Search Results (88)

Background: The role of neoadjuvant endocrine therapy (NET) in patients with luminal tumors is still not well defined in everyday clinical practice. To assess the efficacy of combination NET, we analyzed the outcomes of fulvestrant and aromatase inhibitors (AI) in combination in a real-world population. Methods: This was a single-arm, retrospective longitudinal study of the total population of patients diagnosed with locoregionally advanced, clinical stage II-III, HR+ HER2-, luminal-type eBC, who were treated with the neoadjuvant combination of fulvestrant and AI between 2019 and 2024 at the Clinical University Hospital of Split, Croatia. Results: We enrolled 44 patients in the intention-to-treat (ITT) population, while 34 completed NET and surgery (per-protocol population; PPP). The median duration of NET was 11 months (interquartile range [IQR] of 9–16 months). The best radiological objective response rate (partial or complete response) was achieved by 30 (68.2%) in ITT, and 26 (76.5%) in PPP, defined by radiological examination, breast ultrasound, or MR. In the PPP, the minimal or moderate pathological response according to residual cancer burden (I or II) was observed in 29 (85.3%) patients. The median of absolute changes in Ki-67 was −5 (95% CI: −9 to 0), and the median of relative Ki67 changes was −40% (95% CI: −72% to 0%). Post-surgical Ki-67 was significantly predicted by initial Ki-67, positive lymph nodes, and time from diagnosis to the initiation of NET. Treatment was well tolerated, with no therapy discontinuation or dose reductions needed due to toxicity. The most commonly reported side effects included musculoskeletal pain (45.5%), asthenia (34.1%), and hot flashes (29.5%). Conclusions: Dual hormonal therapy with fulvestrant and AI is an active, easily given, non-toxic, promising neoadjuvant treatment in real-world patients with locally advanced luminal-type eBC who are not candidates for chemotherapy. Full article

Treatment with endocrine therapy (ET) in combination with CDK4/6 inhibitors has improved the outcome of patients with hormone receptor (HR)+/HER2- advanced breast cancer (ABC), but most patients eventually experience disease progression. Since the PI3K-AKT-mTOR (PAM), estrogen receptor (ER), and cyclin-dependent kinase (CDK) pathways are interdependent drivers of HR+/HER2- breast cancer (BC), the simultaneous inhibition of these pathways is expected to enhance anti-tumor control. Here we investigated the molecular and cellular effects of gedatolisib, a multi-target kinase inhibitor of the PAM pathway currently being evaluated in Phase 3 clinical trials, combined with fulvestrant and/or palbociclib in BC cell models. We found that the gedatolisib/fulvestrant/palbociclib triplet inhibited BC cell growth significantly more than the single agents or the palbociclib/fulvestrant doublet, both in vitro and vivo. Specifically, the triplet combination counteracted adaptive responses associated with single drug treatment, such as the reactivation of the CDK-RB-E2F pathway after palbociclib treatment, and inhibited multiple cellular functions, such as cell cycle progression, cell survival, protein synthesis, and glucose metabolism. The triplet combination was effective in treatment-naïve BC cell lines as well as in cell lines adapted to palbociclib and/or fulvestrant, regardless of PIK3CA/PTEN genetic alterations. Our findings provide a mechanistic rationale for conducting clinical studies evaluating gedatolisib in combination with CDK4/6 inhibitors and ET in HR+/HER2- ABC. Full article

