Neoadjuvant letrozole and palbociclib in patients with HR-positive/HER2-negative early breast cancer and Oncotype DX Recurrence Score ≥18: DxCARTES study.

BACKGROUND: The effect of the addition of cyclin-dependent kinases 4 and 6 inhibitors to endocrine therapy in terms of molecular downstaging remains undetermined. Switching from a high-risk to a low risk Recurrence Score (RS) group could provide useful information to identify patients who might not require chemotherapy. The purpose of this study was to assess the biological and clinical activity of letrozole plus palbociclib as neoadjuvant treatment for patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative early breast cancer with an initial Oncotype DX RS ≥18. PATIENTS AND METHODS: Participants were women aged ≥18 years with HR-positive/HER2-negative, Ki67 ≥ 20%, stage II-IIIB early breast cancer with a baseline RS ≥18. Eligible patients with a pretreatment RS 18-25 (cohort A) and 26-100 (cohort B) received six 28-day cycles of letrozole (2.5 mg per day; plus goserelin if pre- or perimenopausal) plus palbociclib (125 mg per day; 3/1 schedule) before surgery. The primary endpoint for both cohorts was the proportion of patients who achieved an RS ≤25 at surgery or a pathological complete response (pCR). RESULTS: A total of 67 patients were enrolled, among which 65 were assessable for the primary endpoint (32 patients in cohort A and 33 in cohort B). At surgery, 22 (68.8%) patients in cohort A and 18 (54.5%) patients in cohort B had an RS ≤25 or a pCR [only 1 (3.0%) patient in cohort B], meeting the primary endpoint in cohort B (P < 0.01), but not in cohort A (P = 0.98). No new safety signals were identified. CONCLUSIONS: The efficacy of neoadjuvant treatment with letrozole plus palbociclib does not seem to depend on pretreatment RS for patients with RS ≥18. However, around half of patients with HR-positive/HER2-negative early breast cancer with an RS 26-100 at baseline achieved molecular downstaging with this regimen.

Clinical significance of serum estradiol monitoring in women receiving adjuvant aromatase inhibitor for hormone receptor-positive early breast cancer.

PURPOSE: The limited understanding of long-term estradiol (E2) suppression poses challenges to the effectiveness of adjuvant therapy with aromatase inhibitors (AI), necessitating comprehensive serum E2 monitoring to address this issue. Therefore, our objective was to investigate serum E2 levels in women undergoing adjuvant AI treatment and evaluate the significance of such monitoring. PATIENTS AND METHODS: In this prospective cohort study, we recruited women who had received adjuvant AI treatment, including those who underwent ovarian function suppression (OFS). Serum E2 levels were measured using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). The primary endpoint was the proportion of women with E2 levels exceeding 2.72 pg/mL, indicating inadequate suppression achieved with AI therapy. RESULTS: A total of 706 patients were enrolled, including 482 women with OFS in combination with AI. Among them, 116 women (16.4 %) exhibited E2 levels exceeding 2.72 pg/mL. The majority of serum E2 elevations (77.6 %) occurred within the first two years of initiating endocrine therapy. Younger age, no prior chemotherapy, shorter duration of the current treatment regimen, and lower follicle stimulating hormone (FSH) levels were associated with inadequate E2 suppression. Serum E2 concentrations demonstrated dynamic variations and occasional rebound following adjuvant AI therapy. CONCLUSIONS: Despite receiving adjuvant AI treatment for nearly two years, a certain proportion of patients failed to achieve the adequate threshold of E2 suppression. Our findings emphasize the significance of monitoring serum E2 levels during adjuvant AI therapy, particularly within the first two years. Further research is imperative to facilitate a more comprehensive comprehension of E2 monitoring.

Updates in Systemic Treatment of Hormone Receptor-Positive Early-Stage Breast Cancer.

