Search Results (888)

Background: Therapeutic resistance following cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) represents a key unmet need in hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2−) metastatic breast cancer (mBC). Treatment paradigms have advanced from non-targeted options, such as fulvestrant monotherapy or everolimus-based combinations, to precision medicine strategies, including inhibitors of the PI3K/AKT pathway, oral selective estrogen receptor degraders (SERDs), and novel ER-modulating agents, often guided by biomarkers and molecular surveillance. Methods: This narrative review synthesizes evidence from randomized clinical trials, real-world studies, and biomarker-driven analyses published from 2010 to 2026, with emphasis on next-generation sequencing (NGS)-guided genomic profiling, targeted pathway therapies, and circulating tumor DNA (ctDNA)-based proactive interventions in the post-CDK4/6i setting. This review was conducted and reported in accordance with the SANRA recommendations for narrative reviews. Results: Early second-line standards, including fulvestrant and alpelisib for PIK3CA-mutated tumors, established the basis for biomarker-guided treatment in hormone receptor–positive, HER2-negative metastatic breast cancer. With the widespread use of CDK4/6 inhibitors in the first-line setting, the optimal post-progression strategy has shifted toward molecularly selected combination approaches rather than single-agent endocrine therapy, as endocrine monotherapy has shown limited efficacy in acquired resistance. Multiple randomized studies have demonstrated that adding targeted agents to endocrine therapy improves progression-free survival compared with hormonal therapy alone, supporting combination regimens as the preferred strategy after CDK4/6 inhibitor progression, except in carefully selected patients with low disease burden, indolent biology, or frailty where tolerability is a major concern. Precision-based trials have further refined this approach. Elacestrant improved progression-free survival in ESR1-mutated disease in the EMERALD trial, capivasertib plus fulvestrant demonstrated significant benefit in tumors harboring AKT/PIK3CA/PTEN pathway alterations in CAPItello-291, and inavolisib plus palbociclib and fulvestrant achieved both progression-free and overall survival improvement in PIK3CA-mutated patients with early relapse in INAVO120. Real-world analyses further support the effectiveness of these biomarker-directed strategies across diverse clinical subgroups. Comprehensive genomic profiling has identified multiple resistance mechanisms, including ESR1 mutations, PI3K/AKT/mTOR pathway activation, RB1 loss, and FGFR alterations, which may co-occur and reduce sensitivity to endocrine monotherapy. While ESR1 and PI3K pathway alterations now guide approved therapies, FGFR alterations remain investigational targets, with ongoing trials evaluating selective FGFR inhibitors. Proactive switching approaches evaluated in SERENA-6 and PADA-1 demonstrate that serial circulating tumor DNA (ctDNA) monitoring can detect emergent ESR1 mutations before radiographic progression, providing a clinically actionable lead time for early therapeutic modification and extending endocrine-based disease control by approximately 5 to 7 months. Conclusions: Post-CDK4/6i management increasingly relies on NGS-guided precision approaches, integrating pathway-specific therapies and ctDNA surveillance to tailor sequencing based on resistance profiles, prior ET response, and tumor heterogeneity. Future investigations into novel ER degraders and multi-targeted combinations hold potential to further optimize algorithms, extend non-chemotherapy options, and enhance survival in HR+/HER2− mBC. Full article

