e15143 Background: Sacituzumab govitecan (SG) is an antibody-drug conjugate approved for advanced triple-negative and HR+/HER2- breast cancer. Its drug, SN-38, is metabolized by UGT1A1. Although some studies suggest higher toxicity in patients carrying the UGT1A1*28 allele, evidence on the impact of UGT1A1 variants on dose management and treatment exposure remains limited. We explored SG safety and tolerability according to UGT1A1 genotype. Methods: We conduct a single-center retrospective observational study of patients with advanced breast cancer treated with SG. Patients are grouped as Normal-Group (NG) (*1/*1) or Risk-Group(RG) (carriers of *28 allele: *1/*28 or *28/*28). In the present analysis we present the data of the first patients included regarding dose reductions due to toxicity, severe adverse events (≥Grade(G)3; CTCAE v5.0), G2, treatment exposure (number of cycles) and Grow-Colony Stimulating Factor (G-CSF) use. Categorical variables were compared using Fisher's exact tests (two sides) and continuous variables using the Mann-Whitney U test (exact two-sided p value). Results: Since June 2025 till beginning January 2026, 17 patients were included (NG n=8; RG n=9). Median age was 48 and 55 years in NG and RG respectively, rest of baseline characteristics were broadly comparable between groups (Table). Dose reductions due to toxicity occurred more frequently in the RG 66.7% vs 37.5 in the NG. Treatment exposure was numerically lower among RG with mean rank number of cycles 6.81 vs 10.19 in the NG. Rates of any ≥G3 toxicity were 44.4% vs 28.6%, ≥G3 neutropenia 33.3% vs 28.6%, and any ≥G2 toxicity 44.4% vs 42.9% respectively for the RG and NG. High G-CSF use was observed in both cohorts (RG 88.9% and NG 83.3%). Conclusions: The presence of the UGT1A1*28 polymorphism in patients treated with SG in our population is associated with frequent toxicity-related dose reductions, lower treatment exposure, and higher rates of ≥G3 toxicities, including ≥G3 neutropenia (although a high use of G-CSF was observed). This study is ongoing, and additional patients are needed to clarify the clinical utility of proactive UGT1A1 genotyping for optimal SG management. Clinical characteristics and UGT polymorphism. UGT1A1 Normal (*1/*1) Risk (*28) p-value ECOG Asymptomatic (0) 7 (87.5%) 4 (44.4%) 0.131 Symptomatic (≥1) 1 (12.5%) 5 (55.6%) Hepatic Metastases No 2 (25.0%) 3 (33.3%) 1.000 Yes 6 (75.0%) 6 (66.7%) Tumoral Burden (n. of metastatic sites) < 3 metastatic sites 4 (50.0%) 5 (55.6%) 1.000 ≥ 3 metastatic sites 4 (50.0%) 4 (44.4%) SG* Line therapy Early (2nd-3rd line) 6 (75.0%) 7 (77.8%) 1.000 Late (≥4th line) 2 (25.0%) 2 (22.2%) HER2 Status HER2-0 (Neg) 3 (37.5%) 5 (55.6%) 0.637 HER2-Low 5 (62.5%) 4 (44.4%)

A mild, sustainable, and cost-effective arylation of rosin-acids is reported. This new approach, based on a regio- and diastereoselective Friedel-crafts alkylation, enabled the synthesis of fourteen new resin acid derivatives. Selected compounds were screened for cytotoxic activity against three human tumor cell lines. Remarkably, quinone 14 exhibited significant activity: Against HL-60 cells (IC₅₀ = 5.94 μM) cell, and phenol 11f displayed selective cytotoxic activity against HT-29 cells (IC₅₀ = 8.90 μM) cells. Flow cytometry confirmed apoptosis as the primary mechanism of cell death, reaching 78% in HL-60 (14) and 72.6% in HT-29 (11 g), with minimal necrosis. Cell-cycle analysis showed S-phase arrest in HL-60 (14) and G0/G1 arrest in HT-29 (11f/11 g). Consistently, ΔΨm assays showed near-complete collapse in HL-60 (14) and significant depolarization in HT-29 (11 g). In addition, the anti-inflammatory activity of some synthesized compounds was assessed in LPS-stimulated RAW 264.7 macrophages. All tested compounds achieved 70-100% NO inhibition at subcytotoxic concentrations. Derivatives 13 and 14 showed the highest activity (IC50 NO = 0.85 μM and 5.43 μM, respectively). Overall, this green arylation approach enables rapid access to 7-aryl methyl ester dehydroabietic acid libraries with significant cytotoxic and anti-inflammatory activities.