OPINION STATEMENT: Hormone-receptor positive (HR +) and human epidermal growth factor receptor 2 (HER2) negative early breast cancer (eBC) is a heterogeneous disease with several contributing factors for increased risk of recurrence, including tumor features, individual biomarkers, and genomic risk. The current standard approach in the management of HR + /HER2neg eBC includes chemotherapy and endocrine therapy (ET), and additional therapies based on risk profile, menopausal status, and genetics are sometimes appropriate. The risk of recurrence is more pronounced in patients with high-risk eBC including large tumor size, nodal involvement, high proliferative index, and genetic predisposition. In premenopausal patients with high-risk eBC, ovarian function suppression in combination with adjuvant ET improves survival. In postmenopausal patients, extended aromatase inhibitor (AI) therapy can be considered. Recent trials have identified novel treatment approaches to reduce the risk of recurrence in high-risk HR + /HER2neg eBC including the addition of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors to adjuvant ET. For patients with germline BRCA1/BRCA2 mutations, adjuvant poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have been shown to improve overall survival (OS). However, despite these recent advances, the risk of recurrence remains substantial, highlighting an area of unmet need. There are several ongoing clinical trials further investigating the role of CDK 4/6 inhibitors and immunotherapy in high-risk HR + /HER2neg eBC.

Comparative efficacy of THR-ß agonists, FGF-21 analogues, GLP-1R agonists, GLP-1-based polyagonists, and Pan-PPAR agonists for MASLD: A systematic review and network meta-analysis.

AIMS: To compare the efficacy of thyroid hormone receptor beta (THR-ß) agonists, fibroblast growth factor 21 (FGF-21) analogues, glucagon-like peptide-1 receptor agonists (GLP-1RAs), GLP-1-based polyagonists, and pan-peroxisome proliferator-activated receptor (Pan-PPAR) agonists in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: A database search for relevant randomized double-blind controlled trials published until July 11, 2024, was conducted. Primary outcomes were the relative change in hepatic fat fraction (HFF) and liver stiffness assessed non-invasively by magnetic resonance imaging proton density fat fraction and elastography. Secondary outcomes included histology, liver injury index, lipid profile, glucose metabolism, blood pressure, and body weight. RESULTS: Twenty-seven trials (5357 patients with MASLD) were identified. For HFF reduction, GLP-1-based polyagonists were most potentially effective (mean difference [MD] -51.47; 95 % confidence interval [CI]: -68.25 to -34.68; surface under the cumulative ranking curve [SUCRA] 84.9) vs. placebo, followed by FGF-21 analogues (MD -47.08; 95 % CI: -58.83 to -35.34; SUCRA 75.5), GLP-1R agonists (MD -37.36; 95 % CI: -69.52 to -5.21; SUCRA 52.3) and THR-ß agonists (MD -33.20; 95 % CI: -43.90 to -22.51; SUCRA 36.9). For liver stiffness, FGF-21 analogues were most potentially effective (MD -9.65; 95 % CI: -19.28 to -0.01; SUCRA 82.2) vs. placebo, followed by THR-ß agonists (MD -5.79; 95 % CI: -9.50 to -2.09; SUCRA 58.2), and GLP-1RAs (MD -5.58; 95 % CI: -15.02 to 3.86; SUCRA 54.7). For fibrosis improvement in histology, GLP-1-based polyagonists were most potentially effective, followed by FGF-21 analogues, THR-ß agonists, Pan-PPAR agonists, and GLP-1R agonists; For MASH resolution in histology, GLP-1-based polyagonists were most potentially effective, followed by THR-ß agonists, GLP-1R agonists, FGF-21 analogues, and Pan-PPAR agonists. THR-ß agonists are well-balanced in liver steatosis and fibrosis, and excel at improving lipid profiles; FGF-21 analogues are effective at improving steatosis and particularly exhibit strong antifibrotic abilities. GLP-1R agonists showed significant benefits in improving liver steatosis, glucose metabolism, and body weight. GLP-1-based polyagonists have demonstrated the most potential efficacy overall in terms of comprehensive curative effect. Pan-PPAR agonists showed distinct advantages in improving liver function and glucose metabolism. CONCLUSION: These results illustrate the relative superiority of the five classes of therapy in the treatment of MASLD and may serve as guidance for the development of combination therapies.

Advances in the mechanism of CDK4/6 inhibitor resistance in HR+/HER2- breast cancer.