Background and Objectives: Standard treatment in metastatic breast cancer with positive estrogen receptors and negative HER2neu is represented by CDK4 inhibitors combined with aromatase inhibitors or fulvestrant. Palliative radiotherapy is indicated for symptoms or local–regional control. Multiple preclinical data suggest a potential synergistic effect when CDK4/6 inhibitors and radiotherapy are administered concurrently. We are trying to address some questions and/or to establish correlations within a subgroup of patients with unusual toxicities, the safety of combined treatments, the correlation with radiotherapy techniques and fractionation schemas. Also, we are aware that some organs at risk of a rapid turnover are more vulnerable to the occurrence of acute toxicities. Materials and Methods: This retrospective study includes 20 patients with metastatic breast cancer, treated with CDK4 inhibitors and radiotherapy on 29 disease sites; we followed the compliance and toxicities of combined treatments. Results: Regarding the recorded hematological toxicities, grade 1 associated with CDK4 inhibitors, occurring anterior radiotherapy was recorded; grade 2, leucopenia during radiotherapy presented in three cases without radiotherapy interrupting and leucopenia with neutropenia grade 3 presented in one case after pleural secondary lesion’s irradiation. Non-hematological grade 3 toxicities occurred in two cases: one case with grade 3 enteritis, at 2 weeks from bone metastases irradiation—iliac bone (in field toxicity) and one case with radiodermitis during radiotherapy on the breast and lymph node level, in the second week of external radiotherapy (RTE). Conclusions: In all analyzed cases, we obtained control of irradiated lesions. Secondary toxicities occurred only in irradiated areas. A close monitoring of patients during combined treatment must be considered and we are confident that in the future it will be possible to identify the subgroup of patients with a high risk of unusual toxicities occurring; additionally, we hope that using more conforming radiotherapy techniques minimizes the organ being at risk from radiation doses. Full article

Background: Palbociclib, when combined with endocrine therapy, represents a valuable treatment option for patients diagnosed with hormone receptor (HR) positive/human epidermal growth factor receptor 2 (HER2) negative advanced breast cancer (BC) or metastatic breast cancer (MBC). Approved in Europe following phase II/III trials, it became the first CDK4/6 inhibitor used alongside hormone therapy. Available real-world data demonstrate the strong performance of Palbociclib in unselected, heavily pretreated patient groups. Our retrospective, observational, multicenter study, conducted in six Romanian institutions during a follow-up period of 2.5 years, aimed to assess Palbociclib’s safety and effectiveness in clinical practice. Objectives: The primary endpoints included response rate such as overall response rate (ORR), duration of response (DOR), disease control rate (DCR) and best clinical response (BCR), progression free survival (PFS) and overall survival (OS). The secondary objectives focused on treatment duration with aromatase inhibitors (AI) or fulvestrant and subsequent therapies after disease progression. Grade 3/4 adverse events were individually recorded. Exploratory analysis evaluated the potential predictive biomarkers such as Ki67, lower levels of HER2 expression (HER2-low), and histological or luminal subtype. Methods: Approximately 650 patients were planned for inclusion. PFS and OS were analyzed via the Kaplan–Meier method, with median times, 1- and 2-year estimates, and 95% confidence intervals reported. Conclusions: This study supports the integration of clinical trial evidence into real-world settings, enhancing patient selection and treatment personalization. Full article

A 56-year-old female with a history of Luminal A breast cancer, previously treated with surgery, radiotherapy, and systemic therapy, underwent palliative re-irradiation in November 2024 for painful bone metastases. Three weeks later, following the initiation of Fulvestrant, she developed a grade 3 erythematous reaction localized to the re-irradiated area. The reaction persisted with minimal improvement over two months, despite symptomatic management. No infectious or allergic etiologies were identified, and dosimetric analysis confirmed that the delivered radiation dose to the skin was insufficient to directly induce such a reaction. Notably, the erythema was most pronounced along a pre-existing surgical scar, suggesting a localized inflammatory response. Given the temporal relationship with Fulvestrant administration, we hypothesize a drug-induced recall-like phenomenon, though no previous reports have specifically linked Fulvestrant to such an event. This case underscores the need for awareness of unexpected cutaneous reactions following re-irradiation and highlights the potential role of systemic therapies in modulating local tissue responses. Full article

Labisia pumila var. alata (LP) is an herbaceous shrub commonly used by women to promote health and vitality, alleviate postmenopausal symptoms, and enhance libido. Research indicates that LP possesses significant oestrogenic and antiproliferative properties towards breast cancer; however, the specific mechanisms involved remain unclear. We investigate the oestrogenic effects of LP in inducing apoptosis in human breast adenocarcinoma (MCF-7) cells and the mechanisms underlying this process. Docking analysis reveals that the phytoestrogens in LP can bind to oestrogen receptors (ER), specifically ERα and ERβ. MTT assays demonstrate that LP has a dose- and time-dependent antiproliferative effect on MCF-7 cells. Furthermore, the antiproliferative activity of LP on MCF-7 cells is inhibited by Fulvestrant, indicating that its effects are mediated through oestrogen receptors. Flow cytometry analysis shows that the antiproliferative effect of LP results from the induction of apoptosis in MCF-7 cells. The activation of caspase 3, along with caspase 8 and caspase 9, suggests that LP triggers apoptosis through both intrinsic and extrinsic pathways. The findings regarding the aqueous extract of LP and its impact on the proliferative activity of MCF-7 cells may have significant therapeutic and preventive implications for future drug development, particularly in the context of breast cancer. Full article

