A prospective study of HER3 expression pre and post neoadjuvant therapy of different breast cancer subtypes: implications for HER3 imaging therapy guidance.

PURPOSE: HER3, a member of the EGFR receptor family, plays a central role in driving oncogenic cell proliferation in breast cancer. Novel HER3 therapeutics are showing promising results while recently developed HER3 PET imaging modalities aid in predicting and assessing early treatment response. However, baseline HER3 expression, as well as changes in expression while on neoadjuvant therapy, have not been well-characterized. We conducted a prospective clinical study, pre- and post-neoadjuvant/systemic therapy, in patients with newly diagnosed breast cancer to determine HER3 expression, and to identify possible resistance mechanisms maintained through the HER3 receptor. EXPERIMENTAL DESIGN: The study was conducted between May 25, 2018 and October 12, 2019. Thirty-four patients with newly diagnosed breast cancer of any subtype (ER ± , PR ± , HER2 ±) were enrolled in the study. Two core biopsy specimens were obtained from each patient at the time of diagnosis. Four patients underwent a second research biopsy following initiation of neoadjuvant/systemic therapy or systemic therapy which we define as neoadjuvant therapy. Molecular characterization of HER3 and downstream signaling nodes of the PI3K/AKT and MAPK pathways pre- and post-initiation of therapy was performed. Transcriptional validation of finings was performed in an external dataset (GSE122630). RESULTS: Variable baseline HER3 expression was found in newly diagnosed breast cancer and correlated positively with pAKT across subtypes (r = 0.45). In patients receiving neoadjuvant/systemic therapy, changes in HER3 expression were variable. In a hormone receptor-positive (ER +/PR +/HER2-) patient, there was a statistically significant increase in HER3 expression post neoadjuvant therapy, while there was no significant change in HER3 expression in a ER +/PR +/HER2+ patient. However, both of these patients showed increased downstream signaling in the PI3K/AKT pathway. One subject with ER +/PR -/HER2- breast cancer and another subject with ER +/PR +/HER2 + breast cancer showed decreased HER3 expression. Transcriptomic findings, revealed an immune suppressive environment in patients with decreased HER3 expression post therapy. CONCLUSION: This study demonstrates variable HER3 expression across breast cancer subtypes. HER3 expression can be assessed early, post-neoadjuvant therapy, providing valuable insight into cancer biology and potentially serving as a prognostic biomarker. Clinical translation of neoadjuvant therapy assessment can be achieved using HER3 PET imaging, offering real-time information on tumor biology and guiding personalized treatment for breast cancer patients.

A metabolic regulator for parietal cells.

The orphan nuclear receptor ERRγ directs the differentiation of acid-secreting gastric cells.

Prognostic value of Maspin protein level in patients with triple negative breast cancer.

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.

Activation of GPER1 by G1 prevents PTSD-like behaviors in mice: Illustrating the mechanisms from BDNF/TrkB to mitochondria and synaptic connection.

BACKGROUND: G1 is a specific agonist of G protein-coupled estrogen receptor 1 (GPER1), which binds and activates GPER1 to exert various neurological functions. However, the preventive effect of G1 on post-traumatic stress disorder (PTSD) and its mechanisms are unclear. OBJECTIVE: To evaluate the protective effect of G1 against synaptic and mitochondrial impairments and to investigate the mechanism of G1 to improve PTSD from brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) signaling. METHODS: This study initially detected GPER1 expression in the hippocampus of single prolonged stress (SPS) mice, utilizing both Western blot and immunofluorescence staining. Subsequently, the effects of G1 on PTSD-like behaviors, synaptic, and mitochondrial functions in SPS mice were investigated. Additionally, the involvement of BDNF/TrkB signaling involved in the protection was further confirmed using GPER1 antagonist and TrkB inhibitor, respectively. RESULTS: The expression of GPER1 was reduced in the hippocampus of SPS mice, and G1 treatment given for 14 consecutive days significantly improved PTSD-like behaviors in SPS mice compared with model group. Electrophysiological local field potential (LFP) results showed that G1 administration for 14 consecutive days could reverse the abnormal changes in the gamma oscillation in the CA1 region of SPS mice. Meanwhile, G1 administration for 14 consecutive days could significantly improve the abnormal expression of synaptic proteins, increase the expression of mitochondria-related proteins, increase the number of synapses in the hippocampus, and ameliorate the damage of hippocampal mitochondrial structure in SPS mice. In addition, G15 (GPER1 inhibitor) and ANA-12 (TrkB inhibitor) blocked the ameliorative effects of G1 on PTSD-like behaviors and aberrant expression of hippocampal synaptic and mitochondrial proteins in SPS mice and inhibited the reparative effects of G1 on structural damage to hippocampal mitochondria, respectively. CONCLUSION: G1 improved PTSD-like behaviors in SPS mice, possibly by increasing hippocampal GPER1 expression and promoting BDNF/TrkB signaling to repair synaptic and mitochondrial functional impairments. This study would provide critical mechanism for the prevention and treatment of PTSD.