Among women, breast cancer is the most prevalent form of a malignant tumour. Among the subtypes of breast cancer, hormone receptor (HR) positive and human epidermal growth factor receptor (HER2) negative kinds make up the biggest proportion. The advent of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, which are dependent on cell cycle proteins, has greatly enhanced the prognosis of patients with advanced HR+/HER2- breast cancer. This is a specific treatment that stops the growth of cancer cells by preventing them from dividing. Nevertheless, the drug resistance of the disease unavoidably impacts the effectiveness of treatment and the prognosis of patients. This report provides a thorough analysis of the current research advancements about the resistance mechanism of CDK4/6 inhibitors in HR+/HER2- breast cancer. It presents an in-depth discussion from numerous viewpoints, such as aberrant cell cycle regulation and changes in signalling pathways. In response to the drug resistance problem, subsequent treatment strategies are also being explored, including switching to other CDK4/6 inhibitor drugs, a combination of novel endocrine therapeutic agents, an optimal combination of targeted therapies and switching to chemotherapy. An in-depth study of the resistance mechanism can assist in identifying creative tactics that can overcome or postpone drug resistance, alleviate the problem of restricted treatment strategies following drug resistance and enhance the prognosis of patients.

Receptor activity-modifying protein modulation of parathyroid hormone-1 receptor function and signaling.

Introduction: Receptor activity-modifying proteins (RAMPs) are known to modulate the pharmacology and function of several G-protein-coupled receptors (GPCRs), including the parathyroid hormone 1 receptor (PTH1R). However, the precise effects of different RAMPs on PTH1R signalling and trafficking remain poorly understood. This study investigated the impact of RAMP2 and RAMP3 on PTH1R function using a range of PTH and PTH-related protein (PTHrP)-derived ligands. Methods: We employed FRET imaging to assess PTH1R interactions with RAMPs. Cell surface expression of PTH1R was evaluated in the presence of RAMPs. PTH1R-mediated cAMP accumulation, ß-arrestin recruitment, and calcium signalling were measured in response to various ligands. Antibody-capture scintillation proximity assays were used to examine G-protein activation patterns. Results: PTH1R preferentially interacted with RAMP2 and, to a lesser extent, RAMP3, but not with RAMP1. RAMP3 co-expression reduced cell surface expression of PTH1R. RAMP2 significantly enhanced PTH1R-mediated signalling responses to PTH (1-34), PTHrP (1-34), PTH (1-84), and PTH (1-17) analogue ZP2307, while RAMP3 co-expression attenuated or abolished these responses. Full-length PTHrP analogues exhibited lower potency and efficacy than PTHrP (1-34) in activating PTH1R. RAMP2 increased the potency and/or efficacy of these analogues, whereas RAMP3 reduced these responses. RAMP2 differentially modulated G-protein activation by PTH1R in a ligand-dependent manner, with PTH (1-34) and PTHrP (1-34) inducing distinct patterns of G-protein subtype activation. Discussion: These findings highlight the complex role of RAMPs in regulating PTH1R signalling and trafficking, revealing differential effects of RAMP2 and RAMP3 on receptor function. The data suggest that targeting the PTH1R/RAMP2 complex may be a promising strategy for developing novel bone anabolic therapies by leveraging biased agonism and functional selectivity. Further research using physiologically relevant models is needed to elucidate the therapeutic potential of this approach.

Capivasertib and fulvestrant for patients with HR-positive/HER2-negative advanced breast cancer: analysis of the subgroup of patients from Japan in the phase 3 CAPItello-291 trial.

BACKGROUND: In CAPItello-291, capivasertib-fulvestrant significantly improved progression-free survival (PFS) versus placebo-fulvestrant in the overall and PIK3CA/AKT1/PTEN-altered population with hormone receptor-positive (HR-positive)/human epidermal growth factor receptor 2-negative (HER2-negative) advanced breast cancer. Capivasertib-fulvestrant is approved in Japan for the treatment of patients with one or more tumor biomarker alterations (PIK3CA, AKT1 or PTEN). Here, we report outcomes in the CAPItello-291 subgroup of patients from Japan. METHODS: Adults with HR-positive/HER2-negative advanced breast cancer whose disease had relapsed or progressed during or after treatment with an aromatase inhibitor, with or without previous cyclin-dependent kinase 4/6 (CDK4/6) inhibitor therapy, were randomly assigned (1:1 ratio) to receive capivasertib or placebo, plus fulvestrant. The dual primary endpoint was investigator-assessed PFS in the overall and PIK3CA/AKT1/PTEN-altered population. Safety was a secondary endpoint. RESULTS: Of 708 patients randomized in CAPItello-291, 78 were from Japan (37 randomized to capivasertib-fulvestrant and 41 to placebo-fulvestrant). In the Japan subgroup, PFS numerically favored the capivasertib-fulvestrant arm (hazard ratio 0.73; 95% CI 0.40-1.28), consistent with the analysis of PFS in the global population. Similarly, in the Japan subgroup of patients with PIK3CA/AKT1/PTEN-altered tumors, PFS favored the capivasertib-fulvestrant arm (hazard ratio 0.65; 95% CI 0.29-1.39), consistent with the global population. The adverse event profile of capivasertib-fulvestrant in the Japan subgroup was broadly similar to that in the global population; no new safety concerns were identified. CONCLUSION: Outcomes in the Japan subgroup were broadly similar to those of the global population, supporting the clinical benefit of capivasertib-fulvestrant in treating HR-positive/HER2-negative advanced breast cancer that has progressed on, or after, an endocrine-based regimen.