Protein kinase C iota (PKCι) is an atypical PKC isoform overexpressed in several human cancers and associated with tumor initiation, maintenance, and resistance to therapy. Meroxest, a synthetic naphthoquinone merosesquiterpene previously shown to exert antitumor activity in breast cancer models, has an incompletely defined mechanism of action. Here, we profiled meroxest against a 410-kinase panel and synthesized a focused set of analogues to obtain preliminary PKCι-oriented structure-activity information. At 10 μM, meroxest reduced PKCι enzymatic activity to 52% of control and Cdc7/cyclin B1 activity to 63%, identifying PKCι as the most inhibited kinase in the panel while also indicating that additional kinase targets may contribute to the biological activity of this scaffold. Docking studies supported a plausible interaction of meroxest within the PKCι catalytic site, including hydrogen-bond contacts with Gly398 and Phe423 consistent with an ATP-competitive binding mode. Biochemical evaluation of a focused library against PKCι at 10 μM showed that preservation of the quinone framework was important for activity, whereas most structural modifications produced only limited changes under the assay conditions used. Compound 19, lacking the methyl substituent on the naphthoquinone ring, showed a modest improvement relative to meroxest. Overall, these results support PKCι as a leading candidate target emerging from the meroxest kinase profile and identify compound 19 as a scaffold for further optimization. Future studies will focus on further optimization to improve the modest PKCι inhibitory potency, evaluate activity against Cdc7/cyclin B1 beyond the parent compound, and validate target engagement in cell-based assays, aiming to identify optimal candidates.

543 Background: Trastuzumab has significantly improved survival in HER2-positive breast cancer patients. However, around 20% of patients experience cardiotoxicity. Cardiotoxicity has been defined as a ≥10% drop in left ventricular ejection fraction (LVEF) or LVEF <50%, or the appearance of clinical cardiac insufficiency. The HER2/neu 655 A>G polymorphism has been linked to cardiotoxicity risk. This study evaluates the cost-effectiveness of HER2/neu 655 genotyping. Methods: Eighty-eight HER2-positive breast cancer patients treated for early disease with trastuzumab were retrospectively analyzed. All were genotyped for HER2/neu 655 A>G (AA: n=53, AG: n=32, GG: n=3). LVEF was monitored by echocardiography or isotopic ventriculography at baseline and regular intervals. Cardiotoxicity was defined as above. Logistic regression adjusting for hormonal status and anthracycline use estimated the association between genotype and cardiotoxicity. Cost data from the Andalusian Regional Health Service included diagnostic tests, cardiology visits, pharmacologic therapy, and hospitalizations. Results: Among the 53 patients with the AA genotype, 3.7% experienced a decrease in LVEF, while 9.4% developed clinical symptoms. For the AG genotype (32 patients), 9.3% showed an LVEF reduction, and 28.1% presented clinical symptoms. In the GG genotype group (3 patients), 1 patient (33.3%) developed clinical symptoms. AG carriers had a significantly higher risk of cardiotoxicity than AA patients (OR adjusted for hormonal status and anthracycline treatment =4.42; p=0.037). HER2/neu 655 A>G genotyping costs €38. Asymptomatic LVEF reductions usually required 3 cardiology visits including echocardiography (€121.05 each), and one year of pharmacological treatment (carvedilol and/or enalapril therapy; €84.72 total). Cardiac insufficiency costs range from €2,992.61 (grade 1) to €9,363.56 (grade 4). Conclusions: HER2/neu 655 genotyping is cost-effective for identifying patients at higher risk of trastuzumab-induced cardiotoxicity. The low cost of genotyping is outweighed by the potential savings in preventing severe cardiac events. Genotype-driven monitoring and proactive cardiac and targeted cardiovascular risk management in AG carriers could reduce both the incidence and severity of cardiotoxicity.

