Search Results (103)

Endocrine therapy is the mainstay for estrogen receptor (ER) α-positive breast cancer (BC), yet many patients display acquired resistance. We then screened natural compounds using human ERα-positive BC cells and identified perillyl alcohol (POH), a monoterpene from perilla, that reduces ERα protein levels. Chemoproteome analysis using POH-immobilized nanomagnetic beads revealed adenine nucleotide translocase 2 (ANT2), a mitochondrial inner membrane protein, as a direct target of POH. Molecular dynamics (MD) simulations predicted POH binding to the central pore of ANT2, which functions in ATP transport. ANT2 depletion reduced ERα levels, and public datasets indicate that high ANT2 expression correlates with poor prognosis in ERα-positive BC. POH also inhibited the growth of Tamoxifen- and Fulvestrant-resistant BC cells. RNA sequencing showed that fatty acid elongation-related genes were upregulated in Fulvestrant-resistant cells but downregulated by ANT2 depletion. Both ANT2 depletion and POH treatment led to the accumulation of intracellular lipid droplets in Fulvestrant-resistant cells, consistent with impaired fatty acid elongation. Finally, in silico screening using MD simulations identified venetoclax and nystatin as potential ANT2 pore binders. Both compounds reduced ERα levels in ERα-positive BC cells and increased lipid droplet formation in Fulvestrant-resistant cells. These findings highlight ANT2 as a druggable target against endocrine-resistant BC. Full article

Activating PIK3CA mutations occur in approximately 40% of hormone receptor-positive (HR+)/HER2-negative breast cancers and represent a major driver of endocrine resistance. The PI3Kα-selective inhibitor alpelisib, in combination with fulvestrant, significantly improves progression-free survival in patients with PIK3CA-mutant disease, as demonstrated in the SOLAR-1 trial. However, this therapeutic strategy is frequently complicated by treatment-induced hyperglycemia, a metabolic disturbance that promotes oxidative stress, mitochondrial dysfunction, and inflammatory signaling, thereby increasing cardiovascular vulnerability. Sodium–glucose cotransporter-2 (SGLT2) inhibitors have emerged as cardiometabolic modulators with benefits extending beyond glucose lowering. In this study, we used a human cardiomyocyte in vitro model designed to recapitulate the hyperglycemic metabolic milieu observed in breast cancer patients receiving PI3Kα-targeted therapy, to investigate whether the SGLT2 inhibitor dapagliflozin directly protects cardiomyocytes from alpelisib- and fulvestrant-induced injury. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were cultured under hyperglycemic conditions (25 mM glucose) to mimic the metabolic environment associated with PI3Kα inhibitor-induced dysglycemia. Cells were exposed to alpelisib (100 nM) and fulvestrant (100 nM), alone or in combination, in the absence or presence of dapagliflozin (1 μM). Cardiomyocyte viability was assessed using the MTS assay, mitochondrial function by TMRM-based mitochondrial membrane potential (ΔΨm) measurements, and apoptosis by caspase-3 quantification. Cardiomyocyte injury was evaluated by release of cardiac troponin I and heart-type fatty acid binding protein (H-FABP). Lipid peroxidation markers (MDA and 4-HNE) were measured to assess oxidative membrane damage. Intracellular inflammasome-related signaling (NLRP3 and MyD88) and secreted inflammatory mediators (IL-1β, IL-18, IL-6, TNF-α, and CCL2) were quantified by ELISA. Exposure to alpelisib, particularly in combination with fulvestrant, significantly reduced cardiomyocyte viability, induced mitochondrial depolarization, and increased caspase-3-mediated apoptotic signaling. These alterations were accompanied by elevated lipid peroxidation (MDA and 4-HNE) and increased release of cardiac injury biomarkers (troponin I and H-FABP). Alpelisib-based treatments also activated inflammasome-related signaling, as indicated by increased intracellular NLRP3 and MyD88 levels and enhanced secretion of pro-inflammatory mediators (IL-1β, IL-18, IL-6, TNF-α, and CCL2). Co-treatment with dapagliflozin significantly attenuated these alterations, preserving mitochondrial membrane potential, reducing apoptotic signaling, limiting oxidative membrane damage, and suppressing inflammatory cytokine release. This study provides evidence that alpelisib-based therapy under hyperglycemic conditions is associated with oxidative, mitochondrial, and inflammatory stress responses in human cardiomyocytes, recapitulating key features of cardiometabolic stress relevant to PI3Kα-targeted therapy. Importantly, dapagliflozin markedly attenuated these alterations, supporting a potential cardioprotective role that may extend beyond glycemic control. These findings provide a mechanistic rationale for further investigation of SGLT2 inhibition as a cardiometabolic protective strategy in patients receiving PI3Kα inhibitor-based cancer therapy. Full article