Loss of Hormone Receptor Expression after Exposure to Fluid Shear Stress in Breast Cancer Cell Lines.

Following metastatic spread, many hormone receptor positive (HR+) patients develop a more aggressive phenotype with an observed loss of the HRs estrogen receptor (ER) and progesterone receptor (PR). During metastasis, breast cancer cells are exposed to high magnitudes of fluid shear stress (FSS). Unfortunately, the role for FSS on the regulation of HR expression and function during metastasis is not fully understood. This study was designed to elucidate the impact of FSS on HR+ breast cancer. Utilizing a microfluidic platform capable of exposing breast cancer cells to FSS that mimics in situ conditions, we demonstrate the impact of FSS exposure on representative HR+ breast cancer cell lines through protein and gene expression analysis. Proteomics results demonstrated that 540 total proteins and 1473 phospho-proteins significantly changed due to FSS exposure and pathways of interest included early and late estrogen response. The impact of FSS on response to 17ß-estradiol (E2) was next evaluated and gene expression analysis revealed repression of ER and E2-mediated genes (PR and SDF1) following exposure to FSS. Western blot demonstrated enhanced phosphorylation of mTOR following exposure to FSS. Taken together, these studies provide initial insight into the effects of FSS on HR signaling in metastatic breast cancer.

Pathological Changes Following Neoadjuvant Endocrine Therapy (NAET): A Multicentre Study of 391 Breast Cancers.

Oestrogen receptor (ER)-positive breast cancer (BC) is generally well responsive to endocrine therapy. Neoadjuvant endocrine therapy (NAET) is increasingly being used for downstaging ER-positive tumours. This study aims to analyse the effect of NAET on a well-characterised cohort of ER-positive BC with particular emphasis on receptor expression. This is a retrospective United Kingdom (UK) multicentre study of 391 patients who received NAET between October 2012 and October 2020. Detailed analyses of the paired pre- and post-NAET morphological changes and hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) expression were performed. The median duration of NAET was 86 days, with median survival and overall survival rates of 380 days and 93.4%, respectively. A total of 90.3% of cases achieved a pathological partial response, with a significantly higher rate of response in the HER2-low cancers. Following NAET, BC displayed some pathological changes involving the tumour stroma including central scarring and an increase in tumour infiltrating lymphocytes (TILs) and tumour cell morphology. Significant changes associated with the duration of NAET were observed in tumour grade (30.6% of cases), with downgrading identified in 19.3% of tumours (p < 0.001). The conversion of ER status from positive to low or negative was insignificant. The conversion of progesterone receptor (PR) and HER2 status to negative status was observed in 31.3% and 38.1% of cases, respectively (p < 0.001). HER2-low breast cancer decreased from 63% to 37% following NAET in the paired samples. Significant morphological and biomarker changes involving PR and HER2 expression occurred following NAET. The findings support biomarker testing on pre-treatment core biopsies and post-treatment residual carcinoma.

Metformin Prevents Tumor Cell Growth and Invasion of Human Hormone Receptor-Positive Breast Cancer (HR+ BC) Cells via FOXA1 Inhibition.