Background/Objectives. Breast cancer is the most frequently diagnosed cancer worldwide, with approximately 15% classified as Triple-Negative Breast Cancer (TNBC). TNBC is characterized by the absence of estrogen receptor (ER) and progesterone receptor (PR), and the lack of HER2 overexpression, limiting use of targeted therapies. Current TNBC treatment relies heavily on chemotherapy, most commonly taxanes including paclitaxel that stabilize microtubules, disrupt chromosome separation and induce apoptosis. TNBCs frequently develop chemoresistance after multiple treatment cycles, highlighting a critical unmet need for novel therapeutic strategies. This study addresses this challenge by targeting salt-inducible kinase 2 (SIK2), which is overexpressed in 85% of TNBCs compared to normal breast tissue. Methodes. In collaboration with Arrien Pharmaceuticals and Greenfire Biologics, we developed ARN-3261/GRN-300, a novel orally bioavailable SIK2 inhibitor and evaluated its ability to sensitize TNBC cells to paclitaxel in vitro and in vivo. Results. GRN-300 demonstrated strong synergy with paclitaxel in all eight TNBC cell lines tested, as indicated by favorable combination indices. In xenograft models, the combination therapy significantly enhanced tumor growth inhibition and prolonged survival compared to either agent alone. Mechanistic studies showed that GRN-300 disrupts the anaphase-promoting complex/cyclosome (APC/C) pathway by downregulating key mitotic regulators, including CDC27, CDK1, and PLK1, thereby potentiating G2/M cell cycle arrest and apoptosis. Conclusions. Together, these findings establish GRN-300 as a promising therapeutic agent that enhances paclitaxel efficacy through complementary disruption of mitotic regulatory pathways, providing strong preclinical rationale for clinical development in TNBC. Full article

Background/Objectives: CDK4/6i and ET improve outcomes in HR-positive, HER2-negative breast cancer, but their benefits differ between early-stage (EBC) and metastatic disease (MBC). We aimed to compare the efficacy and toxicity of CDK4/6i plus ET versus ET alone across these disease settings. Methods: We conducted a meta-analysis of phase III randomized trials identified through MEDLINE, EMBASE, and Web of Science up to 1 October 2025. Twenty-two trials (18 MBC, n = 6364; 4 EBC, n = 17,741) met the inclusion criteria. Two reviewers extracted data and assessed risk of bias. The study followed PRISMA 2020 guidelines (PROSPERO: CRD420251132302). Outcomes included overall survival (OS), progression-free survival (PFS), invasive disease-free survival (iDFS), distant relapse-free survival (DRFS), response rates, treatment discontinuation (TDR), dose reductions (DRR), and grade 3–4 adverse events. Results: In MBC, CDK4/6i improved OS (HR: 0.78, 95% CI: 0.72–0.85) and PFS (HR: 0.53, 95% CI: 0.50–0.56) and increased objective response, clinical benefit, and disease control rates along with TDR, DRR, and grade 3–4 adverse events. In EBC, iDFS improved, whereas OS (HR: 0.92, 95% CI: 0.75–1.12; p = 0.40) and DRFS did not. TDR, DRR, and grade 3–4 adverse events were increased. Conclusions: CDK4/6i confer significant OS and PFS benefits in MBC, supporting first-line use. In EBC, no OS benefit was observed, and toxicity was increased, underscoring the need for individualized risk–benefit assessment. Longer follow-up is warranted to clarify survival outcomes. Full article

Background/Objectives: Liposarcoma represents a heterogeneous group of mesenchymal malignancies with distinct molecular profiles and clinical behaviors. While localized disease is managed with surgical resection, advanced or metastatic liposarcoma poses a significant therapeutic challenge due to limited response to traditional cytotoxic chemotherapy. This review summarizes current evidence-based systemic therapies and highlights recent advances in subtype-driven treatment strategies. Methods: We review key clinical trials supporting the use of anthracycline regimens, trabectedin, eribulin, and nuclear export inhibition with selinexor, as well as emerging targeted approaches directed at MDM2 and CDK4 amplification. In addition, we discuss the evolving role of immunotherapy, including checkpoint inhibitors and engineered T-cell receptor therapies targeting cancer–testis antigens. Results: Integrating molecular biology with therapeutic development, we emphasize the importance of histologic and genomic classification in guiding treatment selection and clinical trial design. Conclusion: Continued progress in biomarker-driven strategies and rational combination therapies is expected to further refine personalized treatment approaches and improve outcomes for patients with advanced liposarcoma. Full article