Background: Alpelisib plus fulvestrant improves outcomes in PIK3CA-mutated, hormone receptor-positive, HER2-negative metastatic breast cancer. However, on-target hyperglycemia often leads to dose modification or discontinuation. We aimed primarily to determine whether evening alpelisib after a ≥5 h fast with low-carbohydrate guidance reduces severe hyperglycemia versus standard morning dosing, and secondarily, to assess time to first grade 3–4 hyperglycemia, efficacy, and quality of life (QoL). Methods: ITACA was an open-label, randomized, phase IIb trial in three Croatian centers. Patients progressing on endocrine therapy were randomized 1:1 to evening alpelisib 300 mg after a ≥5 h fast with low-carbohydrate guidance or standard morning alpelisib, both with fulvestrant. The primary endpoint was the exposure-adjusted incidence rate (EAIR) of first grade 3–4 hyperglycemia within 90 days or 30 days post-discontinuation. Secondary endpoints were time to first grade 3–4 hyperglycemia, efficacy, and QoL. Results: Forty-two patients were randomized (21 per arm). Median age was 60 vs. 63 years in the evening vs. morning arms. In the safety set, EAIR of first grade 3–4 hyperglycemia was 378 vs. 742 per 100 person-years (11/21 vs. 14/20 patients with ≥1 event, unadjusted IRR 0.51, 95% CI 0.23–1.12). Adjusted Poisson models favored evening dosing. Analyses suggested delayed onset (median 73 vs. 9.5 days), with no detriment in efficacy or QoL. Conclusions: Evening alpelisib preceded by fasting and low-carbohydrate guidance may improve metabolic tolerability without compromising efficacy or QoL. These findings support evaluation in a larger trial incorporating prospective metabolic adherence and pharmacokinetic assessments. Full article

Most patients with advanced/metastatic hormone receptor-positive, HER2-negative breast cancer receive first-line therapy with cycline-dependent kinase 4/6 inhibitors plus endocrine therapy. Almost universally, these patients eventually progress due to the emergence of resistant cancer clones. Targeting the PIK3CA/AKT1/PTEN pathway is a way of overcoming resistance. Recently, the oral, selective AKT kinase inhibitor capivasertib has been approved for the treatment of estrogen receptor-positive/human HER2-growth factor receptor-2 advanced BC with alterations in PIK3CA/AKT1/PTEN, in combination with fulvestrant after progression on endocrine therapy. We performed a narrative review to recapitulate the available evidence about capivasertib in the management of advanced hormone receptor-positive, HER2-negative breast cancer, focusing on studies that address preclinical rationale, pharmacology, and clinically relevant problems. Full article

Background: The optimal timing of adjuvant chemotherapy after cytoreductive surgery in epithelial ovarian cancer remains uncertain, and perioperative wound-healing responses may transiently create a pro-tumorigenic and drug-resistant microenvironment. This study aimed to characterize time-dependent wound-induced transcriptomic alterations and to identify pharmacologic agents capable of reversing these responses. Methods: An ID8 murine ovarian cancer model was used to compare no treatment, anesthesia alone, and anesthesia plus surgical wounding mimicking futile laparotomy. Tumors were collected at baseline, 1 day (T1), 1 week (T2), and 2 weeks (T3) after intervention. RNA sequencing was performed, and wound-specific differentially expressed genes (WsDEGs) were defined by excluding anesthesia- and progression-related signatures. Functional enrichment analyses were conducted, followed by transcriptome-based drug repurposing using the REMEDY platform to identify compounds predicted to reverse wound-induced gene expression profiles. Results: Surgical wounding significantly increased tumor burden at T1. Transcriptomic analyses revealed distinct, time-dependent wound-associated programs. At T1, WsDEGs were enriched in inflammatory signaling, coagulation, angiogenesis, and immune cell migration, with Vorinostat and Homoharringtonine identified as top candidates to counteract these signatures. At T2, pathways related to cell survival, adhesion, and morphogenesis predominated, with LY-2090314, Artesunate, and Birinapant emerging as potential modulators. At T3, cell-cycle regulation and lipid metabolic pathways were dominant, and Fulvestrant, Atorvastatin, Imatinib, and ABT-737 were predicted to inhibit these processes. Conclusions: Perioperative surgical wounding induces dynamic, stage-specific transcriptomic programs that may promote ovarian cancer progression and alter drug responsiveness. These findings support time-adapted perioperative pharmacologic strategies to optimize postoperative cancer therapy. Full article

