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Mechanisms of resistance to tyrosine kinase inhibitor-targeted therapy and overcoming strategies.

Tyrosine kinase inhibitor (TKI)-targeted therapy has revolutionized cancer treatment by selectively blocking specific signaling pathways crucial for tumor growth, offering improved outcomes with fewer side effects compared with conventional chemotherapy. However, despite their initial effectiveness, resistance to TKIs remains a significant challenge in clinical practice. Understanding the mechanisms underlying TKI resistance is paramount for improving patient outcomes and developing more effective treatment strategies. In this review, we explored various mechanisms contributing to TKI resistan

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… In the PADA‐1 trial, patients with detected ESR1 mutations were randomized to receive fulvestrant with continued CDK4/6 inhibitor therapy, when this group was compared with those continuing AI and CDK4/6 inhibitor therapy, an improvement in PFS was observed. … The PFS benefit observed with early fulvestrant use after detection of ESR1 mutations may not be compensated for by later fulvestrant use after disease progression. 399 These data suggest that detecting resistance‐related mutations in ctDNA earlier rather than later (at radiographic progression) may …

Complexity and clinical significance of drug-drug interactions (DDIs) in oncology: challenging issues in the care of patients regarding cancer-associated thrombosis (CAT).

Cancer patients have an increased risk of developing venous thromboembolic events. Anticoagulation management includes prophylactic or therapeutic doses of low molecular weight heparins (LMWHs) or direct oral anticoagulants (DOACs). However, the management of thrombosis in patients with cancer is complex due to various individual and disease-related factors, including drug-drug interactions (DDIs). Furthermore, DDIs may impact both, cancer and venous thrombosis, treatment effectiveness and safety; their relevance is highlighted by the advances in cancer therapeutics. Given that these new oncol

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… Inhibitor No No CUP, Ewing, Lung, NETs, Osteosarcoma, Ovarian, Testicular, Thymoma Etoposide Inducer/weak inhibitor Inhibitor No 97% Breast, Kidney, NETs Everolimus Weak inhibitor and substrate Inhibitor and substrate No 74% Breast Exemestane Substrate No No 90% Melanoma Fotemustin No No No 25-30% Breast Fulvestrant … Osteosarcoma, Ovarian, Testicular, Thymoma | Etoposide | Inducer/weak inhibitor | Inhibitor | No | 97% Breast, Kidney, NETs | Everolimus | Weak inhibitor and substrate | Inhibitor and substrate | No | 74% Breast | Exemestane | Substrate | No | No | 90% Melanoma | Fotemustin | No | No | No | 25-30% Breast | Fulvestrant …

Customized Marketing Strategies for Cancer Immunocyte Therapy Based on its Distinctive Attributes.

Cancer constitutes a persistent global health challenge, and immunocyte therapy has emerged as one approach in oncological care. This narrative review aimed to systematically analyze, synthesize, and critically interpret the therapeutic characteristics, advantages, market landscape, and current access barriers of cancer immunocyte therapy, based on thematic clustering and cross‑study integration of clinical evidence, market data, and industry reports. Immunocyte therapy exhibits distinctive features including personalization, long‑term immune memory, and observed efficacy in refractory maligna

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… Drug interactions reduce therapeutic efficacy Hormone-dependent tumors Tamoxifen, Letrozole, Fulvestrant, Bicalutamide, Leuprorelin, Abiraterone Low Low High (standardized) [ 33–38 ] Targeted therapy 1. Inhibit abnormal signal pathways 2. Targeted inhibition of tumor angiogenesis 3. … Drug interactions reduce therapeutic efficacy | Hormone-dependent tumors | Tamoxifen, Letrozole, Fulvestrant, Bicalutamide, Leuprorelin, Abiraterone | Low | Low | High (standardized) | [ 33–38 ] Targeted therapy | 1. Inhibit abnormal signal pathways 2. Targeted inhibition of tumor angiogenesis 3. …

Systematic review and meta-analysis comparing zoledronic acid administered at 12-week and 4-week intervals in patients with bone metastasis.