Tauopathies, including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal lobar degeneration with tau pathology, are unified by pathogenic tau misfolding, post-translational modification, aggregation, and network-level spread. Yet decades of drug development that predominantly pursued single nodes (e.g., one kinase, one aggregation inhibitor, one monoclonal antibody epitope) have repeatedly delivered late-stage disappointments, underscoring a central lesson: tauopathy behaves less like a linear pathway and more like a coupled system of proteostasis failure, neuroinflammation, synaptic-mitochondrial stress, and metabolic dysregulation. This review examines rhizomes (notably Zingiberaceae genera such as Curcuma, Zingiber, Alpinia, Kaempferia, and Boesenbergia) as chemically diverse “multi-target platforms” whose bioactives can engage several tau-relevant nodes simultaneously. We synthesise evidence across tau phosphorylation (GSK-3β/CDK5 and upstream stress signalling), tau aggregation and seeding, autophagy-lysosome and proteasome pathways, redox-mitochondrial resilience, neuroinflammatory circuits (NF-κB/NLRP3), and neuro-metabolic signalling (insulin-PI3K-AKT, AMPK-mTOR). A translational lens is applied throughout, focusing on drug-likeness and CNS multiparameter optimisation; BBB permeability and efflux; metabolism and bioavailability constraints; and formulation strategies (nanoparticles, phytosomes, engineered exosomes) that may render rhizome-derived scaffolds more clinically plausible. We conclude that rhizomes offer credible mechanistic hypotheses for tau modulation, but progress depends on rigorous standardisation, realistic exposure matching, biomarker-driven study design, and a shift from “single-compound optimism” to network pharmacology with translational discipline. Full article

Background/Objectives: The prognostic significance of the uric acid-to-albumin ratio (UAR) in patients with hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer treated with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors has not been adequately investigated. This study aimed to investigate the association between baseline UAR and survival outcomes in this patient population. Methods: This retrospective study included HR-positive/HER2-negative metastatic breast cancer patients treated with ribociclib or palbociclib at Necmettin Erbakan University between May 2020 and April 2025. UAR was calculated by dividing the serum uric acid level (mg/dL) by the serum albumin level (g/dL). Based on receiver operating characteristic (ROC) analysis, the optimal cut-off value for UAR was identified as 1.0 (AUC = 0.67; sensitivity 68%; specificity 58%). Patients were subsequently classified into two groups as UAR < 1 and UAR ≥ 1. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method and compared with the log-rank test. Independent prognostic factors were evaluated using Cox regression analyses. Results: A total of 118 eligible patients were included in the analysis, including 34 (28.8%) in the UAR < 1 group and 84 (71.2%) in the UAR ≥ 1 group. The proportion of postmenopausal patients was significantly higher in the UAR ≥ 1 group (p = 0.01). Kaplan–Meier analysis showed that median PFS was not reached in the UAR < 1 group, whereas it was 33.05 months in the UAR ≥ 1 group (log-rank p = 0.06). Median OS was not reached in the UAR < 1 group and was 50.7 months in the UAR ≥ 1 group (p = 0.017). Multivariate Cox regression analysis demonstrated that UAR < 1 was associated with improved PFS (HR = 0.65; 95% CI: 0.34–0.89; p = 0.04). Postmenopausal status emerged as an independent adverse prognostic factor for PFS (HR = 1.92; 95% CI: 1.10–4.05; p = 0.04). In addition, UAR < 1 was associated with a reduced risk of mortality in the OS analysis (HR = 0.61; 95% CI: 0.26–0.87; p = 0.01). Conclusions: Lower baseline UAR was associated with more favorable survival outcomes in HR-positive/HER2-negative metastatic breast cancer patients treated with CDK4/6 inhibitors. As an inexpensive and easily accessible biomarker derived from routine laboratory parameters, UAR may provide additional prognostic information for clinical risk stratification. Full article