Women with type 2 diabetes (T2D) have a higher risk of being diagnosed with breast cancer and have worse survival than non-diabetic women if they do develop breast cancer. However, more research is needed to elucidate the biological underpinnings of these relationships. Here, we found that forkhead box A1 (FOXA1), a forkhead family transcription factor, and metformin (1,1-dimethylbiguanide hydrochloride), a medication used to treat T2D, may impact hormone-receptor-positive (HR+) breast cancer (BC) tumor cell growth and metastasis. Indeed, fourteen diabetes-associated genes are highly expressed in only three HR+ breast cancer cell lines but not the other subtypes utilizing a 53,805 gene database obtained from NCBI GEO. Among the diabetes-related genes, FOXA1, MTA3, PAK4, FGFR3, and KIF22 were highly expressed in HR+ breast cancer from 4032 breast cancer patient tissue samples using the Breast Cancer Gene Expression Omnibus. Notably, elevated FOXA1 expression correlated with poorer overall survival in patients with estrogen-receptor-positive/progesterone-receptor-positive (ER+/PR+) breast cancer. Furthermore, experiments demonstrated that loss of the FOXA1 gene inhibited tumor proliferation and invasion in vitro using MCF-7 and T47D HR+ breast cancer cell lines. Metformin, an anti-diabetic medication, significantly suppressed tumor cell growth in MCF-7 cells. Additionally, either metformin treatment or FOXA1 gene deletion enhanced tamoxifen-induced tumor growth inhibition in HR+ breast cancer cell lines within an ex vivo three-dimensional (3D) organoid model. Therefore, the diabetes-related medicine metformin and FOXA1 gene inhibition might be a new treatment for patients with HR+ breast cancer when combined with tamoxifen, an endocrine therapy.

Silkworm (Bombyx mori L.) Has Beneficial Effects on Menopausal Symptoms by Enhancing Estrogen Receptor Signaling in Ovariectomized Mice.

Existing hormone replacement therapy for menopause has drawbacks, necessitating new treatment agents. Silkworms have demonstrated estrogenic properties, offering promising alternatives. We assessed the therapeutic effects of freeze-dried silkworm powder (SWP) on menopausal symptoms using an ovariectomized (OVX) mouse model. The experimental design comprised a sham surgery group (Sham), an OVX control group, a low-dose SWP group post-OVX (80 mg/kg, OVX-SWP-L), a high-dose SWP group post-OVX (160 mg/kg, OVX-SWP-H), and an estradiol treatment group post-OVX (OVX-E2). Treatments were administered orally thrice weekly over eight weeks; body weight was monitored weekly. The SWP-treated groups (SWP-L and SWP-H) exhibited less weight gain and increased uterine thickness than the OVX control. Molecular analyses demonstrated that SWP significantly enhanced the phosphorylation of estrogen receptor alpha (ERα), ERK, and AKT. Furthermore, biochemical assays revealed reduced serum neutral lipids across all SWP treatment groups. Notably, HDL-cholesterol levels were significantly increased in the SWP-L group compared to the OVX group. Serum estradiol concentrations were elevated in all the SWP groups, with significant increases in the high-dose group. These findings indicate that SWP may promote the activation of estrogen receptor signaling and improve symptoms associated with estrogen deficiency during menopause.

Genetic susceptibility to breast cancer increases the risk of neutropenia and agranulocytosis: insights from Mendelian randomization.

PURPOSE: The causal relationship between breast cancer and its estrogen receptor (ER) subtypes and neutropenia and agranulocytosis is unclear. METHODS: In two-sample Mendelian randomization (MR), we used inverse variance weighting (IVW), Bayesian weighted MR (BWMR), MR-Egger, weighted median, simple mode, and weighted mode methods to analyze causality for ER-positive breast cancer, ER-negative breast cancer, overall breast cancer, and drug-induced neutropenia and agranulocytosis. To validate the results, we performed the analysis again using GWAS data on neutropenia from different databases. In multivariable MR (MVMR), we assessed the independent effects of ER-positive and ER-negative breast cancer on causality. RESULTS: Two-sample MR analysis showed a causal relationship between ER-positive breast cancer (IVW odds ratio (OR) = 1.319, P = 7.580 × 10-10), ER-negative breast cancer (OR = 1.285, P = 1.263 × 10-4), overall breast cancer (OR = 1.418, P = 2.123 × 10-13), and drug-induced neutropenia and a causal relationship between ER-positive breast cancer (OR = 1.349, P = 1.402 × 10-7), ER-negative breast cancer (OR = 1.235, P = 7.615 × 10-3), overall breast cancer (OR = 1.429, P = 9.111 × 10-10), and neutropenia. Similarly, ER-positive breast cancer (OR = 1.213, P = 5.350 × 10-8), ER-negative breast cancer (OR = 1.179, P = 1.300 × 10-3), and overall breast cancer (OR = 1.275, P = 8.642 × 10-11) also had a causal relationship with agranulocytosis. MVMR analysis showed that ER-positive breast cancer remained causally associated with drug-induced neutropenia (OR = 1.233, P = 4.188 × 10-4), neutropenia (OR = 1.283, P = 6.363 × 10-4), and agranulocytosis (OR = 1.142, P = 4.549 × 10-3). Heterogeneity analysis and pleiotropy test showed that our results were reliable. CONCLUSION: Our study provides genetic evidence for a causal association between breast cancer and its estrogen receptor subtypes and neutropenia. In clinical practice, in addition to focusing on therapeutic factors, additional attention should be given to breast cancer patients to avoid severe neutropenia.