Background: Tamoxifen, an antiestrogen prodrug, is widely used in treating hormone receptor-positive breast cancer. Its efficacy largely depends on its conversion to the active metabolite endoxifen by the CYP2D6 enzyme, which exhibits varying levels of activity based on genetic polymorphisms. Current clinical practice guidelines recommend an initial gynecological examination with transvaginal ultrasound before starting tamoxifen. If no abnormalities are detected, the patient begins tamoxifen without additional gynecological follow-up unless symptomatic (e.g., spotting or vaginal bleeding). This study explores the cost-effectiveness of CYP2D6 genotyping to predict patients at higher risk of toxicity. Methods: This analysis utilized data from our dose escalation trial (EudraCT: 2007-002942-40), where poor metabolizers (PM) received increased doses of tamoxifen. All women were treated with 20 mg/day of tamoxifen for 5 years, except PM, who received 20 mg/day for 4 months, 40 mg/day for the next 4 months, and 60 mg/day for another 4 months before returning to 20 mg/day for the remainder of the 5 years. The costs for managing adverse events, updated in May 2024, were obtained from the Andalusian Health Service. These costs provide a detailed financial perspective based on public data, including costs for consultations, diagnostic procedures, follow-up treatments, and hospitalization, reflecting Grade 2 complexity. Additionally, we calculated the cost of CYP2D6 genotyping, covering expenses for DNA extraction, analysis using KASP assays, and proration of personnel and equipment costs. We analyzed the incidence of specific side effects: osteoarticular pain, hot flashes, asthenia, and gynecological alterations. Results: Only gynecological alterations showed significant differences between CYP2D6 phenotypes. The incidence of gynecological adverse events was significantly higher in slow metabolizer (SM) patients (44.8%) compared to rapid metabolizer (RM) patients (15.2%, p=0.001). Adverse events quantified as average cost per patient include endometrial hyperplasia (€8544,81), endometrial polyps (€1834,56), adenocarcinoma (€9467,96), and endometrial thickening (€1132,27). Although costs related to medications, secondary events, extended hospital stays, or patient evolution were not included, our study recorded an average of 0.75 emergency visits per patient (range: 0-4), each costing €208.47 without hospital admission or observation. The cost of CYP2D6 genotyping is minimal (€10.98) compared to managing gynecological adverse events. Conclusion: Considering the significant impact of CYP2D6 polymorphisms on the occurrence of gynecological adverse events and the substantial cost of managing these events, our results advocate for the implementation of CYP2D6 genotyping. Given its demonstrated cost-effectiveness, we propose CYP2D6 genotyping for all patients scheduled to receive tamoxifen. For those with a predicted SM phenotype, we recommend protocolized gynecological follow-up at least once a year, along with thorough clinical monitoring. Any emerging symptoms should prompt immediate referral to gynecology for evaluation and examination. This approach not only enhances the quality of care but also aligns with healthcare efficiency objectives. Citation Format: Isabel Blancas, Xando Díaz-Villamarín, Carlos José Rodríguez-González, Rocío Morón-Romero, Fernando Rodríguez-Serrano. Cost-Effectiveness of CYP2D6 Genotyping in the Management of Tamoxifen Therapy for Breast Cancer Patients: A Focus on Adverse Events [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-03-24.