Molecular characterization and stage-dependent gene expression of gonadotropin receptors in Pacific bluefin tuna, Thunnus orientalis, ovarian follicles.

To understand the physiological mechanisms by which pituitary-derived gonadotropins (Gths), follicle-stimulating hormone (Fsh) and luteinizing hormone (Lh) regulate asynchronous oocyte development, we investigated the function and expression of Fsh and Lh receptors (Fshr and Lhr, respectively) in Pacific bluefin tuna (PBT, Thunnus orientalis). As a first, we cloned the full-length cDNAs encoding PBT Fshr and Lhr. Recombinant PBT Fsh and Lh single-chain proteins were produced in abundance using stable CHO-DG44 cell lines and were subsequently purified from the culture medium, culminating in their yields being 87.0 and 88.2%, respectively. An in vitro reporter assay using homologous recombinant Gths revealed that PBT Fshr and Lhr responded strongly to their corresponding ligands in a dose-dependent manner, with no cross-activation over a wide range of concentrations. Moreover, quantitative expression analysis of Fshr and Lhr at the follicle level showed that fshr gene expression was highly upregulated in the ovarian follicles through vitellogenesis, while lhr expression was significantly upregulated and peaked in fully vitellogenic ovarian follicles. These findings suggest that asynchronous-type oocyte development is primarily attributed to the differential function and expression of Gthrs, rather than the ligand, in PBT.

Triple-Negative Papillary Carcinoma of the Breast: A Case Report.

Papillary carcinoma is a rare form of breast malignancy, representing only a small percentage of newly diagnosed breast cancers. Bloody nipple discharge is the most consistent symptom reported among patients. These lesions are visualized histologically as fibrovascular cores lined with proliferating neoplastic epithelial cells. Papillary breast carcinomas are characterized by estrogen receptor (ER), progesterone receptor (PR), and/or human epidermal growth factor receptor 2 (HER2) positivity, allowing for targeted therapeutic approaches with favorable outcomes. Triple-negative papillary carcinoma (TNPC) is a rare variant that lacks this characteristic hormone receptor expression, creating a unique challenge in diagnosis and management. Here, we highlight the case of a 43-year-old asymptomatic female with TNPC following an abnormal screening mammogram that revealed a suspicious mass in the left breast. Surgical excision with clear margins remains the cornerstone of treatment, with adjuvant chemotherapy considered for high-risk cases. As there is limited evidence on the efficacy of targeted therapies and hormone-based treatments, this case analyzes the diagnostic criteria, therapeutic options, and prognosis of TNPC to prompt further investigation into specific treatment strategies.

Thyroid Endocrine Disruption and Mechanism of the Marine Antifouling Pollutant 4,5-Dichloro-2-n-octyl-4-isothiazolin-3-one.

The antifoulant 4,5-dichloro-2-n-octyl-4-isothiazolin-3-one (DCOIT) is an emerging pollutant in the marine environment, which may disrupt the thyroid endocrine system. However, DCOIT toxicity in relation to thyroid endocrine disruption and the underlying mechanisms remains largely unclear. In this study, in vivo, in silico, in vitro, and ex vivo assays were performed to clarify DCOIT's thyroid toxicity. First, marine medaka (Oryzias melastigma) were exposed to environmentally realistic concentrations of DCOIT for an entire life cycle. The results demonstrated that DCOIT exposure potently stimulated the hypothalamic-pituitary-thyroid axis, characterized by hyperthyroidism symptom induction and prevalent key gene and protein upregulation in the brain. Moreover, the in silico and in vitro results evidenced that DCOIT could bind to thyroid hormone receptor ß (TRß) and interact synergistically with triiodothyronine, thus promoting GH3 cell proliferation. The CUT&Tag experiment found that DCOIT interfered with the affinity fingerprint of TRß to target genes implicated in thyroid hormone signaling cascade regulation. Furthermore, ex vivo, Chem-seq revealed that DCOIT directly bound to the genomic sequences of thyrotropin-releasing hormone receptor b and thyroid-stimulating hormone receptor in marine medaka brain tissues. In conclusion, the current multifaceted evidence confirmed that DCOIT has a strong potency for thyroid endocrine system disruption and provided comprehensive insights into its toxicity mechanisms.