Comparative biological activity of palbociclib and ribociclib in hormone receptor-positive breast cancer.

This study examines the biological effects of palbociclib and ribociclib in hormone receptor-positive breast cancer, pivotal to the HARMONIA prospective phase III clinical trial. We explore the downstream impacts of these CDK4/6 inhibitors, focusing on cell lines and patient-derived tumor samples. We treated HR+ breast cancer cell lines (T47D, MCF7, and BT474) with palbociclib or ribociclib (100 nM or 500 nM), alone or combined with fulvestrant (1 nM), over periods of 24, 72, or 144 h. Our assessments included PAM50 gene expression, RB1 phosphorylation, Lamin-B1 protein levels, and senescence-associated ß-galactosidase activity. We further analyzed PAM50 gene signatures from the CORALLEEN and NeoPalAna phase II trials. Both CDK4/6 inhibitors similarly inhibited proliferation across the cell lines. At 100 nM, both drugs partially reduced p-RB1, with further decreases at 500 nM over 144 h. Treatment led to reduced Lamin-B1 expression and increased senescence-associated ß-galactosidase activity. Both drugs enhanced Luminal A and reduced Luminal B and proliferation signatures at both doses. However, the HER2-enriched signature significantly diminished only at the higher dose of 500 nM. Corresponding changes were observed in tumor samples from the CORALLEEN and NeoPalAna studies. At 2 weeks of treatment, both drugs significantly reduced the HER2-enriched signature, but at surgery, this reduction was consistent only with ribociclib. Our findings suggest that while both CDK4/6 inhibitors effectively modulate key biological pathways in HR+/HER2- breast cancer, nuances in their impact, particularly on the HER2-enriched signature, are dose-dependent, influenced by the addition of fulvestrant and warrant further investigation.

Dual-targeting class I HDAC inhibitor and ATM activator, SP-1-303, preferentially inhibits estrogen receptor positive breast cancer cell growth.

Dual-targeting chromatin regulation and DNA damage repair signaling presents a promising avenue for cancer therapy. Applying rational drug design, we synthesized a potent dual-targeting small molecule, SP-1-303. Here, we report SP-1-303 as a class I isoform selective histone deacetylase (HDAC) inhibitor and an activator of the ataxia-telangiectasia mutated protein (ATM). In vitro enzymatic assays demonstrated selective inhibition of HDAC1 and HDAC3. Cellular growth inhibition studies show that SP-1-303 differentially inhibits growth of estrogen receptor positive breast cancer (ER+ BC) cells with effective growth inhibition concentrations (EC50) for MCF-7 and T47D cells ranging from 0.32 to 0.34 µM, compared to 1.2-2.5 µM for triple negative breast cancer cells, and ~12 µM for normal breast epithelial cells. Western analysis reveals that SP-1-303 decreases estrogen receptor alpha (ER-α) expression and increases p53 protein expression, while inducing the phosphorylation of ATM and its substrates, BRCA1 and p53, in a time-dependent manner in ER+ BC cells. Pharmacokinetic evaluation demonstrates an area under the curve (AUC) of 5227.55 ng/ml × h with an elimination half-life of 1.26 h following intravenous administration in a rat model. Collectively, SP-1-303 emerges as a novel second generation class I (HDAC1 and HDAC3) selective HDAC inhibitor, and ATM activator, capable of modulating ER expression, and inhibiting growth of ER+ BC cells. Combined targeting of class I HDACs and ATM by SP-1-303 offers a promising therapeutic approach for treating ER+ breast cancers and supports further preclinical evaluation.