Background: Evidence on the efficacy of alpelisib in combination with fulvestrant after progression on CKD4/6 inhibitors (CDK4/6i) is derived from a single non-comparative prospective study. Conversely, the effectiveness of everolimus plus exemestane on PIK3CA-mutant metastatic breast cancer (BC) after CDK4/6i failure has never been investigated in a prospective study. In this retrospective study, we compared alpelisib plus endocrine therapy (ET) with everolimus plus exemestane in patients with PIK3CA-mutant metastatic BC post-CDK4/6i progression. Methods: We tracked 40 patients treated with alpelisib plus ET and 22 treated with everolimus plus exemestane. We further identified 42 patients who did not harbor PIK3CA mutations (PIK3CA-wild-type group) and received everolimus as a subsequent treatment after progression on CDK4/6i. The timeframe spanned from 1st March 2020 to 30th November 2024. Results: The median progression-free survival (PFS) for the alpelisib group was 4.9 months compared to 4.5 months for the everolimus group [Hazard ratio (HR), 1.22; 95% CI, 0.65–2.28; p-value = 0.53]. The median overall survival (OS) was 9.6 months and 18.3 months for alpelisib and everolimus, respectively (HR, 0.67; 95% CI, 0.25–1.76; p-value = 0.47). Median PFS in the PIK3CA-mutant everolimus plus ET group was 4.5 months (95% CI, 2.8–6.7) compared to 5 months (95% CI, 3.5–6.9) for the PIK3CA-wild-type everolimus plus ET group (HR, 0.77; 95% CI, 0.46–1.29; p-value = 0.32). The most common side effects in the alpelisib group were hyperglycemia (57.5%), rash (27.5%), and anorexia (22.5%), while the most common side effects in the everolimus group were fatigue (40.9%) and stomatitis (27.3%). Conclusions: Our results regarding the efficacy of alpelisib plus ET were inferior to those reported in the current literature. Conversely, outcomes of everolimus plus exemestane were consistent with the current literature, denoting that the combination is an acceptable treatment option for patients with PIK3CA-mutant metastatic BC. Full article

Canadian real-world data (RWD) regarding palbociclib as a first-line therapy for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (MBC) is limited. The PALbociclib CANadian (PALCAN) study examined palbociclib utilization patterns as first-line treatment for HR+/HER2− MBC using Alberta health administrative data. The final PALCAN cohort included 472 female patients with a median age of 64 years and a median follow-up time of 22.8 months (IQR: 0.7–88.2). The median (95% CI) duration of treatment was 13.8 (12.7–15.1) months in the overall cohort (IQR: 5.6, 24.8 months), and the probability of treatment discontinuation within the first year was 45%. Aromatase inhibitors (AIs) and fulvestrant were the accompanying endocrine therapies (ETs) in 83% (N = 393) and 14% (N = 64) (15 with unknown accompanying therapy) of patients, respectively. The median duration of treatment for patients receiving an AI as an accompanying therapy was 15.1 (13.6–17.4) months and 7.9 months (5.8–12.6) for patients receiving fulvestrant, which may suggest endocrine resistance in the latter group. The PALCAN data provides insights into practice patterns and the effectiveness of palbociclib as a first-line therapy in female patients with HR+/HER2− breast cancer in the Canadian real-world setting. Full article

Around 30% of patients with hormone receptor-positive (HR+) breast cancer acquire resistance to endocrine therapy combined with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), which are first-line treatments in metastatic settings. Therefore, we aimed to identify loci associated with resistance to endocrine therapy and CDK4/6i; this was achieved using retroviral vectors, which randomly insert gene-disrupting elements into the genome, causing gene expression alterations and potentially leading to therapy resistance. ER-positive ZR75.1 breast cancer cells transduced with retroviral vectors were treated with endocrine (tamoxifen, fulvestrant) or CDK4/6i monotherapies (abemaciclib, palbociclib, ribociclib) or a combination of fulvestrant and ribociclib. DNA was extracted, and virus integration sites (VISs) were characterized according to the detection frequency and read depth using next-generation sequencing (VIS-NGS). Resistance-associated VIS loci were identified when differentially presented in treated samples compared to controls. Well-established tamoxifen resistance genes (BCAR1, BCAR3, EGFR) were detected, enabling the validation of our approach. Thirty-seven VIS loci were associated with resistance to fulvestrant and ribociclib monotherapies. Twenty of these loci were also identified as candidates for resistance to other CDK4/6i and to fulvestrant and ribociclib combination therapy, including TRPS1 and TRIM24—genes that are involved in resistance to endocrine therapy but have not yet been associated with resistance to CDK4/6i. The identification of unique and shared resistance-associated loci highlights the complexity of resistance pathways. Full article