Approximately 70–80% of breast cancers are estrogen receptor-positive (ER+), with 65% of these cases also being progesterone receptor-positive (ER+PR+). In most cases of ER+ advanced breast cancer, endocrine therapy (ET) serves as the first-line treatment, utilizing various drugs that inhibit ER signaling. These include tamoxifen, a selective estrogen receptor modulator (SERM); fulvestrant, a selective estrogen receptor degrader (SERD); and aromatase inhibitors (AIs), which block estrogen synthesis. However, intrinsic or acquired hormone resistance eventually develops, leading to disease progression. The combination of ET with cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) has been shown to significantly increase progression-free survival (PFS) and, in some cases, overall survival (OS). CDK4/6is works by arresting the cell cycle in the G1 phase, preventing DNA synthesis, and enhancing the efficacy of ET. This review highlights the key mechanisms of resistance to ET, whether used alone or in combination with biological agents, as well as emerging therapeutic strategies aimed at overcoming resistance. Addressing ET resistance remains a work in progress, and in the near future, better patient selection for different therapeutic approaches is expected through the identification of more precise biological and genetic markers. In particular, liquid biopsy may provide a real-time portrait of the disease, offering insights into mechanisms driving ET resistance and cancer progression. Full article

Background: Fibroblast growth factor (FGF) signaling plays a crucial role in several cellular functions in cancer cells. Tasurgratinib, formerly known as E7090, is an orally available FGF receptor (FGFR)1–3 selective inhibitor. Here, we present the effects of tasurgratinib on the resistance to CDK4/6 inhibitors and endocrine therapy (ET) in a preclinical model. Methods: Estrogen receptor (ER)⁺ breast cancer (BC) patient-derived xenograft (PDX) models harboring ESR1 wild-type or ESR1 mutation were used as animal models. An in vitro cell proliferation assay of ER⁺ BC cell lines treated with fulvestrant or palbociclib + fulvestrant was conducted in the presence of FGF2 and FGF10, with or without tasurgratinib. Results: Among five ER⁺ BC PDX models, OD-BRE-0438 and OD-BRE-0704 showed higher sensitivities to tasurgratinib with prior palbociclib + fulvestrant than without it. In these models, palbociclib + fulvestrant treatment upregulated the expression of several FGF ligand mRNAs. In vitro, FGF2 and FGF10 decreased the sensitivity to both fulvestrant and palbociclib + fulvestrant, which was restored by co-treatment with tasurgratinib. Consistently, fulvestrant + tasurgratinib and elacestrant + tasurgratinib showed antitumor activity in ER⁺ BC PDX models harboring ESR1 wild-type and ESR1 mutation, respectively. In these models, fulvestrant or elacestrant upregulated the expression of several FGF ligand mRNAs. Conclusions: FGF signaling plays a role in resistance to CDK4/6 inhibitors and ET in ER⁺ BC. Tasurgratinib has the potential to exhibit significant antitumor activity in combination with ET against ER⁺ BC via FGF signaling inhibition. These findings indicate the therapeutic potential of tasurgratinib in treating ER⁺ BC. Full article