CYP2D6 is a key enzyme involved in converting tamoxifen into its active metabolites. However, polymorphisms in CYP2D6 lead to variable enzymatic capacities. We aimed to examine the impact of CYP2D6 polymorphisms on tamoxifen-derived side effects in breast cancer patients. Eighty-six patients with hormone receptor–positive breast cancer who received tamoxifen were classified as poor (PM), intermediate (IM), normal (NM), or ultrarapid (UM) metabolizers according to Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. All patients received 20 mg/day tamoxifen for 5 years, except PM, who were dose-escalated (20 mg/day for 4 months, 40 mg/day for 4 months, 60 mg/day for 4 months, then back to 20 mg/day). Adverse events—osteoarticular pain, hot flashes, asthenia, and uterine changes—were analyzed by Kaplan–Meier and Cox regression. A propensity score–matched (PSM) subgroup was also examined. Rapid metabolizers (RM: NM + UM) consistently showed fewer uterine changes compared to slow metabolizers (SM: PM + IM) in both the entire cohort (HR 0.20, p = 0.001) and the PSM subgroup (HR 0.07, p = 0.011). Excluding PM and UM, comparison of IM vs. NM showed similar differences (complete group: HR 0.20, p = 0.002; PSM subgroup: HR 0.23, p = 0.068). Other side effects (joint pain, hot flashes, asthenia) were not significantly associated with CYP2D6 phenotype. Uterine alterations in breast cancer patients treated with tamoxifen appear linked to decreased CYP2D6 activity, although we observed no association between CYP2D6 and other toxicities. These findings suggest closer monitoring for uterine toxicity in individuals with impaired CYP2D6 metabolism.

PURPOSE:Ascending aorta (AAo) acute pathology still has an open-surgery indication with a high mortality rate associated to cardiopulmonary bypass and circulatory arrest. In these cases, the endovascular aortic approach could be an excellent option. The aim of the present study is to detail an optimized technique for the endovascular treatment of AAo diseases, based on thoracic endovascular aortic repair (TEVAR) and transcatheter aortic valve implantation (TAVI) procedures. TECHNIQUE:The procedure implies the usual preparation for TEVAR and TAVI implants. A transient pacemaker lead is necessary to deliver the prosthesis under "rapid pacing." As in the TAVI technique, a final high-support guidewire is placed at the left ventricle. The proximal landing zone is the sinotubular junction (zone 0B). Transesophageal echocardiography is essential to ensure aortic valve function and patency in coronary arteries during the delivery. To assess a potential occlusion of the brachiocephalic artery, a guidewire is positioned in the descending aorta from the axillary artery. Finally, a noncovered stent is implanted to stabilize the AAo prosthesis. CONCLUSION:The technique presented here can standardize a safe and reproducible procedure to endovascular repair of AAo diseases. However, new devices specifically designed for the AAo could facilitate the transcatheter approach. CLINICAL IMPACT:Ascending aorta acute pathology still has an open-surgery indication with high mortality rate associated to cardiopulmonary bypass and circulatory arrest. Moreover, near 30% of patients are not considered suitable for surgery because of age, critical situation or the presence of severe comorbidities. The present study provides a detailed and optimized technique for the endovascular treatment of ascending aorta disease, based on TEVAR and TAVI procedures.

HER2 overexpression in breast cancer correlates with poor outcomes. The incorporation of Trastuzumab into the treatment regimen has notably improved patient prognoses. However, cardiotoxicity emerges in approximately 20