Background/Objectives: The development of effective oncologic therapies with fewer adverse effects is often limited by the intrinsic and acquired resistance of tumor cells. Hybrid molecules, rationally designed to combine different pharmacophores, represent a promising strategy by providing synergistic effects, dose reduction, and a lower risk of resistance. In this study, the antitumor potential and mechanisms of action of 22 novel hybrid compounds derived from xanthene and pyran scaffolds (SJ022–SJ103) were investigated. The hybrids were initially evaluated through in vitro screening in four breast, three ovarian, and two prostate cancer cell lines, followed by the selection of T-47D, OVCAR-3, and LNCaP cells for detailed assays assessing cytotoxicity, apoptosis, cell cycle distribution, DNA damage, caspase-3/7 activity, morphology, and PI3K/AKT/mTOR pathway modulation. Methods: Cytotoxicity assays were performed in the selected cell lines, while mechanistic studies included apoptosis and cell cycle analysis by flow cytometry, γH2AX detection, Western blotting for PI3K/AKT/mTOR pathway proteins, and 3D spheroid assays. Combinatorial effects with hormone therapies (tamoxifen, fulvestrant, and letrozole) and the AKT inhibitor MK2206 were evaluated. AKT silencing by esiRNA and molecular docking was performed to confirm target engagement. Results: SJ028 demonstrated broad activity across all tested cell lines, whereas SJ064 and SJ078 exhibited higher selectivity. Treatments induced apoptosis, S/G2-M arrest, and DNA damage, accompanied by decreased phospho-AKT levels and stable PI3K and mTOR expression. In 3D models, the hybrids increased caspase-3/7 activity and necrotic core expansion. Co-administration with hormone therapies resulted in synergistic effects in breast and ovarian cancer cells, reducing IC₅₀ values by more than 50% in both parental and resistant models, while combinations with MK2206 were antagonistic across all tumor subtypes. AKT silencing abrogated cytotoxicity, and docking confirmed SJ028 binding to AKT. Conclusions: Xanthene- and pyran-based hybrids—particularly SJ028, SJ064, and SJ078—showed strong antitumor activity through apoptosis induction, cell cycle arrest, and PI3K/AKT pathway modulation. Their preserved efficacy in resistant models and synergistic interactions with hormone therapies contrasted with the antagonism observed with AKT inhibition, highlighting their potential as promising candidates for the treatment of hormone-responsive and -resistant cancers. Full article

Background: Ovarian hyperstimulation syndrome (OHSS) remains a major complication during controlled ovarian stimulation, particularly in women with high estradiol levels. This study aimed to investigate whether bazedoxifene or fulvestrant could be effective in preventing OHSS. Methods: Forty 22-day-old Wistar albino rats were randomly assigned to four groups (n = 10 each). Group 1 received saline (negative control). Group 2 received pregnant mare serum gonadotropin (PMSG) plus hCG (positive control). Group 3 received PMSG + hCG plus fulvestrant, and Group 4 received PMSG + hCG plus bazedoxifene. Rat weight, peritoneal fluid, follicle counts, serum estradiol and VEGF levels, and ovarian ER/VEGF immunoreactivity were evaluated. Results: Peritoneal fluid was absent in controls but detected in 80% of positive controls and 40% of both treatment groups. Tertiary follicles and atresia were significantly higher in OHSS rats compared to controls. Fulvestrant reduced stromal ER expression, while bazedoxifene increased it. Both drugs decreased ascites formation and weight gain. Fulvestrant treatment showed unexpectedly elevated serum estradiol levels, likely due to assay interference. Conclusions: Fulvestrant and bazedoxifene may reduce OHSS severity by lowering ascites formation and weight gain. These agents could be potential therapeutic candidates for OHSS with appropriate timing and dosage. Full article