[Application of 21-gene recurrence risk score in patients with breast cancer].

Objective: To investigate the relationship between 21-gene recurrence risk score (21-Gene RS) and the prognosis and clinicopathological features of hormone receptor (HR) positive, HER2-negative early breast cancer patients who did not receive neoadjuvant therapy. Methods: A total of 469 patients with HR positive and HER2-negative early breast cancer who received surgical treatment in the First Affiliated Hospital, Zhejiang University School of Medicine from January 2014 to October 2017 were selected. Their clinicopathological data were retrospectively analyzed. Tumor tissue samples were collected from patients, and the expression of 21-gene was detected by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR). The 21-Gene RS was calculated according to the Trial Assigning Individualized Options for Treatment (TAILORx) RS grouping and National Surgical Adjuvant Breast and Bowel Project B-20 (NSABP B-20) RS grouping principles. Patients were divided into low (21-Gene RS<11 or 21-Gene RS<18), intermediate (11≤21-Gene RS<26 or 18≤21-Gene RS<31) and high (21-Gene RS≥26 or 21-Gene RS≥31) risk groups, and the clinicopathological features and prognostic differences of patients in different risk groups were compared. Statistical data were compared by chi-square test. Survival analysis was performed using Kaplan-Meier curve analysis and the differences between groups were compared using Log-rank test. Multivariate analysis was conducted by COX regression analysis. Results: Based on TAILORx RS grouping, the proportions of low-risk, intermediate-risk and high-risk groups among the 469 patients were 18.8% (88/469), 48.2% (226/469) and 33.0% (155/469), respectively. Based on NSABP B-20 RS grouping, the proportion of low-risk, intermediate-risk and high-risk groups were 43.1% (202/469), 37.5% (176/469) and 19.4% (91/469), respectively. The association of 21-Gene RS with histological grading, luminal typing, Ki-67 expression, and chemotherapy and treatment modalities were statistically significant (P<0.05) regardless of TAILORx RS grouping or NSABP B-20 RS grouping. Kaplan-Meier survival curve suggested poor prognosis in high-risk group (P<0.05, Log-rank test). Multivariate COX regression analysis showed that surgical method and 21-Gene RS were risk factors affecting the prognosis of patients. Conclusions: 21-Gene RS is significantly associated with the prognosis of patients with HR-positive, HER2-negative, early-stage breast cancer not receiving neoadjuvant therapy, as well as with their clinicopathological characteristics such as patients' histologic grade, luminal typing, Ki-67 expression, and whether or not they are treated with chemotherapy or other treatment modalities.The 21-Gene RS threshold of 11 and 26 or 18 and 31 can be used to grade the prognosis in Chinese patients with early-stage breast cancer. More researches are needed to guide the selection of postoperative adjuvant therapy for patients with HR-positive and HER2-negative early-stage breast cancer.

[Clinicopathological features of breast cancer with HER2 low expression: a real-world retrospective study].

Objective: To investigate the clinical and pathological characteristics of breast cancer with HER2 low expression. Methods: The data from 3 422 patients with invasive breast cancer which archived in Peking Union Medical College Hospital between April 2019 and July 2022 were retrospectively reviewed. Among them, 136 patients were treated with neoadjuvant chemotherapy. The tumor size, histological type, tumor differentiation, lymph node metastasis, Ki-67 index, the status of estrogen receptor, progesterone receptor and HER2 as well as pathological complete response (pCR) rate were collected. Results: The HER2 status of 3 286 patients without neoadjuvant therapy, 616 (616/3 286, 18.7%) score 0, 1 047 (1 047/3 286, 31.9%) score 1+, 1 099 (1 099/3 286,33.4%) score 2+ and 524 (524/3 286,15.9%) score 3+ by immunohistochemistry (IHC). Among the 1 070 IHC 2+ cases, 161 were classified as HER2 positive by reflex fluorescence in situ hybridization (FISH) assay. In our cohort, 1 956 cases of HER2-low (IHC 1+ and IHC 2+/FISH-) breast cancer were identified. Compared to the HER2 IHC 0 group, HER2-low tumors more frequently occurred in patients with hormone receptor (HR) positive (P<0.001), Ki-67 index below 35% (P<0.001), well or moderate differentiation (P<0.001) and over the age of 50 (P=0.008). However, there were no significant differences in histological type, tumor size, and lymph node metastasis between HER2-low and HER2 IHC 0 group. For patients who had neoadjuvant therapy, the pCR rate in the patients with HER2-low was lower than those with HER2 IHC 0 (13.3%, 23.9%), but there was no significant difference. Although HER2-low breast cancers showed a slightly lower pCR rate than HER2 IHC 0 tumors, no remarkable difference was observed between tumors with HER2-low and HER2 IHC 0 regardless of hormone receptor status. Conclusions: The clinicopathological features of HER2-low breast cancers are different from those with HER2 IHC 0. It is necessary to accurately distinguish HER2-low breast cancer from HER2 IHC 0 and to reveal whether HER2-low tumor is a distinct biological entity.