Effects of L-NAME and air exposure on mitochondrial energetic markers, thyroid hormone receptor/regulator system and stress/ease-responsive receptor expression in the brain/gut axis of zebrafish.

As a signal molecule, nitric oxide (NO) has several physiological actions in fish. However, the action of NO on the brain/gut axis, a classic inter-organal axis that bridges the gastrointestinal tract and the CNS, still requires more understanding. The short-term in vivo action of a NO inhibitor, N-omega-nitro-L-arginine methyl ester (L-NAME), on mitochondrial energetic markers and the receptor expression of thyroid hormone (TH) and neuroendocrine hormones involved in stress/ease response was tested in the brain/gut axis of zebrafish exposed to either in non-stressed or air-exposed condition. L-NAME treatment decreased the NO content in brain and gut segments in non-stressed fish but rose upon L-NAME treatment in air-exposed fish that corresponded with the activation of inos, nnos, hif1a and hif1an transcript expressions. The brain/gut segments that showed spatial and differential sensitivity to L-NAME, modified the transcript expression patterns of stress (adra2da, adrb1, nr3c2)- and ease-responsive (htr2b, slc6a4a, mtnr1aa) hormone receptors. The expression pattern of the TH receptor/regulator system (thra, thrb, dio1, dio2, dio3) becomes more active in gut segments than brain segments upon L-NAME challenge in stressed zebrafish. The data provide evidence for a novel role of NO as an integrator of brain/gut axis segments in zebrafish, where the endogenously produced NO in mid-brain/posterior-gut axis aligns together upon air-exposure stress, providing a lead role to the posterior gut that activates and directs the neuroendocrine receptor expressions of stress/ease responsive genes. The data further invites studies exploring the therapeutic potential of L-NAME in this biomedical model to control the brain/gut axis segments.

Neoadjuvant Chemotherapy with Concurrent Letrozole for Estrogen Receptor-Positive and HER2-Negative Breast Cancer: An Open-Label, Single-Center, Nonrandomized Phase II Study (NeoCHAI).

The role of combining neoadjuvant endocrine therapy with conventional chemotherapy remains unclear; therefore, we conducted an open-label, single-center, nonrandomized phase II trial to assess the effect of this combination. Patients with previously untreated stage II or III HR-positive, HER2-negative breast cancer received concurrent letrozole 2.5 mg with standard neoadjuvant chemotherapy. The primary endpoint was pathologic complete response (pCR) at the time of surgery. We used Simon's minimax two-stage design; a pCR rate > 6% was necessary at the first stage to continue. Between November 2017 and November 2020, 53 women were enrolled in the first stage of the trial. Their median age was 49 years (range, 33-63), and 60% of them were premenopausal. Subsequently, 66% and 34% of patients with clinical stages II and III, respectively, were included; 93% had clinically node-positive disease. Two patients (4%) achieved pCR after neoadjuvant chemo-endocrine treatment, which did not satisfy the criteria for continuing to the second stage. The overall response rate was 83%. During the median follow-up of 53.7 months, the 3-year disease-free survival and overall survival rates were 87% and 98%, respectively. Neutropenia was the most common grade 3/4 adverse event (40%), but rarely led to febrile neutropenic episodes (4%). Myalgia (32%), nausea (19%), constipation (17%), heartburn (11%), oral mucositis (9%), and sensory neuropathy (9%) were frequently observed, but classified as grade 1 or 2. No deaths occurred during preoperative treatment. The addition of letrozole to standard neoadjuvant chemotherapy was safe and beneficial in terms of overall response rate, but did not provide a higher pCR rate in locally advanced HR-positive, HER2-negative breast cancer. Further research is needed to enhance neoadjuvant treatment strategies for this cancer subtype.

Shifting the Paradigm: The Transformative Role of Neoadjuvant Therapy in Early Breast Cancer.