Background/Objectives: Diffuse large B cell lymphoma (DLBCL) is a highly heterogeneous and aggressive lymphoma with a high incidence rate. Although modern therapeutic approaches have significantly improved patient survival rates, treatment relapse and drug resistance remain major clinical challenges. Programmed cell death (PCD) promotes tumorigenesis and regulates the tumor microenvironment (TME) and drug sensitivity. Exploring the application potential of PCD in DLBCL could pave the way for new treatment strategies for this malignancy. Methods: We systematically analyzed 13 types of PCD pathways and integrated transcriptomic and clinical data from 832 DLBCL patients (GSE10846, GSE11318, and GSE87371). A PCD-based prognostic signature, termed the Programmed Cell Death Score (PCDS), was constructed using 20 key PCD-related genes. Its clinical relevance was evaluated through survival analysis, drug response profiling, and tumor immune infiltration assessment using CIBERSORT, ESTIMATE, and ssGSEA algorithms. Results: The PCDS robustly stratified patients by survival and outperformed conventional clinical indicators such as age, stage, Eastern Cooperative Oncology Group (ECOG), and lactate dehydrogenase (LDH) in prognostic prediction. High-PCDS tumors were associated with immune suppression, characterized by reduced CD8⁺ T cell infiltration, elevated M2 macrophages, and increased programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) expression. Drug sensitivity analysis revealed that high-PCDS patients may benefit more from agents like sorafenib and fulvestrant, while low-PCDS patients responded better to NU7441. Functional validation using DLBCL cell lines and xenografts confirmed the oncogenic role of a representative gene (CTH) within the model. Conclusions: This study presents a novel prognostic scoring system derived from multiple PCD pathways that effectively stratifies DLBCL patients by risk and therapeutic responsiveness. Notably, the PCDS is closely associated with key immunological characteristics of the TME. These findings advance personalized treatment strategies and support clinically relevant decision-making in DLBCL. Full article

Low-grade-serous ovarian carcinomas (LGSOC) are rare tumors characterized by a high recurrence rate and limited treatment options. Most LGSOC are estrogen receptor (ER)-positive and demonstrate alterations in the RAS/MAPK pathway. Avutometinib is a dual RAF/MEK clamp, whereas defactinib and VS-4718 are focal adhesion kinase (FAK) inhibitors. Fulvestrant is an ER antagonist/degrader. We assessed the preclinical efficacy of fulvestrant, avutometinib + VS-4718 (FAKi), and the triple combination in a chemotherapy/aromatase inhibitor-resistant LGSOC patient-derived tumor xenograft (PDX) model. Tissue obtained from a LGSOC patient wild-type for KRAS/NRAS/BRAF mutations in progression after chemotherapy/anastrozole was transplanted into female CB17/lcrHsd-Prkdc/SCID mice (PDX-OVA(K)250). The animals were treated with either saline/control, fulvestrant, avutometinib/FAKi, or the triple combination of avutometinib/FAKi/fulvestrant. Avutometinib and FAKi were given five-days on and two-days off through oral gavage. Fulvestrant was administered subcutaneously weekly. Mechanistic studies were performed ex vivo using Western blot assays. Animals treated with the triple combination demonstrated stronger tumor growth inhibition compared to all the other experimental groups including control/saline (p < 0.001), single-agent fulvestrant (p = 0.04 from day eight and onwards), and avutometinib/FAKi (p = 0.02 from day 18). Median survival for mice treated with saline/control was 29 days while mice in all other experimental groups were alive at day 60 (p < 0.0001). Treatment was well tolerated across all experimental treatments. By Western blot, exposure of OVA(K)250 to the triple combination demonstrated a decrease in phosphorylated MEK (p-MEK) and p-ERK levels. The addition of fulvestrant to avutometinib/FAKi is well tolerated in vivo and enhances the antitumor activity of avutometinib/FAKi in a LGSOC-PDX model with acquired resistance to chemotherapy/aromatase inhibitors. These results support the clinical evaluation of avutometinib/defactinib in combination with fulvestrant or an aromatase inhibitor in patients with recurrent LGSOC. Full article