Eff ect of platelet-rich autoplasma on endometrial thickness and receptor sensitivity to estrogen and progesterone.

AIM: The effect of platelet-rich autoplasma on endometrial thickness and receptor sensitivity to estrogen and progesterone. MATERIALS AND METHODS: This prospective clinical study included 200 patients. The participants in the study were divided into two groups. The first control group received hormone replacement therapy (HRT). The second study group received an intrauterine infusion of platelet-rich autoplasma (PRP group). On the 19th day of the menstrual cycle, an ultrasound examination was performed to assess endometrial thickness, as well as an immunohistochemical analysis to determine receptor sensitivity to estrogen and progesterone. RESULTS: In the course of the study, we found that the use of platelet-rich autoplasma increased the thickness of the endometrium by 0.85 mm; the average thickness of the endometrium in the group who received PRP therapy was 8.25 (8.25-8.61)  mm; and in the group of patients who only received HRT, it was 7.40 (7.34-7.65)  mm. The sensitivity of receptors to estrogen in the experimental group increased by 3.5, in the experimental group it was 75.00 (71.43-74.22), and in the control group it was 71.50 (67.05-70.85). The sensitivity of receptors to progesterone also increased by 9.0, in the experimental group it was 95.0 (91.4-93.8), and in the control group it was 86.0 (83.47-86.27). CONCLUSION: Due to the action of platelet factors, PRP therapy has a positive effect on the endometrium, increasing its thickness and improving its receptivity. Therefore, it can be concluded that this method can find great practical application to improve the outcomes of assisted reproductive technology programs.

Ferritin and Serum Iron in a Causal Relationship with Estrogen Receptor-Negative Breast Cancer: a Two-Sample Mendelian Randomization Study.

BACKGROUND: The aim of this study was to explore the causal relationship between different serum iron statuses (ferritin, transferrin, transferrin saturation, and serum iron) and the occurrence of estrogen receptor (ER)-positive or ER-negative breast cancer. METHODS: The summary data on serum iron status exposure were gathered from the IEU OpenGWAS Project, the UK Biobank, and other databases. Concurrently, the summary data for ER+ and ER- breast cancer are sourced from the Breast Cancer Association Consortium (BCAC). By examining the causal link between iron status and breast cancer, we deployed five distinct Mendelian randomization (MR) algorithms, namely MR-Egger, inverse variance weighted (IVW), weighted median, simple mode, and MR-PRESSO. To assess heterogeneity and horizontal pleiotropy, Cochran's Q and MR-Egger algorithms were applied, respectively. RESULTS: Elevated ferritin levels are associated with an increased risk of ER-negative breast cancer (OR(IVW) = 1.042, 95% CI (1.005, 1.081), p = 0.025; OR (weighted median) = 1.050, 95% CI (1.001, 1.102), p = 0.046; and OR (MR-PRESSO) = 1.042, 95% CI (1.005, 1.081), p = 0.039). Conversely, an increase in the serum iron level is linked to a reduced risk of ER-negative breast cancer (OR (IVW) = 0.791, 95% CI (0.649, 0.962), p = 0.019; and OR (MR-PRESSO) = 0.791, 95% CI (0.649, 0.962), p = 0.028). However, there is no evidence of a causal relationship between transferrin, transferrin saturation, and ER-negative breast cancer. For ER-positive breast cancer, none of the four different iron statuses demonstrated a causal relationship. CONCLUSIONS: Ferritin is positively correlated with ER-negative breast cancer, while serum iron is negatively associated with ER-negative breast cancer. However, there is no causal relationship between the four iron statuses and ER-positive breast cancer.

