PSM showed that patients achieved an improved OS and BCSS from adjuvant RT (P < 0.005). In the subgroup analysis, there was no survival benefit trend from adjuvant RT in patients who were ≥ 80 years, or those with T1mic+T1a, T1b tumors. The use of RT following BCS in older women with T1-2N0 ER-negative breast cancer is associated with improve OS and BCSS. However, the potential benefit may be relatively limited for patients ≥ 80 years, or those with T1mic+T1a, T1b tumors.

DECRESCENDO: de-escalating chemotherapy in HER2-positive, estrogen receptor-negative, node-negative early breast cancer.

The human epidermal growth factor receptor 2 (HER2)-enriched intrinsic subtype represents up to 75% of all HER2-positive hormone receptor (HR)-negative breast cancer (BC). Optimizing HER2-targeting therapy in this population might allow the omission of anthracycline-based chemotherapy, which is associated with potentially severe toxicities. DECRESCENDO (NCT04675827) is a large, multicenter, single-arm phase II trial in patients with HR-negative, HER2-positive, node-negative early BC evaluating a neoadjuvant pertuzumab and trastuzumab fixed-dose combination administered subcutaneously plus taxane-based chemotherapy followed by adjuvant treatment, adapted according to response to neoadjuvant therapy. The primary end point is the 3-year recurrence-free survival rate in patients with 'HER2-enriched' tumors and a pathological complete response. This flexible care substudy offers adjuvant treatment administration outside the hospital to some patients.

Clinicopathological characteristics of HER2-low breast cancer: a retrospective study

Human Epidermal Growth Factor Receptor-2 (HER2)-negative breast cancers (BCs) contain HER2-low and HER2-zero ones. HER2-low breast cancer has been receiving wide-spread concerns as the marvelous effect of novel anti-HER2 antibody-drug conjugates, however, the characteristic remains unknown. Our aim was to explore the differences of clinicopathological indicators and survival outcomes between HER2-low and HER2-0 breast cancers. We retrospectively analyzed 501 invasive breast cancer patients with complete data on HER2 status from 2017 to 2021 in our single center, of whom 415 HER2 negative patients were included for subsequent analysis. Each cohort was further divided into hormone receptor (HR) positive and HR negative subgroup. Clinicopathological factors and survival outcomes were collected and compared between HER2-low BCs and HER2-0 BCs. HER2-low BCs was obviously higher in HR positive BCs, with 277 (90.5%) HER2-low HR positive patients, 29 (9.5%) HER2-low HR negative patients, 68 (62.4%) HER2-0 HR positive patients and 41 (37.6%) HER2-0 HR negative patients (P < 0.001). Significant differences between HER2-low BCs and Her2-0 BCs were observed in lymph node ratio (LNR) (mean rank, 215 vs. 188 P = 0.014), estrogen receptor (ER)expression (90.5% vs. 62.4% P < 0.001), progesterone receptor (PR) expression (84.3% vs. 56.9% P < 0.001), Ki-67 expression (46.4% vs. 61.5% P < 0.001), androgen receptor (AR) expression (68% vs. 50.5% P < 0.001), adjuvant chemotherapy (69% vs. 79.8% P = 0.03). HER2-low BCs had lower histological grade than HER2-0 BCs, with grade I–II (68.7% vs. 43.1%) and grade III (22.2% vs. 43.1%) P < 0.01. No statistical differences were detected between the two groups for DFS and DDFS. Our results demonstrated that HR and AR status was closely related to HER2-low breast cancers. Further exploration about survival prognosis of HER2-low breast cancer is badly needed.

Identification of PIMREG as a novel prognostic signature in breast cancer via integrated bioinformatics analysis and experimental validation.