Background/Objectives: Determining homologous recombination repair (HRR) status in metastatic castration-resistant prostate cancer (mCRPC) is essential to ensure access to targeted therapies, particularly PARP inhibitors. Yet, variability in testing access and analysis performance exists. This study evaluated feasibility and outcomes of a centralized HRR testing strategy in Spain for prostate cancer patients. Methods: A total of 1412 formalin-fixed paraffin-embedded (FFPE) tumor samples from mCRPC patients from 89 Spanish institutions within a centralized multicenter molecular testing program were analyzed using a standardized 38-gene-based next-generation sequencing (NGS) assay in a central laboratory (HRR OncoKit, Health in Code, Valencia, Spain), which included five clinically relevant HRR genes: BRCA1, BRCA2, CHEK2, ATM, and CDK12. Results: HRR gene pathogenic or likely pathogenic alterations were identified in 18% (CI 95% = 16–20) of the patients, with BRCA2 being the most frequently altered gene (6%), followed by ATM (5%), CDK12 (4%), BRCA1 (2%), and CHEK2 (1%). Eleven percent had variants of uncertain significance. Only 13% of the samples were rejected due to poor DNA quality, low tumor content or sample age exceeding 5 years, and 2% of the samples analyzed failed since the minimum library technical quality score was not achieved. The average turnaround time for results was 18 ± 3 days. Conclusions: Centralized HRR testing in mCRPC patients in Spain was feasible, efficient and reliable, identifying pathogenic alterations in 18% of the cases, similarly to the prevalence described in the literature. This testing approach facilitates precision medicine by improving the detection of actionable HRR alterations. Full article

Introduction: In the treatment of hormone receptor-positive (HR+), HER2-negative (HER2−) metastatic breast cancer (MBC), the current guidelines recommend endocrine therapy combined with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors as the preferred first-line treatment to preserve quality of life. Ribociclib is a CDK4/6 inhibitor that has been used in combination with aromatase inhibitors or fulvestrant in patients with HR+, HER2− metastatic breast cancer. Various adverse drug reactions associated with ribociclib have been reported, including cutaneous reactions, hepatotoxicity, and hematologic toxicity. In this study, we aimed to evaluate the clinical manifestations and risk factors of dermatologic toxicities in patients with metastatic breast cancer treated with ribociclib. Methods: This retrospective study included patients with metastatic/recurrent breast cancer who were prescribed ribociclib from April 2021 to December 2024 at a single institution. We retrospectively reviewed the medical records of these patients to identify the frequency of cutaneous adverse events, the time of onset, and the clinical characteristics of skin reactions. Logistic regression analysis was performed on several clinical factors, including body surface area (BSA) and concomitant medications, to identify risk factors associated with the occurrence of cutaneous adverse events. Results: A total of 110 patients with MBC were enrolled during the study period. The median age was 53 years (range, 28–82); all 110 patients (100.0%) were female; the median BSA was 1.56 m² (range, 1.29–2.07); and 32 patients (29.1%) were premenopausal. Ribociclib plus letrozole was administered in 48 patients (43.6%) and ribociclib plus fulvestrant in 29 patients (26.4%). An additional 33 patients (30.0%) received ribociclib plus letrozole with a gonadotropin-releasing hormone (GnRH) agonist. Cutaneous adverse events occurred in 29 patients (26.4%), and the median time to onset was 84 days (range, 3–498). The cutaneous adverse event patterns included pruritus, erythematous macular rash, eczematous rash/contact dermatitis, vitiligo, urticarial reactions, polymorphous light eruption, toxic epidermal necrolysis (TEN), and desquamation. Grade 1 or 2 cutaneous adverse events occurred in 93.1% of patients; Grade 3 toxicity occurred in one patient; and Grade 4 toxicity, namely toxic epidermal necrolysis (TEN), was reported in one patient. Dose reduction was required in three patients (10.3%), and permanent discontinuation of ribociclib occurred in one patient. Clinical improvement was achieved in the majority of patients (86.2%) with cutaneous adverse events following supportive care. Logistic regression analysis revealed that age, Eastern Cooperative Oncology Group (ECOG) performance status, body surface area (BSA), treatment regimen, and use of cholesterol-lowering medications were not independently associated with the development of cutaneous adverse events. Conclusion: CDK4/6 inhibitors represent one of the most important treatment options for HR+/HER2− metastatic breast cancer. Regardless of their clinical efficacy, cutaneous adverse events remain a common source of patient discomfort. Therefore, careful clinical attention and appropriate supportive care are essential to improve patients' quality of life. Full article