Background: CDK4/6 inhibitors (CDK4/6i) combined with hormone therapies have demonstrated clinical benefit in HR+, HER2- breast cancer patients. However, the onset of resistance remains a concern and highlights a need for therapeutic strategies to improve outcomes. The objective of this study was to develop an in vitro model to better understand the mechanisms of resistance to CDK4/6i + hormone therapies and identify therapeutic strategies with potential to overcome this resistance. Methods: The HR+, HER2− T47D breast cancer cell line genetically modified with a Geminin–Venus reporter construct was treated with CDK4/6i (abemaciclib or palbociclib) in combination with 4-hydroxytamoxifen (tamoxifen). Resistant cells were identified by cell sorting for Geminin (%GEM+), a marker of the S/G2/M phases of the cell cycle, and confirmed by treatment with tamoxifen plus the CDK4/6i used to drive resistance. In resistant cells, following treatment with CDK4/6i + ET (tamoxifen or fulvestrant), the effects on cell proliferation (%GEM+) and viability, gene expression, and protein analysis to evaluate CDK4/6–cyclin D complex composition were examined. Results: Palbociclib + tamoxifen-resistant (PTxR) cells treated with abemaciclib + ET showed decreased %GEM+, %Ki67, and colony formation ability, compared to abemaciclib + tamoxifen-resistant (ATxR) cells treated with palbociclib + ET. Additionally, PTxR cells showed increased CDK4-p21 interaction, compared to ATxR. The CDK6 levels were greater in ATxR cells compared to PTxR cells, associated with CDK4/6i resistance. Additionally, abemaciclib + fulvestrant continued to robustly decrease pRb levels in PTxR models compared to palbociclib + fulvestrant in ATxR models. Transcriptome analysis revealed a depression of the cell cycle and E2F- and Rb-related genes in PTxR cells following treatment with abemaciclib + ET, not present in ATxR cells treated with palbociclib + ET. Both resistant models showed increased EGFR-related gene expression. Conclusion: Taken together, we describe CDK4/6i-dependent mechanisms resulting in early-onset resistance to CDK4/6i + ET, using clinically relevant drug concentrations, in preclinical breast cancer cell models. The characterization of these preclinical models post progression on CDK4/6 inhibitor + ET treatment highlights the potential that the specific sequencing of CDK4/6 inhibitors could offer to overcome acquired resistance to CDK4/6i + ET. Abemaciclib + fulvestrant is currently under clinical investigation in patients with HR+, HER2− breast cancer and progression on prior CDK4/6i + ET (NCT05169567, postMONARCH). Full article

Background: Clinical trials in metastatic hormone receptor-positive (HR+) human epidermal growth factor receptor-2 (HER2)-negative patients have shown that cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors both increase response rates and provide survival benefits. The efficacy of these therapies needs to be supported by real-life data. In this study, we aimed to evaluate treatment response, survival and affecting factors in patients with HR+/HER2− metastatic breast cancer (MBC) who were followed up with CDK 4/6 inhibitors in our center. Materials and methods: A retrospective analysis of 120 patients with HR+/HER2− MBC treated with ribociclib or palbociclib in combination with letrozole or fulvestrant was performed. Results: Median progression-free survival (mPFS) was 24 months in the general population, 27 months in the ribociclib arm and 20 months in the palbociclib arm, with no significant difference in progression-free survival (PFS) in both arms (p = 0.25). The mPFS was longer in the ribociclib + letrozole arm compared to palbociclib + letrozole (27 vs. 20 months, respectively). PFS was also longer in patients receiving ribociclib + fulvestrant compared to palbociclib + fulvestrant but not statistically significant (33 vs. 21 months, respectively). Median overall survival (mOS) was not reached, but 3-year overall survival (OS) was statistically significantly longer in the ribociclib arm (87% vs. 55.5%, respectively, p = 0.03). Conclusion: Palbociclib and ribociclib are first-line treatment options for metastatic HR+/HER2− disease and have similar efficacy. In our study, while the mPFS was not statistically significant in both arms, the 3-year OS rate was higher in the ribociclib arm and statistically significant. Our findings were confirmed in randomized studies comparing both agents head-to-head. Full article