547 Background: Tamoxifen is widely used in treating hormone receptor-positive breast cancer. It is primarily metabolized by the CYP2D6 enzyme to yield active metabolites. However, CYP2D6 polymorphisms have been associated with a differential response to tamoxifen. In a clinical trial involving an early dose escalation of tamoxifen in poor metabolizers, we found endoxifen concentration levels similar to those of patients with extensive phenotype, and no long-term survival differences among CYP2D6 phenotypes. However, the impact of that dose escalation on side effect incidence was not addressed. Methods: In this study, we analyzed the incidence of specific side effects - osteoarticular pain, hot flashes, asthenia, and uterine alterations - in 86 breast cancer patients, differentiated by their CYP2D6 phenotype estimated according to the Clinical Pharmacogenetics Implementation Consortium. In poor metabolizers, the tamoxifen standard dose of 20 mg/day was escalated to 40 mg/day and 60 mg/day for 4 months each, and then treated with 20 mg/day until completing the treatment. Kaplan-Meier analysis and Cox proportional hazards regression model were employed to assess the relationship between the CYP2D6 phenotype and the incidence of these side effects. Results: The median follow-up time was 139.5 months. The analyses revealed that only uterine changes showed significant differences between CYP2D6 phenotypes, with a lower incidence in extensive metabolizers (P-value < 0.001 in Kaplan-Meier; HR in Cox of 0.195, 95% CI 0.073 - 0.521, P = 0.001). This finding persisted after adjustment for the covariates tumor grade, size, nodal status, chemotherapy, and radiotherapy in multivariate Cox regression (HR 0.098, 95% CI 0.020 - 0.466, P = 0.004). Selection of a subgroup through Propensity Score Matching (21 vs 21) corroborated these results. The spectrum of uterine changes and pathologies included endometrial hyperplasia, polyps, adenocarcinoma, myometrial or endometrial thickening, and the presence of multiple myomas. Conclusions: Our study indicates that an early increase in tamoxifen dose in poor metabolizer patients according to CYP2D6 polymorphisms may significantly affect the incidence of uterine changes, but not the incidence of osteoarticular pain, hot flashes, or asthenia. Clinical trial information: 2007-002942-40/ES .

Breast cancer (BC) remains a widespread disease worldwide, despite advances in its detection and treatment. microRNAs (miRNAs) play a significant role in cancer, and their presence within exosomes may confer several advantages in terms of tumor initiation, propagation, immune evasion, and drug resistance compared to freely circulating miRNAs in the blood. The objective of this study was to conduct a systematic review to analyze the role of exosomal miRNAs present in serum or plasma as biomarkers in BC. Bibliographic sources were collected from various databases with no starting date limit until March 2023. The search terms used were related to "breast cancer," "microRNAs," and "exosomes". Following the search, inclusion and exclusion criteria were applied, resulting in a total of 46 articles. Data were extracted from the selected studies and summarized to indicate the miRNAs, type of dysregulation, sample source, number of patients and controls, and clinical relevance of the miRNAs. We carried out an enrichment study of the microRNAs that appeared in at least 3 studies, those that were suitable for selection were miR-16, miR-21 and miR-155. Exosomal miRNAs isolated from blood samples of patients diagnosed with BC could be valuable in the clinical setting. They could provide information about early diagnosis, disease progression, recurrence, treatment response, and metastases. It is crucial to reach a consensus on the specific exosomal miRNAs to detect and the most appropriate type of sample for comprehensive utilization of miRNAs as biomarkers for BC.

La endocarditis infecciosa (EI) es una patología que conlleva una elevada morbimortalidad y representa un problema creciente de salud pública. El tratamiento quirúrgico es necesario en más de la mitad de los casos, y su principal finalidad es eliminar totalmente el tejido infectado y reconstruir la anatomía cardiaca normal, incluyendo la reparación o la sustitución de la/s válvula/s afectada/s. El presente estudio se centra en describir el procedimiento más apropiado para la cirugía de reparación mitral en casos de EI, atendiendo a la literatura y a la amplia experiencia adquirida por parte del equipo quirúrgico. De igual modo, hemos recopilado a través de una búsqueda sistemática de la literatura los resultados que se han ido reportando sobre la cirugía reparadora en comparación con el reemplazo valvular mitral. La técnica quirúrgica descrita requiere de un estudio minucioso del grado de afectación y desestructuración de los distintos segmentos valvulares. Consideramos que la resección con interposición de parche de pericardio y/o implante de neocuerdas de Goretex® es la técnica estándar que permite obtener resultados reproducibles. La revisión estructurada de las evidencias científicas disponibles verifica la seguridad de la reparación mitral para el tratamiento de la EI, aportando beneficios significativos en comparación con el reemplazo valvular. Los resultados quirúrgicos evaluados sugieren que la cirugía de reparación mitral debería ser considerada el procedimiento de elección para el tratamiento quirúrgico de la EI, siempre que sea técnicamente posible. Infective endocarditis (IE) is a pathology with a high morbidity and mortality rate and represents a growing public health problem. Surgical treatment is necessary in more than half of the cases, and its main purpose is to completely remove the infected tissue and reconstruct normal cardiac anatomy, including repair or replacement of the affected valve(s). The present study focuses on describing the most appropriate procedure for mitral repair surgery in cases of IE, based on the literature and the extensive experience gained by the surgical team. Likewise, we have compiled through a systematic search of the literature the results that have been reported on reparative surgery compared to mitral valve replacement. The surgical technique described requires a thorough study of the degree of involvement and destructuring of the different valve segments. We consider resection with pericardial patch interposition and/or Goretex® neochord implantation to be the standard technique that allows reproducible results. The structured review of the available scientific evidence verifies the safety of mitral repair for the treatment of IE, providing significant benefits compared to valve replacement. The evaluated surgical results suggest that mitral repair surgery should be considered the procedure of choice for the surgical treatment of IE, whenever technically feasible.