Phosphatidylinositol binding clathrin assembly protein interacting mitotic regulator (PIMREG) expression is upregulated in a variety of cancers. However, its potential role in breast cancer (BC) remains uncertain. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were used to gather relevant information. The expression of PIMREG and its clinical implication in BC were assessed by using Wilcoxon rank-sum test. The prognostic value of PIMREG in BC was evaluated through the Cox regression model and nomogram, and visualized by Kaplan-Meier survival curves. Genes/proteins that interact with PIMREG in BC were also identified through GeneMANIA and MaxLink. Gene set enrichment analysis (GSEA) was then performed. The correlations of the immune cell infiltration and immune checkpoints with the expression of PIMREG in BC were explored via TIMER, TISIDB, and GEPIA. Potential drugs that interact with PIMREG in BC were explored via Q-omic. The siRNA transfection, CCK-8, and transwell migration assay were conducted to explore the function of PIMREG in cell proliferation and migration. PIMREG expression was significantly higher in infiltrating ductal carcinoma, estrogen receptor negative BC, and progestin receptor negative BC. High expression of PIMREG was associated with poor overall survival, disease-specific survival, and progression-free interval. A nomogram based on PIMREG was developed with a satisfactory prognostic value. PIMREG also had a high diagnostic ability, with an area under the curve of 0.940. Its correlations with several immunomodulators were also observed. Immune checkpoint CTLA-4 was significantly positively associated with PIMREG. HDAC2 was found as a potentially critical link between PIMREG and BRCA1/2. In addition, PIMREG knockdown could inhibit cell proliferation and migration in BC. The high expression of PIMREG is associated with poor prognosis and immune checkpoints in BC. HDAC2 may be a critical link between PIMREG and BRCA1/2, potentially a therapeutic target.

Molecular features of androgen-receptor low, estrogen receptor-negative breast cancers in the Carolina breast cancer study

PurposeAndrogen receptor (AR) expression is absent in 40–90% of estrogen receptor (ER)-negative breast cancers. The prognostic value of AR in ER-negative patients and therapeutic targets for patients absent in AR remains poorly explored.MethodsWe used an RNA-based multigene classifier to identify AR-low and AR-high ER-negative participants in the Carolina Breast Cancer Study (CBCS; N = 669) and The Cancer Genome Atlas (TCGA; N = 237). We compared AR-defined subgroups by demographics, tumor characteristics, and established molecular signatures [PAM50 risk of recurrence (ROR), homologous recombination deficiency (HRD), and immune response].ResultsAR-low tumors were more prevalent among younger (RFD = + 10%, 95% CI = 4% to 16%) participants in CBCS and were associated with HER2 negativity (RFD = − 35%, 95% CI = − 44% to − 26%), higher grade (RFD = + 17%, 95% CI = 8% to 26%), and higher risk of recurrence scores (RFD = + 22%, 95% CI = 16.1% to 28%), with similar results in TCGA. The AR-low subgroup was strongly associated with HRD in CBCS (RFD = + 33.3%, 95% CI = 23.8% to 43.2%) and TCGA (RFD = + 41.5%, 95% CI = 34.0% to 48.6%). In CBCS, AR-low tumors had high adaptive immune marker expression.ConclusionMultigene, RNA-based low AR expression is associated with aggressive disease characteristics as well as DNA repair defects and immune phenotypes, suggesting plausible precision therapies for AR-low, ER-negative patients.

Differences in Breast Cancers Among American Indian/Alaska Native and non-Hispanic Whites in the USA.

Breast cancer (BC) death rates have not improved for American Indian/Alaska Native (AI/AN) women, whereas, it has significantly decreased for non-Hispanic White (White) women. Delineate the differences in patient and tumor characteristics among AI/AN and Whites with BC, and its impact on age and stage at diagnosis as well as overall survival (OS). Hospital-based, cohort study using the National Cancer Database to identify female AI/AN and Whites diagnosed with BC between the years 2004 and 2016. BC in 6866 AI/AN (0.3%) and 1,987,324 Whites (99.7%) were studied. The median age at diagnosis was 58 for AI/AN and 62 for Whites. AI BC patients traveled double the distance for treatment, lived in lower median income zip codes, had a higher percentage of uninsured, higher comorbidities, lower percentage of Stage 0/I, larger tumor size, greater number of positive lymph nodes, higher proportion of triple negative and HER2-positive BC than Whites. All the above comparisons were significant, p<0.001. Association between patient/tumor characteristics with age and stage at diagnosis was not significantly different between AI/AN and Whites. Unadjusted OS was worse for AI/AN as compared to Whites (HR=1.07, 95% CI=1.01-1.14, p=0.023). After adjustment of all covariates, OS was not different (HR=1.038, 95%CI=0.902-1.195, p=0.601). There were significant differences in patient/tumor characteristics among AI/AN and White BC which adversely impacted OS in AI/AN. However, when adjusted for various covariates, the survival was similar, suggesting that the worse survival in AI/AN is mostly the impact of known biological, socio-economic, and environmental determinants of health.