Zoledronic acid is used to treat patients with bone metastasis, but the optimal dosing interval remains controversial. We therefore performed a systematic review and meta-analysis to compare the efficacy and safety of a 12-week interval of zoledronic acid with the standard 4-week interval. Three randomized controlled trials comprising 2650 patients were analyzed. Using a random-effects model, pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated. No differences in the occurrence of skeletal-related events (SREs: RR = 0.98; 95% CI = 0.86-1.12; P = 0.80) or grade 3/4 advers

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… Randomised, phase II, placebo-controlled, trial of fulvestrant plus vandetanib in postmenopausal women with bone only or bone predominant, hormone-receptor-positive metastatic breast cancer (MBC): the OCOG ZAMBONEY study. …

Emerging role of low-frequency somatic mutations in cancer relapse: from early detection to precision oncology.

Somatic mutations with low variant allele frequencies offer a highly sensitive lens for detecting cancer relapse driven by diverse causes, including clonal evolution and therapy resistance. Advances in next-generation sequencing have enabled robust subclonal variant identification that typically fall below conventional detection limits, supporting a comprehensive understanding of individual molecular profiles that can lead to relapse. These low-level alterations frequently emerge before clinical or radiological relapse and can inform response-adaptive treatment decisions. This review integrate

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… Patients with emergent ESR1 mutations were randomized to either continue the current therapy or switch to fulvestrant. The molecular-guided drug switch was shown to improve PFS (median 11.9 vs 5.7 months) ( 118 ). … Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial . …

Bone-Targeted Agents for the Management of Breast Cancer Patients with Bone Metastases.

Despite advances in adjuvant therapy for breast cancer, bone remains the most common site of recurrence. The goal of therapy for these patients is palliative and focused on maximizing the duration and quality of their life, while concurrently minimizing any disease or treatment-related complications. Bone metastases predispose patients to reduced survival, pain, impaired quality of life and the development of skeletal-related events. With an increased understanding of the pathophysiology of bone metastasis, effective treatments for their management have evolved and are now in widespread clinic

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… trials are ongoing with SRC inhibitors to evaluate bone turnover markers as a specified endpoint in addition to tumour responses in breast cancer, including randomized phase II studies with exemestane [ 71 ] or letrozole administered with or without dasatinib [ 72 ], a randomized phase II study of fulvestrant … Phase II Randomized Trial of Fulvestrant with or without Dasatinib in Men and Postmenopausal Women Who Have Hormone Receptor-Positive Advanced Breast Cancer Previously Treated with an Aromatase Inhibitor. [(accessed on 15 May 2013)]. Available online: http://clinicaltrials.gov . 74. …

FDA-Approved Drugs Containing Amide Functionality in the Last Five Years (2021-2025): Pharmaceutical Use, Trends and Synthetic Approaches.

The amide functional group remains a cornerstone of medicinal chemistry, serving as an indispensable scaffold in the design of modern therapeutics. This review presents an analysis of FDA-approved drugs (small molecules and peptides with MW ®), amides form the structural backbone of peptidomimetics, enabling high-affinity binding to a viral protease. In precision oncology, as seen with adagrasib (Krazati®), the amide acts as a critical, metabolically stable linker that positions a covalent warhead for selective inhibition of a mutant kinase. This analysis underscores that amide's unique combin

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… FDA on 16 November 2023, capivasertib ( 44 , brand name Truqap ® , Figure 31 a) is a small molecule that, in combination with fulvestrant, has an indication for adult patients with advanced or metastatic hormone receptor (HR)-positive, HER2-negative breast cancer that has specific genetic alterations … Fulvestrant serves as the foundational hormonal therapy designed to stop hormone receptor-positive breast cancer cells from growing by inhibiting estrogen action [ 130 ]. The formation of the amide bond in capivasertib is shown in Figure 31 b. …

Charting the Current Landscape and Future Prospects of Cancer Therapy-Related Cardiovascular Toxicity in Cancer Survivors: From Bench to Bedside.