Background/Objectives: Estrogen deficiency-related menopause is associated with various physical and psychological symptoms. Although hormone replacement therapy (HRT) effectively alleviates these symptoms, its long-term use is associated with several side effects such as an increased risk of breast cancer and cardiovascular disease. Consequently, there is a growing interest in some plant-derived phytoestrogens that are considered safer alternatives to estrogen. Recent studies on Scrophularia buergeriana confirmed their anti-inflammatory and antioxidant properties; however, their effects on menopausal health remain unclear. Therefore, the aim of this study was to investigate the estrogen-like effects of S. buergeriana root (SB-R) extract, a potential phytoestrogen. Methods: Briefly, the MCF-7 cell line, a widely used in vitro model for assessing estrogen-like activity, was treated with SB-R extract and 17β-estradiol (E2; positive control) in the presence or absence of ICI 182,780 (Fulvestrant), an estrogen receptor antagonist. An E-screen assay and flow cytometry were performed to assess the effects of the treatments on cell proliferation and the cell cycle, respectively. Additionally, Western blotting and immunofluorescence assays were performed to elucidate the potential mechanisms underlying the estrogen-like effects of SB-R. Result: Treatment with SB-R extract promoted MCF-7 cell proliferation in a manner similar to E2. However, ICI 182,780 co-treatment inhibited the SB-R extract-induced increase in MCF-7 cell proliferation. Additionally, SB-R extract promoted cell cycle progression by increasing the proportion of cells in the S and G2/M phases. Moreover, Western blotting and immunofluorescence assays showed that SB-R extract increased the expression of estrogen receptor alpha (ERα). Furthermore, SB-R treatment activated downstream signaling pathways by enhancing AKT and ERK phosphorylation and upregulated the expression of cell cycle regulators, including cyclin D1, cyclin dependent kinase 4 (CDK4), cyclin E1, and cyclin dependent kinase 2 (CDK2). Conclusions: SB-R exhibits estrogen-like activity by activating ERα-mediated AKT and ERK pathways and thereby increasing the expression of proteins involved in cell cycle regulation. This makes it a promising phytoestrogen candidate and a safer alternative to conventional hormonal therapy for alleviating menopausal symptoms. Full article

HER2-positive breast cancer is an aggressive subtype, often associated with shorter progression-free and overall survival. Estrogen receptor (ER) expression within this subtype leads to distinct growth patterns and treatment responses. Calcitriol, the active form of vitamin D, induces ERα expression in ER-negative breast cancer cells, thereby sensitizing them to the antiproliferative effects of antiestrogens. When combined with neratinib, calcitriol enhanced cell growth inhibition. Therefore, we investigated whether adding calcitriol to the combined treatment with antiestrogens and neratinib could further inhibit the proliferation of HER2-positive breast cancer cells, regardless of their ER status. The BT-474 (ER-positive/HER2-positive) and SK-BR-3 (ER-negative/HER2-positive) breast cancer cell lines were pretreated with calcitriol to modulate ER expression, followed by treatment with calcitriol in combination with neratinib, with or without antiestrogens. Proliferation assays, cell cycle analysis, and Western blotting were then performed to assess treatment effects. The results demonstrated that calcitriol and neratinib, per se, significantly inhibited cell proliferation in a concentration-dependent manner in the HER2-positive cell lines. Notably, calcitriol enhanced the antiproliferative response of combined neratinib and antiestrogen treatment. Calcitriol, alone or in combination, modulated vitamin D receptor and ERα expression, reduced AKT and ERK phosphorylation, and promoted G1 phase arrest. These findings support the potential of this combinatorial approach as a therapeutic strategy for HER2-positive breast cancer. Full article

Breast cancer (BC) is the most common malignancy among Brazilian women, with a high percentage of the cases diagnosed at advanced or metastatic stages (mBC). In Brazil, where 75% of the population depends on the resource-limited public health system (SUS), mBC poses significant treatment challenges and disparities. To characterize this scenario, we conducted an online survey assessing treatment strategies available for HER2-negative, hormone receptor (HR)-positive mBC across public and private health systems. The 48-question survey addressed topics such as waiting time (WT) from oncology unit entry to treatment initiation, availability of oncologic medications, and access to palliative and multidisciplinary care teams. Between 2 August 2022 and 30 September 2022, a total of 180 oncologists were invited, and 150 met the inclusion criteria. The median WT for surgery was 60 days in the SUS versus 30 days in the private sector (p < 0.0001), and for chemotherapy, 30 days in the SUS versus 15 days privately (p < 0.0001). Endocrine therapy was the preferred first-line treatment in the SUS (83.3%), while fulvestrant was available to only 48% of respondents. Additionally, specialized palliative care teams were available according to 66% of SUS respondents compared with 82% in the private system (p = 0.001). These findings underscore persistent disparities in mBC treatment, likely driven by limited governmental health investment. Full article