The use of neoadjuvant systemic therapy (NST) has become increasingly important in the treatment of breast cancer because of its various advantages. These include the ability to downstage tumors without compromising locoregional control and the potential to obtain valuable information about clinical and biological response to therapy with implications for individual prognoses. Surgical response assessment paves the way for response-adapted therapy, and pathological complete response (pCR; defined as ypT0/is ypN0) serves as an additional endpoint for drug development trials. Recommended NST regimens commonly consist of anthracyclines and taxane, with dose-dense anthracyclines and weekly paclitaxel often preferred, whenever feasible. For patients with human epidermal growth factor receptor-2 (HER2)-positive tumors, dual anti-HER2 therapy (trastuzumab and pertuzumab) is indicated together with NST in case of elevated risk of recurrence. For patients with triple-negative breast cancer (TNBC), adding carboplatin to NST correlates with improved pCR and survival rates, as does the addition of immune checkpoint inhibitors. For hormone receptor (HR)-positive/HER2-negative cancers, emerging data on NST including immune checkpoint inhibitors may elevate the significance of NST in high-risk luminal breast cancer. Here, we present a synthesis of the results from neoadjuvant clinical trials that aim at optimizing treatment options for patients with high-risk breast cancer.

The molecular mechanisms of TRß receptor interaction with polychlorinated biphenyls: A multispectral and computational exploration.

The thyroid hormone (TH) system is susceptible to the toxic effects of polychlorinated biphenyls (PCBs). Pollutants may disrupt the TH system by binding to serum TH transport proteins or interacting with thyroid hormone receptors (TRs) in target cells. However, the molecular mechanism of interaction with the Thyroid Hormone Receptor Beta (TRß) is not fully understood. This study employed fluorescence, UV-visible absorption, three-dimensional fluorescence, and Fourier-transform infrared spectroscopy, along with molecular docking and molecular dynamics simulations, to investigate the interaction between TRß and PCBs. Moreover, molecular docking and fluorescence resonance energy transfer (FRET) findings suggest that TRß and PCBs underwent resonance energy transfer consistent with Förster's theory. The root mean square deviation (RMSD) and docking outcomes indicate that the TRß-PCB29 complex exhibited optimal structural stability. Thus, the study concludes that integrating spectroscopic data with molecular docking is essential for a comprehensive analysis. Further analysis of intermolecular interactions using quantum chemistry and reduced density gradient analysis (RDG) analysis revealed that van der Waals forces are the primary drivers of PCBs to TRß.

Breast cancer drugs: FDA approval, development time, efficacy, clinical benefits, innovation, trials, endpoints, quality of life, value, and price.

OBJECTIVE: This study analyzes the development, benefits, trial evidence, and price of new breast cancer drugs with US Food and Drug Administration (FDA) approval. METHODS: We identified 26 drugs with 42 FDA-approved indications for early and metastatic breast cancer (2000-2023). Data were collected from FDA labels, clinicaltrials.gov, and Medicare and Medicaid. Overall survival (OS) and progression-free survival (PFS) hazard ratios (HRs) and tumor response's relative risk (RR) alongside objective response rate (ORR) were meta-analyzed. RESULTS: The median development time for breast cancer drugs was 7.8 years (95% CI 6.2-10.8). 26% of treatments were considered innovative ("first-in-indication") with 88% acting via a targeted mechanism. 64% were small molecules, 19% antibodies, and 18% antibody-drug conjugates. 38% were approved for HR + and 31% for HER2 + breast cancer. 6 indications were for early and 36 for metastatic breast cancer. Indications utilized FDA's special programs: orphan (2%), fast track (24%), accelerated approval (19%), priority review (74%), breakthrough therapy (44%). Approval was predominantly supported by phase 3 trials (88%) of randomized controlled design (66%), enrolling a median of 585 patients (IQR 417-752) at 181 centers (IQR 142-223) across 19 countries (IQR 17-20). New drugs' HR were 0.78 for OS (95% CI 0.74-0.82) and 0.59 for PFS (95% CI 0.54-0.64) with a RR for tumor response of 1.61 (95% CI 1.46-1.76). Median improvements of OS were 2.8 months (IQR 1.8-5.8) and PFS were 4.4 months (IQR 2.2-7.1). In single-arm trials, the average ORR was 31% (95% CI 10-53). In meta-regressions, the correlation between OS/PFS was 0.34 (p = 0.031) and OS/response was 0.01 (p = 0.435). 60% of treatments had a 'high-value' ESMO-MCBS score with 14% demonstrating improvements in quality of life. The median price was $16,013 per month (95% CI 13,097-17,617). There was no association between prices and patient benefit. The median value per life year gained was $62,419 (IQR 25,840-86,062). CONCLUSIONS: Over the past two decades, the development of innovative and effective drugs transformed the treatment landscape for breast cancer patients. Yet, investigators and regulators must safeguard that highly-priced new drugs demonstrate improvements in patient-centered clinical endpoints: overall survival and quality of life.