Cardio-oncology represents an emerging interdisciplinary discipline focusing on optimizing oncologic efficacy while mitigating treatment-related cardiovascular complications. The advent of novel anticancer agents such as targeted therapies, immune checkpoint inhibitors, and endocrine therapies has transformed cancer care, significantly improving survival rates. Nevertheless, prolonged patient survivorship has unmasked clinically significant cardiovascular sequelae, termed cancer therapy-related cardiovascular toxicity (CTR-CVT), which manifests as acute manifestations during therapy and delaye

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… Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol . 2018;36(24):2465–2472. doi: 10.1200/JCO.2018.78.9909 78. Slamon DJ, Neven P, Chia S, et al. … Overall survival with ribociclib plus fulvestrant in advanced breast cancer. N Engl J Med . 2020;382(6):514–524. doi: 10.1056/NEJMoa1911149 79. Hu JR, Florido R, Lipson EJ, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors. …

Maximizing the impact of real-world evidence on cancer treatment: what do we need to achieve it?

There is an increasing number of studies using real-world data to examine outcomes of drugs in clinical practice. Therefore, it is crucial to carefully evaluate their quality and findings, extract valuable insights, acknowledge their limitations and identify gaps to advance further their use in decision-making. Here we provide an overview of the opportunities offered throughout drug lifecycle, and challenges presented by real-world evidence (RWE) studies. We also highlight the importance of the culture of transparency, along with the development of good practices for reporting RWE studies. In

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… Turner NC , Slamon DJ , Ro J Overall survival with palbociclib and fulvestrant in advanced breast cancer . N. Engl. J. Med. 379 ( 20 ), 1926 – 1936 ( 2018 ). 30345905 10.1056/NEJMoa1810527 67. … Kalinsky K , Bianchini G , Hamilton E Abemaciclib plus fulvestrant in advanced breast cancer after progression on CDK4/6 inhibition: results from the Phase III postMONARCH trial . J. Clin. Oncol. 43 ( 9 ), 1101 – 1112 ( 2025 ). 39693591 10.1200/JCO-24-02086 PMC11936477 78. …

Biopsy Techniques for Musculoskeletal Tumors: Basic Principles and Specialized Techniques.

Biopsy is a pivotal component in the diagnostic process of bone and soft tissue tumors. The objective is to obtain adequate tissue without compromising local tumor dissemination and the patient's survival. This review explores contemporary principles and practices in musculoskeletal biopsies, emphasizing the critical role of diagnostic accuracy while also delving into the evolving landscape of liquid biopsies as a promising alternative in the field. A thorough literature search was done in PubMed and Google Scholar as well as in physical books in libraries to summarize the available biopsy tec

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… Early Circulating Tumor DNA Dynamics and Clonal Selection with Palbociclib and Fulvestrant for Breast Cancer. Nat. Commun. 2018;9:896. doi: 10.1038/s41467-018-03215-x. 93. O’Leary B., Cutts R.J., Liu Y., Hrebien S., Huang X., Fenwick K., André F., Loibl S., Loi S., Garcia-Murillas I., et al. … The Genetic Landscape and Clonal Evolution of Breast Cancer Resistance to Palbociclib plus Fulvestrant in the PALOMA-3 Trial. Cancer Discov. 2018;8:1390–1403. doi: 10.1158/2159-8290.CD-18-0264. 94. …

Diagnosis and Treatment of Bone Metastases in Breast Cancer: Radiotherapy, Local Approach and Systemic Therapy in a Guide for Clinicians.