Breast cancer hormone receptor levels and benefit from adjuvant tamoxifen in a randomized trial with long-term follow-up.

BACKGROUND: Hormone receptor positivity predicts benefit from endocrine therapy but the knowledge about the long-term survival of patients with different tumor receptor levels is limited. In this study, we describe the 25 years outcome of tamoxifen (TAM) treated patients. PATIENTS AND METHODS: Between 1983 and 1992, a total of 4,610 postmenopausal patients with early-stage breast cancer were randomized to receive totally 2 or 5 years of TAM therapy. After 2 years, 4,124 were alive and free of breast cancer recurrence. Among these, 2,481 had demonstrated estrogen receptor positive (ER+) disease. From 1988, the Abbot enzyme immunoassay became available and provided quantitative receptor levels for 1,210 patients, for which our analyses were done. RESULTS: After 5 years of follow-up, when all TAM treatment was finished, until 15 years of follow-up, breast cancer mortality for patients with ER+ disease was significantly reduced in the 5-year group as compared with the 2-year group (hazard ratios [HR] 0.67, 95% confidence intervals [CI] 0.55-0.83, p < 0.001). After 15 years, the difference between the groups remained but did not increase further. A substantial benefit from prolonged TAM therapy was only observed for the subgroup of patients with ER levels below the median (HR = 0.62, 95% CI 0.46-0.84, p = 0.002). Similarly, patients with progesterone receptor negative (PR-) disease did benefit from prolonged TAM treatment. For patients with progesterone receptor positive (PR+) disease, there was no statistically significant benefit from more than 2 years of TAM.  Interpretation: As compared with 2 years of adjuvant TAM, 5 years significantly prolonged breast cancer-specific survival. The benefit from prolonged TAM therapy was statistically significant for patients with ER levels below median or PR-negative disease. There was no evident benefit from prolonged TAM for patients with high ER levels or with PR+ tumors.

Effect of PR status on the prognosis of advanced ER-high HER2-negative breast cancer patients receiving CDK4/6 inhibitor combined with endocrine as first-line therapy.

BACKGROUND: This study was designed to evaluate the effect of progesterone receptor (PR) status on the prognosis of advanced estrogen receptor (ER)-high human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients receiving CDK4/6 inhibitor combined with endocrine as first-line therapy. METHODS: Advanced ER-high HER2-negative breast cancer patients who were admitted to Harbin Medical University Cancer Hospital and received cyclin-dependent kinase (CDK)4/6 inhibitor combined with endocrine as first-line therapy were included for analysis. Patients were divided into PR-high group (11-100%), PR-low group (1-10%), and PR-negative group (< 1%) according to the expression of PR. Chi-square test was used to analyze the correlation of variables between groups. COX regression analysis were used to analyze the risk factors of survival. Kaplan-Meier survival curve was used to analyze the differences of progression-free survival (PFS) and overall survival (OS) between groups. RESULTS: Among the 152 patients, 72 were PR-high, 32 were PR-low, and 48 were PR-negative. Compared with PR-negative group, the proportions of disease-free survival (DFS) ≥ 5 years and Ki-67 index ≤ 30% in PR-low group and PR-high group were significant higher. PR-negative patients were more likely to occur first-line progression of disease within 24 months (POD24) than PR-high(P = 0.026). Univariate and multivariate analysis showed that PR-negative and first-line POD24 occurrence were risk factors for survival. Survival curve analysis showed that compared with PR-high group, the PFS and OS were significantly lower in PR-negative group (P = 0.001, P = 0.036, respectively). Patients with first-line POD24 had shorter OS in the overall population as well as in subgroups stratified by PR status. CONCLUSIONS: PR-negative and first-line POD24 occurrence were risk factors of advanced ER-high HER2-negative breast cancer patients receiving CDK4/6 inhibitor combined with endocrine as first-line therapy. PR-negative patients had shortest PFS and OS. Regardless of PR status, first-line POD24 occurrence predicted shorter OS.