Guidelines for the first-line treatment of Hormone Receptor-positive, HER2-negative advanced or recurrent breast cancer have shifted to combination therapies of a CDK4/6 inhibitor and endocrine therapy. However, determining an optimal subsequent therapy following CDK4/6 inhibitor progression remains challenging, especially for tumors lacking actionable mutations. Real-world data suggest that fulvestrant monotherapy is frequently selected in this post-CDK4/6 inhibitor setting. This review examines its therapeutic potential in this evolving landscape. A systematic literature search using PubMed and ClinicalTrials.gov identified 153 clinical trials published between 2017 and November 2024, from which ten studies met our strict inclusion criteria, focusing solely on fulvestrant monotherapy. These trials encompassed 1038 patients who had prior exposure to CDK4/6 inhibitors. The selected studies were categorized into three groups: monotherapy trials (EMERALD, SERENA-2, AMEERA-3, and ELAINE-1), combination therapy trials (CAPItello-291 and VERONICA), and CDK4/6 inhibitor rechallenge trials (post-MONARCH, PACE, PALMIRA, and MAINTAIN). The median progression-free survival for fulvestrant monotherapy was 3.18 months (range 1.9–5.3 months). Factors affecting the efficacy of fulvestrant monotherapy in second-line therapy include prior treatments, treatment duration, and genetic mutations. Given that the efficacy of fulvestrant was short-lived in the second or subsequent lines, participating in clinical trials is a vital option until a novel alternative treatment choice becomes available. Full article

Background: Adherence to oral anticancer therapies among breast cancer patients is an often-overlooked issue. A lack of patient compliance can be caused by several factors, and may hinder the efficacy of prescribed medication, leading to a shorter than expected survival. In this context, few data about adherence to CDK4/6 inhibitors in real-world practice are available. We report here the results of a retrospective analysis of adherence to abemaciclib plus endocrine therapy in a cohort of women with hormone receptor-positive (HR+), epidermal growth factor 2 negative (HER2−) breast cancer. Methods: Abemaciclib adherence was computed as the ratio between the total number of cycles/months that medication was supplied and the months between the first and the last prescription. The proportion of Days Covered (PDC) ranged from 0 to 1. A score of 0.8 (i.e., 80% adherence rate) was the cutoff used to classify the patients as adherent (0.8 ≤ PDC ≤ 1) or non-adherent (0 ≤ PDC < 0.8). The received dose intensity was also calculated. Results: The abemaciclib pharmacy claims of 100 women with HR+/HER2− breast cancer were retrieved. Most patients (91%) were treated in the advanced setting. Abemaciclib was more frequently taken with an aromatase inhibitor (63%) than with fulvestrant (27%). In this population, the adherence rate was high (92.25% + 1.939 SD). The proportion of non-adherent patients taking abemaciclib with PDC <0.8 was 12%. There was a significative correlation between the occurrence of side effects and the use of <5 drugs for non-oncological illnesses, probably reflecting concomitant non-oncological diseases. Conclusions: Adherence to abemaciclib-based therapy is high in a real-life setting, pending the adequate and proactive management of patients. The careful evaluation of patients and detailed information about expected adverse events are essential to ensure adherence to this antineoplastic agent. Full article

Background and Objectives: Early-onset breast cancer (EOBC), particularly in patients under 40, presents with distinct biological characteristics and worse survival outcomes compared to late-onset cases. Despite intensive treatments, EOBC patients, especially those with hormone receptor-positive, HER2-negative (HR+/HER2-) subtypes, show poorer prognosis. CDK4/6 inhibitors, combined with endocrine therapy (ET) have become the standard for HR+/HER2- metastatic breast cancer, yet younger patients are underrepresented in clinical trials. This study aims to evaluate the efficacy of ribociclib and palbociclib with ET in HR+/HER2- metastatic breast cancer, addressing the critical gap in understanding treatment outcomes in younger patient populations. Materials and Methods: This multicenter, retrospective study evaluated the efficacy and safety of cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors, ribociclib, and palbociclib, in combination with endocrine therapy in patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer. Results: A total of 198 patients treated between 2019 and 2023 were analyzed for progression-free survival, overall survival, and prognostic factors. Very early-onset breast cancer, which is diagnosed before the age of 35, was identified as an independent prognostic factor for poor progression-free survival. Additional factors associated with poorer outcomes included liver metastasis, progesterone receptor negativity, high tumor grade, and the concurrent use of fulvestrant with CDK4/6 inhibitors. Both ribociclib and palbociclib demonstrated similar efficacy, and dose reductions due to treatment-related adverse events did not compromise therapeutic outcomes. Conclusions: This study is the first to focus specifically on the treatment of early-onset breast cancer with CDK4/6 inhibitors, providing critical insights into the unique challenges faced by this patient population. The findings underscore the urgent need for personalized treatment strategies, routine genetic testing, and dedicated clinical trials designed to address the specific needs of these high-risk subgroups. By advancing our understanding of the clinical and molecular landscape of early-onset breast cancer and very early-onset breast cancer, this study lays the groundwork for improving outcomes in these underserved patients through tailored therapeutic approaches. Full article