The standard care for metastatic breast cancer (MBC) is systemic therapies with imbrication of focal treatment for symptoms. Recently, thanks to implementation of radiological and metabolic exams and development of new target therapies, oligometastatic and oligoprogressive settings are even more common-paving the way to a paradigm change of focal treatments role. In fact, according to immunophenotype, radiotherapy can be considered with radical intent in these settings of patients. The aim of this literature review is to analyze available clinical data on prognosis of bone metastases from brea

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… Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): Final analysis of the multicentre, double-blind, phase 3 randomised controlled trial Lancet Oncol. …

State-of-the-art imaging for diagnosis of metastatic bone disease.

Metastatic bone disease (MBD) is common-it is detected in up to 65-75% of patients with breast or prostate cancer, in over 35% of patients with lung cancer; and almost all patients with symptomatic multiple myeloma have focal lesions or a diffuse bone marrow infiltration. Metastatic bone disease can cause a variety of symptoms and is often associated with a poorer prognosis, with high social and health-care costs. Population-based cohort studies confirm significantly increased health-care utilization costs in patients presenting with cancer with MBD compared with those without MBD. The prolong

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… She was switched to second-line hormonal therapy with fulvestrant and zoledronic acid on bone disease progression (exam 5, 6), with response in her bone disease only shown on quantitative WB-MRI. … She was switched to second-line hormonal therapy with fulvestrant and zoledronic acid on bone disease progression (exam 5, 6), with response in her bone disease only shown on quantitative WB-MRI. …

Confirmatory Trials in the Evaluation of Anticancer Medicinal Products in Man--PFS2: A Measure of Therapeutic Action-At-A-Distance.

Overall survival (OS) has emerged as the definitive regulatory "be-all, end-all" for the demonstration of benefit in cancer clinical trials. The reason and the rationale for why this is so are easily appreciated: literally a "test of time," OS is a seemingly unambiguous, agenda-free end point, independent of bias-prone variables such as the frequency and methods of assessment, clinical evaluation, and the definition of progression. However, by general consensus, OS is an imperfect end point for several reasons: First, it may often be impractical because of the length, cost, and the size of cli

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… Comparing duration of response and duration of clinical benefit between fulvestrant treatment groups in the CONFIRM trial: application of new methodology. Breast Cancer Res Treat. 2013;138(1):149–155. doi: 10.1007/s10549-012-2395-8. 16. Pervaiz S, Clement MV. …

Bone Effects of Anti-Cancer Treatments in 2024.

Considerable progress has been made in the management of cancer patients in the last decade with the arrival of anti-cancer immunotherapies (immune checkpoint inhibitors) and targeted therapies. As a result, a broad spectrum of cancers, not just hormone-sensitive ones, have seen several patients achieve profound and prolonged remissions, or even cures. The management of medium- and long-term side-effects of treatment and quality of life of patients are essential considerations. This is especially true for bone, as bone fragility can lead to increased fractures and loss of autonomy, ultimately

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… Fracture risk on fulvestrant has not been studied. Effect on BMD Tamoxifen and toremifene preserve or even increase BMD of the lumbar spine, hip, and femoral neck at 2 years in postmenopausal women with breast cancer [ 42 ]. … The effect of BMD on fulvestrant has not been studied. Effect on Bone Remodeling Alone or in combination with AIs, tamoxifen decreases bone turnover [ 42 , 48 ]. Urinary NTX decreases rapidly in the first few months and then gradually over the course of treatment. …

Unexpected massive bleeding caused by extensive maxillary osteonecrosis in a breast cancer patient: a case report.

Diphosphonate application is routinely recommended to treat bone metastasis (BM) in cancer patients. However, the severe side effects of diphosphonate, especially after long-term use, are often overlooked by clinicians. In this article, we describe a case in which a heavily-treated breast cancer patient, suffered from massive bleeding as a result of maxillary osteonecrosis by zoledronic acid (ZA) and apatinib. In October 2018, a 48-year-old Chinese female with breast cancer presented at our department with brain metastases. The patient had experienced progression multiple times and had receive

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… Fulvestrant was administered from October 30, 2018, to April 26, 2019. This patient was heavily treated and her prognosis was poor. Figure 1 Maxillofacial computed tomography (CT) and pathological findings. …

Time to deterioration of patient-reported outcome endpoints in cancer clinical trials: targeted literature review and best practice recommendations.