Background/Objectives: Acute myeloid leukemia (AML) remains in need of more broadly effective therapeutic strategies. THZ1, a covalent CDK7 inhibitor, has shown anti-leukemic activity in AML, but the mechanism underlying its response remains incompletely defined. This study aimed to identify key modulators and related transcriptional programs involved in THZ1 response in AML. Methods: We combined a genome-wide CRISPR/Cas9 screen with functional validation and transcriptomic analyses. Results: TP53 was the top positively selected gene in the CRISPR screen in MOLM-13 cells. THZ1 induced p53 accumulation, and pharmacologic activation of the p53 pathway with idasanutlin further enhanced the early anti-leukemic response to THZ1 at 24 h. TP53 loss reduced the sensitivity of AML cells to THZ1-induced apoptosis, but did not abolish THZ1 responsiveness. Transcriptomic analyses showed that TP53 loss substantially reshaped the transcriptional state, whereas MYC and E2F target programs remained the most consistent pathways linked to THZ1 response. THZ1 also continued to suppress these programs in TP53-knockout MOLM-13 cells and TP53-mutant THP-1 cells. Conclusions: Overall, TP53 contributes to the anti-leukemic response to THZ1 but does not determine it, and THZ1 continues to suppress MYC and E2F target programs after TP53 loss. Full article

Objective: This study aimed to evaluate the prognostic significance of positron emission tomography/computed tomography (PET/CT)-derived sarcopenia in patients with hormone receptor-positive, HER2-negative metastatic breast cancer treated with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Methods: This retrospective single-center study included 77 patients treated between January 2018 and March 2025. Sarcopenia was assessed using skeletal muscle index (SMI) at the L3 level on fluorodeoxyglucose (FDG) PET/CT. Patients were classified as sarcopenic or non-sarcopenic. Clinical, nutritional parameters including body mass index (BMI) and prognostic nutritional index (PNI), and inflammatory parameters including pan-immune inflammation value (PIV) were analyzed. The primary endpoint was progression-free survival (PFS). Results: Sarcopenia was present in 35.1% of patients. After a median follow-up of 38 months, sarcopenic patients had significantly shorter PFS compared with non-sarcopenic patients (18 vs. 38 months; HR: 2.37, 95% CI 1.12–4.99, p = 0.02, multivariable analysis). In multivariable analysis, sarcopenia, recurrent disease, brain metastasis, and liver metastasis were independent predictors of PFS. No significant association was observed between sarcopenia and overall survival. BMI, PNI, and PIV were not associated with survival outcomes. Toxicity profiles were comparable between groups. Conclusions: PET/CT-derived sarcopenia may be a prognostic factor for PFS in patients receiving CDK4/6 inhibitors, whereas conventional nutritional and inflammatory markers are not. These findings support the clinical utility of imaging-based body composition assessment. Prospective studies incorporating functional measures of sarcopenia are warranted. Full article

Advances in molecular oncology have reshaped the management of breast cancer through the development of pathway-specific targeted therapies. In particular, inhibition of HER2, CDK4/6, and PI3K signaling has yielded substantial clinical benefits in molecularly defined patient populations. This review provides an integrated analysis of three representative agents—trastuzumab, abemaciclib, and alpelisib—highlighting their distinct mechanisms of action, clinical efficacy, and translational relevance in breast cancer, with contextual insights into gynecologic oncology. Evidence from pivotal clinical trials and emerging translational studies demonstrates that trastuzumab remains a cornerstone of HER2-positive breast cancer treatment, while also showing activity in HER2-amplified gynecologic malignancies. Abemaciclib, a selective CDK4/6 inhibitor, has significantly improved outcomes in hormone receptor–positive breast cancer and is being actively explored in tumors characterized by cell cycle dysregulation, including endometrial and ovarian cancers. Alpelisib, targeting the PI3Kα isoform, provides meaningful benefit in PIK3CA-mutated breast cancer and represents a promising strategy in gynecologic tumors with aberrant PI3K/AKT/mTOR pathway activation. Collectively, these agents exemplify precision oncology approaches that align therapeutic strategies with tumor biology. Their integration into biomarker-driven, multimodal treatment frameworks underscores a paradigm shift toward personalized cancer care across breast and gynecologic malignancies. Particular emphasis is placed on the translation of molecular diagnostics into clinical decision-making, including patient selection, resistance mechanisms, and sequencing strategies within evolving precision oncology frameworks. Ongoing clinical and translational research will be critical to refine combination strategies, overcome resistance mechanisms, and identify predictive biomarkers to further optimize patient outcomes. Full article