El implante de dispositivos de electroestimulación cardiaca (DECI) constituye una terapia útil para el tratamiento de diferentes cardiopatías. Sin embargo, su utilización no está exenta de complicaciones. La infección relacionada con los dispositivos de electroestimulación es una de las más frecuentes y serias que pueden producirse. La extracción intravenosa del sistema de electroestimulación es un procedimiento seguro y eficaz, dirigido al tratamiento de múltiples situaciones relacionadas con los dispositivos. En el presente artículo abarcamos las complicaciones relacionadas con los procedimientos de extracción, identificamos los factores de riesgo asociados a la morbimortalidad de los pacientes, y establecemos una guía de prevención y tratamiento de las complicaciones cardiovasculares mayores. A pesar del crecimiento del número de procedimientos de extracción y del desarrollo de nuevos instrumentos, su práctica implica un riesgo potencial de complicaciones mayores y de morbimortalidad asociada. La realización de la técnica presentada, la correcta evaluación del riesgo quirúrgico del paciente y la estandarización del tratamiento completo como proceso asistencial son los 3 pilares básicos del tratamiento seguro y eficaz de las complicaciones relacionadas con los DECI. El procedimiento de extracción de los DECI que presentamos es eficaz y debe realizarse en un entorno seguro, implicando necesariamente un quirófano de cirugía cardiovascular, monitorización completa, ecocardiografía transesofágica y posibilidad de realizar esternotomía y cirugía de forma inmediata. Es necesario evaluar las posibles complicaciones y elaborar un proceso asistencial completo, teniendo en cuenta que las decisiones tomadas durante el implante inciden directamente en el potencial riesgo de la extracción. Implantation of cardiac electrostimulation devices (CIED) is a useful therapy for the treatment of various heart diseases. However, its use is not free of complications. Infection related to electrostimulation devices is one of the most common and serious complications. Intravenous removal of the electrostimulation system is a safe and effective procedure, aimed at the treatment of multiple pathological situations related to the devices. In the present article, we cover complications related to extraction procedures, identify risk factors associated with patient morbidity and mortality, and establish a guideline for the prevention and treatment of major cardiovascular complications. Despite the growth in the number of extraction procedures and the development of new instruments, its practice involves a potential risk of major complications and morbi-mortality associated with the treatment. The performance of the technique presented here, the correct assessment of the patient's surgical risk, and the standardization of the entire process are the three basic pillars for a safe and effective treatment of complications related to CIED. The extraction procedure for CIED that we present is effective and should be performed in a safe environment, necessarily involving a cardiovascular surgery operating room, complete monitoring, transesophageal echocardiography, and the possibility of an immediate sternotomy and surgery. It is necessary to evaluate possible complications and develop a complete care process, considering that the decisions made during implantation have a direct impact on the potential risk of extraction.