Genome editing of porcine zygotes via lipofection of two guide RNAs using a CRISPR/Cas9 system.

CRISPR/Cas9-based multiplex genome editing via electroporation is relatively efficient; however, lipofection is versatile because of its ease of use and low cost. Here, we aimed to determine the efficiency of lipofection in CRISPR/Cas9-based multiplex genome editing using growth hormone receptor (GHR) and glycoprotein alpha-galactosyltransferase 1 (GGTA1)-targeting guide RNAs (gRNAs) in pig zygotes. Zona pellucida-free zygotes were collected 10 h after in vitro fertilization and incubated with Cas9, gRNAs, and Lipofectamine 2000 (LP2000) for 5 h. In Experiment 1, we evaluated the mutation efficiency of gRNAs targeting either GHR or GGTA1 in zygotes transfected using LP2000 and cultured in 4-well plates. In Experiment 2, we examined the effects of the culture method on the development, mutation rate, and mutation efficiency of zygotes with simultaneouslydouble-edited GHR and GGTA1, cultured using 4-well (group culture) and 25-well plates (individual culture). In Experiment 3, we assessed the effect of additional GHR-targeted lipofection before and after simultaneous double gRNA-targeted lipofection on the mutation efficiency of edited embryos cultured in 25-well plates. No significant differences in mutation rates were observed between the zygotes edited with either gRNA. Moreover, the formation rate of blastocysts derived from GHR and GGTA1 double-edited zygotes was significantly increased in the 25-well plate culture compared to that in the 4-well plate culture. However, mutations were only observed in GGTA1 when zygotes were transfected with both gRNAs, irrespective of the culture method used. GHR mutations were detected only in blastocysts derived from zygotes subjected to GHR-targeted lipofection before simultaneous double gRNA-targeted lipofection. Overall, our results suggest that additional lipofection before simultaneous double gRNA-targeted lipofection induces additional mutations in the zygotes.

Growth hormone is involved in GATA1 gene expression via STAT5B in human erythroleukemia and monocytic cell lines.

GATAs are a family of transcription factors consisting of six members. Particularly, GATA1 and GATA2 have been reported to promote the development of erythrocytes, megakaryocytes, eosinophils, and mast cells. However, little information is available on the extracellular ligands that promote GATA1 expression. We evaluated whether growth hormone (GH) is an extracellular stimulator that participates in the signal transduction of GATAs, focusing on GATA1 expression in hematopoietic cell lineages. We used a reporter assay, RT-PCR, real-time quantitative PCR, and western blotting to evaluate GH-induced expression of GATA1 and GATA2 in the human erythroleukemic cell line K562 and the non-erythroid cell line U937. GATA1 expression in these hematopoietic cell lines increased at the transcriptional and protein levels in the presence of GH, and was inhibited by a STAT5 specific inhibitor. Cells transfected with activated STAT5B showed increased expression of GATA1. We identified functional STAT5B consensus sequences as binding site-158 bp from the transcription starting site in the GATA1 promoter region. These results suggest that GH directly induces GATA1 expression via GHR/JAK/STAT5 and is related to hematopoietic cell proliferation.

A triple hormone receptor ER, AR, and VDR signature is a robust prognosis predictor in breast cancer.