Background: Acquired resistance to the third-generation EGFR tyrosine kinase inhibitor osimertinib, often mediated by EGFR triple mutations, poses a major clinical challenge in non-small cell lung cancer (NSCLC) treatment. Among these, some rare mutations, such as L858R/T790M/L792H and L858R/T790M/G796R, create steric hindrance that directly interferes with osimertinib binding, yet effective targeted therapeutic strategies for these specific mutations remain lacking. Cudratricusxanthone A (CTXA), a natural xanthone derivative isolated from Cudrania tricuspidata Bur., has demonstrated various pharmacological activities, but its effects against EGFR triple-mutant NSCLC have not been systematically investigated. Methods: Stable Ba/F3 and NIH/3T3 cell lines expressing EGFR L858R/T790M/L792H or L858R/T790M/G796R triple mutations were generated via electroporation. The antiproliferative effects of CTXA were evaluated by MTT/MTS assays, colony formation, and wound healing assays. Cell cycle distribution and apoptosis were analyzed by flow cytometry. Protein expression of EGFR signaling pathway components (p-EGFR, p-ERK, p-AKT, p-STAT3) and cell cycle regulators (Cyclin D1, CDK4) were examined by Western blotting. Molecular docking and 200 ns molecular dynamics simulations were performed to investigate the stability and binding modes of CTXA to the mutant EGFR kinase domains. Results: The successfully established triple-mutant cell lines exhibited high EGFR expression, IL-3-independent growth, and significant resistance to osimertinib. CTXA inhibited the proliferation of all triple-mutant cell lines in a time- and concentration-dependent manner, with 48 h IC₅₀ values ranging from 0.362 to 2.488 μM. Mechanistically, CTXA suppressed EGFR autophosphorylation and downregulated downstream p-ERK, p-AKT, and p-STAT3. CTXA induced G1 phase cell cycle arrest by downregulating Cyclin D1 and CDK4, significantly promoted apoptosis, and inhibited cell migration. Molecular docking revealed that while osimertinib binding was blocked by steric hindrance from His-792 or Arg-796, CTXA adapted to the mutated ATP-binding pockets through multiple hydrogen bonds and extensive hydrophobic interactions. Molecular dynamics simulations confirmed the stable binding of CTXA to both mutant EGFR proteins over the 200 ns simulations. Conclusions: This study demonstrates for the first time that the natural compound CTXA possesses antitumor efficacy against EGFR L858R/T790M/L792H and L858R/T790M/G796R mutants by regulating EGFR-ERK/AKT/STAT3 signaling. Our findings position CTXA as a promising lead compound for tackling this challenging form of acquired resistance and highlight the value of natural products in multi-target antitumor drug discovery. Full article

Systemic lupus erythematosus (SLE) is a polygenic autoimmune disorder where genetic diversity drives significant clinical heterogeneity. This review summarizes the current understanding of the roles of genetic polymorphisms in immunological dysregulation, organ-specific manifestations and therapeutic response heterogeneity in individuals with SLE. The literature was obtained from PubMed, EBSCOhost, Web of Science and Scopus. The narrative review comprised 60 publications published within the last 12 years. The research consistently identifies the major histocompatibility complex (MHC) region as the most significant genetic risk factor for the onset of autoimmunity. Genetic variants in STAT4 and IRF5 exacerbate disease progression by facilitating chronic inflammation. These genetic factors are associated with various clinical outcomes, including renal and neuropsychiatric symptoms. Polymorphisms in HLA class II, TLR7 and FBN2 are notably linked to serious consequences, including lupus nephritis (LN). Progress in targeted therapy signifies a transition to personalized medicine with medications such as anifrolumab, litifilimab, iberdomide and Janus kinase (JAK) or Cyclin-Dependent Kinase (CDK) inhibitors, demonstrating potential for targeting pathways associated with the interferon gene signature and STAT4 polymorphisms. Notwithstanding the problems presented by the heterogeneity of SLE, the identification of risk variations is anticipated to enhance predictive and therapeutic biomarkers, hence facilitating more precise and individualized disease management. Full article