Introduction: Implantation of cardiac electrostimulation devices (CIED) is a useful therapy for the treatment of various heart diseases. However, its use is not free of complications. Infection related to electrostimulation devices is one of the most common and serious complications. Intravenous removal of the electrostimulation system is a safe and effective procedure, aimed at the treatment of multiple pathological situations related to the devices.Objectives and methods: In the present article, we cover complications related to extraction procedures, identify risk factors associated with patient morbidity and mortality, and establish a guideline for the prevention and treatment of major cardiovascular complications.Results: Despite the growth in the number of extraction procedures and the development of new instruments, its practice involves a potential risk of major complications and morbi-mortality associated with the treatment. The performance of the technique presented here, the correct assessment of the patient's surgical risk, and the standardization of the entire process are the three basic pillars for a safe and effective treatment of complications related to CIED. Conclusion: The extraction procedure for CIED that we present is effective and should be performed in a safe environment, necessarily involving a cardiovascular surgery operating room, complete monitoring, transesophageal echocardiography, and the possibility of an immediate sternotomy and surgery. It is necessary to evaluate possible complications and develop a complete care process, considering that the decisions made during implantation have a direct impact on the potential risk of extraction. 2023 Published by Elsevier Espana, S.L.U. on behalf of Sociedad Espanola de Cirugia Cardiovascular y Endovascular. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).

Oligometástasis en cáncer de mama: estrategias y perspectivas para el control local del

Taiwaniaquinoids are a unique family of diterpenoids predominantly isolated from Taiwania cryptomerioides Hayata. Previously, we evaluated the antiproliferative effect of several synthetic taiwaniaquinoids against human lung (A-549), colon (T-84), and breast (MCF-7) tumor cell lines. Herein, we report the in vitro and in vivo antitumor activity of the most potent compounds. Their cytotoxic activity against healthy peripheral blood mononuclear cells (PBMCs) has also been examined. We underscore the limited toxicity of compound C36 in PBMCs and demonstrate that it exerts its antitumor effect in MCF-7 cells (IC50 = 1.8 µM) by triggering an increase in reactive oxygen species, increasing the cell population in the sub-G1 phase of the cell cycle (90 %), and ultimately activating apoptotic (49.6 %) rather than autophagic processes. Western blot results suggested that the underlying mechanism of the C36 apoptotic effects was linked to caspase 9 activation and a rise in the Bax/Bcl-2 ratio. In vivo analyses showed normal behavior and hematological parameters in C57BL/6 mice post C36 treatment. Moreover, no significant impact was observed on the biochemical parameters of these animals, indicating that C36 did not induce liver toxicity. Furthermore, C36 demonstrated a significant reduction in tumor growth in immune-competent C57BL/6 mice implanted with E0771 mouse mammary tumor cells, effectively improving survival rates. These findings position taiwaniaquinoids, particularly compound C36, as promising therapeutic candidates for human breast cancer.

PurposeTamoxifen is a drug used for hormone receptor-positive breast cancers, primarily metabolised by the CYP2D6 enzyme into active metabolites such as endoxifen. CYP2D6 displays varying degrees of activity depending on its genotype. This study aims to analyse the effect of an early increase in tamoxifen dose in poor metabolisers (PM) on survival.MethodsWe enrolled 220 patients diagnosed with breast cancer who were treated with tamoxifen. CYP2D6 polymorphisms were determined, and the phenotype was estimated according to the Clinical Pharmacogenetics Implementation Consortium. Disease-free survival (DFS) and overall survival (OS) were analysed considering the entire patient group, and a subgroup of 110 patients selected by Propensity Score Matching (PSM). All women were treated with 20 mg/day of tamoxifen for 5 years, except PM, who initially received 20 mg/day for 4 months, followed by 40 mg/day for 4 months and 60 mg/day for 4 months before returning to the standard dose of 20 mg/day until completing 5 years of treatment.ResultsThe analysis of the influence of CYP2D6 polymorphisms in the complete group and in the PSM subgroup revealed no significant differences for DFS or OS. Furthermore, DFS and OS were analysed in relation to various covariates such as age, histological grade, nodal status, tumour size, HER-2, Ki-67, chemotherapy, and radiotherapy. Only age, histological grade, nodal status, and chemotherapy treatment demonstrated statistical significance.ConclusionAn early increase in tamoxifen dose in PM patients is not associated with survival differences among CYP2D6 phenotypes.