Select gene mutations associated with survival outcomes in ER-positive ERBB2-negative early-stage invasive breast cancer: A single-institutional tissue bank study.

INTRODUCTION: The prognostic capability of targeted sequencing of primary tumors in patients with estrogen receptor-positive, human epidermal growth factor receptor-2-negative early-stage invasive breast cancer (EBC) in a real-world setting is uncertain. Therefore, we aimed to determine the correlation between a 22-gene mutational profile and long-term survival outcomes in patients with ER+/ERBB2- EBC. PATIENTS AND METHODS: A total of 73 women diagnosed with ER+/ERBB2- EBC between January 10, 2004, and June 2, 2008, were followed up until December 31, 2022. Univariate and multivariate Cox models were constructed to plot the relapse-free survival (RFS) and overall survival (OS). The log-rank test derived p-value was obtained. For external validation, we performed a survival analysis of 1163 comparable patients retrieved from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset. RESULTS: At follow-up, 16 (21.9%) patients had relapsed, while 21 (nearly 29%) harbored mutant genes. Thirty-three missense mutations were detected in 14 genes. The median ages were 51 and 46 years in patients with and without mutations, respectively. Patients with any mutation had a 1.85-fold higher risk of relapse (hazard ratio [HR]: 1.85, 95% confidence interval [CI]: 0.60-5.69) compared to those without any mutation. Patients who harbored any of the six genes (MAP2K4, FGFR3, APC, KIT, RB1, and PTEN) had a nearly 6-fold increase in the risk of relapse (HR: 5.82, 95% CI: 1.31-18.56; p = 0.0069). Multivariate Cox models revealed that the adjusted HR for RFS and OS were 6.67 (95% CI: 1.32-27.57) and 8.31 (p = 0.0443), respectively. METABRIC analysis also demonstrated a trend to significantly worse RFS (p = 0.0576) in the subcohort grouped by having a mutation in any of the six genes. CONCLUSIONS: Our single-institution tissue bank study of Taiwanese women with ER+/ERBB2- EBC suggests that a novel combination of six gene mutations might have prognostic capability for survival outcomes.

Cost-Effectiveness of Adjuvant Abemaciclib and Ribociclib in High-Risk Hormone Receptor-Positive Early Breast Cancer: An Indian Perspective.

PURPOSE: Incorporating adjuvant cyclin-dependent kinase (CDK) 4/6 inhibitors abemaciclib and ribociclib along with endocrine therapy has been shown to improve invasive disease-free survival (iDFS) for hormone receptor-positive (HR+) human epidermal receptor 2-negative (HER2-) early breast cancer (EBC). This study assesses the cost-effectiveness of this strategy, along with adjuvant aromatase inhibitors from an Indian perspective. METHODS: A Markov chain model evaluated the cost-effectiveness of abemaciclib and ribociclib with letrozole compared with letrozole alone for HR+/HER2- EBC from a payer perspective in India. Key measures included lifetime quality-adjusted life-years (QALY), life-years (LY), and total costs. This study explores two scenarios for effectiveness: a best-case (BC) scenario, where the benefit of CDK4/6 inhibitors in improving iDFS lasts a lifetime, and a worst-case (WC) scenario, where benefits disappear after 5 years. Probabilistic sensitivity analyses (PSA) were used to account for simulation uncertainty. RESULTS: In the BC scenario, abemaciclib added 2.17 QALY and 4.96 LY, incurring ₹2,317,957.7 ($27,756.65 in US dollars [USD]) in additional costs. However, the incremental cost-effectiveness ratio (ICER) for abemaciclib exceeded India's willingness-to-pay threshold in the BC and WC scenarios. In the BC scenario, ribociclib added 0.98 QALY and 2.58 LY with added costs of ₹1,711,504.32 ($20,494.6 USD). The ICER for ribociclib also surpassed India's threshold in both scenarios. PSA showed that neither drug was cost-effective at the current market prices in either BC/WC scenario. The cost of abemaciclib and ribociclib needs to be reduced by at least 78.61% and 87.19%, respectively, to be cost-effective in the BC scenario. CONCLUSION: The combination of adjuvant abemaciclib or ribociclib with letrozole is not cost-effective for HR+/HER2- EBC in India in either the BC or WC scenario.