Background/Objectives: The prognostic and predictive role of BMI in patients with HR+/HER2− MBC remains controversial, particularly in the era of CDK4/6 inhibitors. This study aimed to evaluate the association between baseline BMI and clinical outcomes in patients treated with palbociclib in a real-world setting. Methods: We conducted a multicenter retrospective observational cohort study including 326 patients with HR+/HER2− MBC treated with palbociclib in combination with endocrine therapy across six oncology centers in Romania. Only patients who received palbociclib for at least three months were included. Patients were stratified according to BMI into <25 kg/m² and ≥25 kg/m² groups. PFS and OS were the primary endpoints, while ORR and CBR were secondary endpoints. Results: Among the 326 patients, 66.56% were classified as overweight or obese (BMI ≥ 25 kg/m²). Median PFS was 23.66 months in the BMI < 25 group and 26.78 months in the BMI ≥ 25 group, with no statistically significant difference (HR 0.86; 95% CI 0.62–1.20; p = 0.373). Median OS was not reached in the BMI < 25 group and was 43.73 months in the BMI ≥ 25 group, also without a significant difference (HR 0.82; 95% CI 0.52–1.30; p = 0.397). ORR (29.07% vs. 28.89%) and CBR (90.70% vs. 88.33%) were comparable between BMI groups. In multivariate analysis, liver metastases and brain metastases were independently associated with worse outcomes, whereas BMI was not an independent prognostic factor. Conclusions: In this selected real-world cohort of patients with HR+/HER2− MBC who tolerated at least three months of palbociclib, baseline BMI was not associated with treatment response, PFS, or OS. While clinically informative, these results should not be interpreted as definitive evidence that body weight has no influence on palbociclib efficacy, given the methodological constraints of the analysis. BMI alone may be insufficient to capture the complex interplay between body composition and treatment outcomes, highlighting the need for more refined biomarkers of body composition in this setting. Full article

The taxane family of compounds, including paclitaxel, docetaxel (Taxotere), and cabazitaxel (Jevtana), are common drugs used in chemotherapy for the frontline treatment of most major types of cancer. Alopecia, the dramatic loss of hair, is a common side effect that became a symbol of the suffering of many cancer patients. Concerted efforts have been made to understand the mechanism of taxane toxicity to hair follicles and, thus, prevention methods. Taxanes act by stabilizing cellular microtubules, which consequently cause mitotic arrest and then failure, as microtubules play critical functions in chromosome segregation. Hair follicle matrix cells are highly proliferative and thus are exceedingly sensitive to taxanes. We review the cellular mechanism-based strategies under investigation to counter taxane-induced hair follicle damage. These include the application of cyclin kinase inhibitors to block mitotic entry, the practical method using scalp cooling to reduce exposure of scalp hair follicles to drugs during infusion, the requirement of p53 action for hair follicle damage, and the recently discovered method of using low-intensity ultrasound to break taxane-stabilized microtubules and thus reverse taxane toxicity in hair follicle matrix cells. The concept of low-intensity ultrasound as an antidote to taxanes may have the potential to provide a practical and compelling strategy to counter alopecia in cancer treatment using taxanes. Tweet: Taxanes (paclitaxel/docetaxel) are powerful microtubule-stabilizing cancer drugs, but they also cause adverse effects, including alopecia. New research discoveries of temporary microtubule disruption by low-intensity ultrasound may counteract taxane toxicity and prevent alopecia during cancer chemotherapy. “Mechanistic-based strategies for the prevention of taxane-induced hair follicle damage in cancer chemotherapy” OUTLINE: 1. Taxane/paclitaxel mechanism of action in cancer therapy. 2. Taxane side effects: Alopecia (hair loss). 3. p53 dependence of taxane-induced hair follicle damage. 4. Research efforts to counter taxane -induced alopecia by CDK4/6i. 5. Prevention of taxane chemotherapy side effects using scalp cooling. 6. Discovery of low-intensity ultrasound as an antidote for taxane cytotoxicity, and potential prevention of alopecia in chemotherapy using taxanes. 7. Summary and prospective. Full article