BACKGROUND: Despite evidence indicating the dominance of cell-of-origin signatures in molecular tumor patterns, translating these genome-wide patterns into actionable insights has been challenging. This study introduces breast cancer cell-of-origin signatures that offer significant prognostic value across all breast cancer subtypes and various clinical cohorts, compared to previously developed genomic signatures. METHODS: We previously reported that triple hormone receptor (THR) co-expression patterns of androgen (AR), estrogen (ER), and vitamin D (VDR) receptors are maintained at the protein level in human breast cancers. Here, we developed corresponding mRNA signatures (THR-50 and THR-70) based on these patterns to categorize breast tumors by their THR expression levels. The THR mRNA signatures were evaluated across 56 breast cancer datasets (5040 patients) using Kaplan-Meier survival analysis, Cox proportional hazard regression, and unsupervised clustering. RESULTS: The THR signatures effectively predict both overall and progression-free survival across all evaluated datasets, independent of subtype, grade, or treatment status, suggesting improvement over existing prognostic signatures. Furthermore, they delineate three distinct ER-positive breast cancer subtypes with significant survival in differences-expanding on the conventional two subtypes. Additionally, coupling THR-70 with an immune signature identifies a predominantly ER-negative breast cancer subgroup with a highly favorable prognosis, comparable to ER-positive cases, as well as an ER-negative subgroup with notably poor outcome, characterized by a 15-fold shorter survival. CONCLUSIONS: The THR cell-of-origin signature introduces a novel dimension to breast cancer biology, potentially serving as a robust foundation for integrating additional prognostic biomarkers. These signatures offer utility as a prognostic index for stratifying existing breast cancer subtypes and for de novo classification of breast cancer cases. Moreover, THR signatures may also hold promise in predicting hormone treatment responses targeting AR and/or VDR.

Major pathologic response and long-term clinical benefit in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer after neoadjuvant chemotherapy.

BACKGROUND: The majority of HR+/HER2-breast cancer patients can also achieve long-term survival despite not attaining pCR, indicating limited prognostic value of pCR in this population. This study aimed to identify novel pathologic end points for predicting long-term outcomes in HR+/HER2-breast cancer after neoadjuvant chemotherapy. METHODS: We analyzed HR+/HER2-breast cancer patients with stage II-III tumors who underwent curative surgery after neoadjuvant chemotherapy from three hospitals. Major pathologic response (MPR), defined as the presence of Miller-Payne grades 3-5 and positive lymph node ratio of ≤10 %, was used as a pathological evaluation indicator. We assessed the association between MPR and event-free survival (EFS) and performed Multivariable Cox regression to identify independent factors associated with EFS. RESULTS: From January 2010 to December 2020, 386 patients were included in the final analysis. 28 patients (7.3 %) achieved pCR and 118 patients (30.6 %) achieved MPR. The median duration of follow-up was 54.4 months,5-year EFS was 87 % in the MPR group vs. 68 % in the non-MPR group. Multivariate analysis showed that low PR expression, high clinical stage, lower Miller-Payne grades and Positive lymph node ratio were independent poor prognostic factors for EFS (all P values < 0.05). The prognostic effect of MPR remained in multivariable models (hazard ratio (HR), 0.45; 95 % confidence interval (CI), 0.26-0.76; P = 0.008), In non-pCR patients, those who achieved MPR exhibited a similar EFS compared with pCR patients (HR, 2.25; 95 % CI, 0.51-9.84; P = 0.28). CONCLUSION: MPR may be a novel pathologic end point in HR+/HER2-breast cancer after neoadjuvant chemotherapy, holding greater applicability in the prognosis evaluation than pCR.

Patient-reported outcome and survival in premenopausal hormone receptor-positive breast cancer patients at moderate to high risk: comparing toremifene with aromatase inhibitor in a real-world study.

Toremifene, a selective estrogen receptor modulator, is commonly used in China for premenopausal breast cancer patients. This real-world study aimed to compare patient-reported outcome (PRO) and survival between toremifene and aromatase inhibitor (AI) plus ovarian function suppression (OFS) in patients with moderate-/high-risk premenopausal hormone receptor (HR)-positive breast cancer. The primary endpoint was PROs, assessed using SF-36 and EQ-5D-5L questionnaires between January and March 2023. A total of 392 patients were included, with 171 receiving toremifene and 221 receiving AI. The toremifene group showed significantly higher scores in the role physical (p = 0.034) and mental health (p = 0.009) dimensions of SF-36 and lower anxiety/depression (AD) scores (p = 0.038) in EQ-5D-5L compared to AI group. The estimated 5- and 8-year disease-free survival (DFS) rates were similar in toremifene and AI groups: 96.5% versus 91.9%, and 87.4% versus 87.8% (p = 0.39), respectively. Adverse event rates were similar in two groups, except for a greater risk of endometrial thickening (p < 0.001) and a lower occurrence of morning stiffness (p < 0.001) in the toremifene compared to the AI group. Premenopausal HR-positive breast cancer patients receiving toremifene plus OFS had better role physical and mental health outcomes and lower AD dimensions than those receiving AI plus OFS. Both treatments had comparable DFS and favorable tolerability profiles.