BackgroundTime to deterioration (TTD) endpoints are often utilized in the analysis of patient-reported outcome (PRO) data in oncology clinical trials but different endpoint definitions and analysis frameworks exist that can impact result interpretation. This review examined the analysis, reporting and heterogeneity of TTD endpoints in the literature, the impact of analysis methods on results, and provides recommendations for future trials.MethodsA targeted literature review of articles published between 2017 and 2022 was performed to collate TTD endpoints reported in oncology randomized contro

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… Kaufman PA Toi M Neven P Health-related quality of life in MONARCH 2: abemaciclib plus fulvestrant in hormone receptor-positive, HER2-negative advanced breast cancer after endocrine therapy Oncologist 2020 25 2 e243 e251 10.1634/theoncologist.2019-0551 32043763 PMC7011625 Kaufman PA, Toi M, Neven P et … al (2020) Health-related quality of life in MONARCH 2: abemaciclib plus fulvestrant in hormone receptor-positive, HER2-negative advanced breast cancer after endocrine therapy. …

Molecularly Targeted Therapies in Oncology: Mechanisms, Resistance, and Combination Strategies.

Targeted therapies are reshaping oncology by enabling treatment selection based on actionable molecular alterations, improving precision, and reducing unnecessary toxicity. This review provides an up-to-date overview of current targeted treatment modalities and the medicinal chemistry principles that support their discovery and optimization. We synthesize evidence on small-molecule and biologic strategies spanning receptor and non-receptor kinases and their major signaling axes (PI3K-AKT-mTOR and RAS-RAF-MEK-ERK), apoptosis regulation (BCL-2 family), DNA repair via poly(ADP-ribose) polymerase

Critical considerations in the administration of antineoplastic therapy for patients with malignant solid tumors undergoing hemodialysis.

Patients with chronic kidney disease exhibit a higher risk of developing malignancies, and among those with end-stage renal disease (ESRD) on dialysis, approximately 7% are diagnosed with new-onset tumors within five years. Patients with ESRD who are receiving antineoplastic treatment exhibit a significantly higher incidence and greater severity of adverse effects associated with antineoplastic agents compared to individuals with normal renal function. This complexity involves multiple factors, including the therapy options and dose adjustment of antineoplastic agents, drug-related toxicities,

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… Exemestane, letrozole, and fulvestrant all had only a small portion excreted unaltered in the urine. Thus, dose adjustments are not required for the use of selective estrogen receptor modulators in patients undergoing hemodialysis ( 23 , 110 , 111 ). … Pharmacokinetics, efficacy and safety of palbociclib and fulvestrant in a patient with hormone receptor-positive, human epidermal growth factor receptor 2 negative metastatic breast cancer with end-stage renal disease undergoing hemodialysis: A case report. …

Keyword Index for Volume 109

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… tomography-computed tomography 1445 focal adhesion turnover 2810 folate 2175 FOLFOX/XELOX 2765 follicular lymphoma 1287 follow-up 29, 312, 623, 866, 1766 food 2904 four-and–a-half LIM domains protein 2 114 FOXO3 protein 387 FOXO3a 1198 fragile sites 2347 FSH 1522 FTO 872 fucosyltransferase 3014 fulvestrant …

Keyword Index for Volume 90

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… redistribution 1450 fluoropyrimidines 526, 1190, 1740 fluorouracil 2338 FNA 595 foci 2356 foetal antigens 1374 folate 1969 folinic acid 1710 follicular adenoma 1600 follicular carcinoma 1600 follicular undifferentiation 492 follow-up 1144 fractional polynomials 794 free radicals 1274 fruits 2167 fulvestrant …