Background: The treatment of hormone receptor positive (HR+), HER-2 negative metastatic breast cancer (MBC) has radically changed over the last few years. CDK4/6 inhibitors combined with endocrine therapy have become the standard of care as a front-line therapeutic approach, conferring a significant improvement in progression-free survival and overall survival compared to traditional endocrine therapy (ET) alone. However, the wide administration of these drugs in clinical practice paved the way for the emergence of new intrinsic and acquired mechanisms of resistance that seem to compromise second-line treatment effectiveness. In this context, fulvestrant monotherapy appears disqualified. Materials and Methods: we evaluated a population of 30 women currently treated in our oncology unit with HR+/HER2- metastatic breast cancer, receiving fulvestrant 500 mg every 28 days after progression to first-line therapy with CDK 4/6 inhibitors combined with aromatase inhibitors. Results: Of 30 patients observed, 23 progressed to fulvestrant with a median PFS of 3.7 months (range 1–9.7 months). Conclusions: our real-life experience suggests that second-line fulvestrant monotherapy confers very poor disease control and is quite an inadequate therapeutic option. CDK4/6i administration beyond progression could possibly be considered as more valid option, in the absence of targetable mutations or newer, more effective drugs. Full article

Background/Objectives: The first reimbursed prescription for palbociclib (Palbo) in breast cancer patients in Romania was issued in July 2018. The objective of this study is to assess the efficacy, safety, and adherence to Palbo in combination with aromatase inhibitor (AI) or fulvestrant in a real-world cohort of HR+/HER2− breast cancer patients from Romania. Methods: A retrospective analysis of reimbursed Palbo prescriptions was conducted using data extracted from the electronic database of the Romanian Health Insurance House, Dolj County, for disease code 124 (breast cancer), covering the period from 2018 to 2023. The primary outcome assessed was time to treatment discontinuation (TTD), with secondary outcomes including overall survival (OS) and Palbo adherence (which was measured by medication possession ratio). Results: A total of 125 patients were identified, with a median age of 62 years (IQR, 53–70), and 98% were female. Two treatment combinations were observed: Palbo + Aromatase Inhibitor (AI) in 104 patients (83.2%) and Palbo + fulvestrant in 21 patients (16.8%). The median TTD for the entire cohort was 19 months (95%CI, 19.3–24.9 months). In patients treated with Palbo + AI, the median TTD was not available/reached [NA] (95%CI, 36.0-NA months). For those receiving Palbo+fulvestrant, the median TTD was 25.0 months (95%CI, 13.0-NR months). No significant differences in TTD were observed among the two treatment combinations (χ² = 1.33, df = 1, log-rank p = 0.249). The 12- and 36-month TTD rates were higher for Palbl combined with AI than combined with fulvestrant: 77.8% [95%CI, 69.7–86.7%] vs. 71.8% [95%CI, 53.6–96.2%], and 56.3% [95%CI, 45.9–69%] vs. 49.7% [95%CI, 29.7–83.2%], respectively. The median OS was 38 months (95%CI, 25.5–50.9). When treatment involved Palbo + AI, the median OS was NA (95%CI, 54.8-NA) months. When treatment involved Palbo + fulvestrant, the median was 50.8 (95%CI, 34.1-NA) months. Related to OS, no significant differences were found between the two types of treatments (log-rank p = 0.638). The 24- and 36-month OS rates were higher for Palbo combined with AI than combined with fulvestrant: 76.9% [95%CI, 69.2–85.5%] vs. 81% [95%CI, 65.8–99.6%], and 67.9% [95%CI, 59.2–77.8%] vs. 65.3% [95%CI, 47.4–90.0%], respectively. The mean adherence in our study was 0.91 ± 0.1. We found no correlation between adherence to Palbo and OS (Spearman’s rho = 0.04, p = 0.593). Conclusions: While both AI and fulvestrant remain viable options, the lack of significant differences in survival between these combinations suggests that treatment choice can be tailored to individual patient needs. Full article