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Journal of Clinical Oncology : Official... Jun 2024Long-term outcomes of patients with stage I human epidermal growth factor receptor 2 (HER2)-positive breast cancer receiving adjuvant trastuzumab emtansine (T-DM1)...
Adjuvant Trastuzumab Emtansine Versus Paclitaxel Plus Trastuzumab for Stage I Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: 5-Year Results and Correlative Analyses From ATEMPT.
PURPOSE
Long-term outcomes of patients with stage I human epidermal growth factor receptor 2 (HER2)-positive breast cancer receiving adjuvant trastuzumab emtansine (T-DM1) remain undefined, and prognostic predictors represent an unmet need.
METHODS
In the ATEMPT phase II trial, patients with stage I centrally confirmed HER2-positive breast cancer were randomly assigned 3:1 to adjuvant T-DM1 for 1 year or paclitaxel plus trastuzumab (TH). Coprimary objectives were to compare the incidence of clinically relevant toxicities between arms and to evaluate invasive disease-free survival (iDFS) with T-DM1. Correlative analyses included the HER2DX genomic tool, multiomic evaluations of HER2 heterogeneity, and predictors of thrombocytopenia.
RESULTS
After a median follow-up of 5.8 years, 11 iDFS events were observed in the T-DM1 arm, consistent with a 5-year iDFS of 97.0% (95% CI, 95.2 to 98.7). At 5 years, the recurrence-free interval (RFI) was 98.3% (95% CI, 97.0 to 99.7), the overall survival was 97.8% (95% CI, 96.3 to 99.3), and the breast cancer-specific survival was 99.4% (95% CI, 98.6 to 100). Comparable iDFS was observed with T-DM1 irrespective of tumor size, hormone receptor status, centrally determined HER2 immunohistochemical score, and receipt of T-DM1 for more or less than 6 months. Although ATEMPT was not powered for this end point, the 5-year iDFS in the TH arm was 91.1%. Among patients with sufficient tissue for HER2DX testing (n = 187), 5-year outcomes significantly differed according to HER2DX risk score, with better RFI (98.1% 81.8%, hazard ratio [HR], 0.10, = .01) and iDFS (96.3% 81.8%, HR, 0.20, = .047) among patients with HER2DX low-risk versus high-risk tumors, respectively.
CONCLUSION
Adjuvant T-DM1 for 1 year leads to outstanding long-term outcomes for patients with stage I HER2-positive breast cancer. A high HER2DX risk score predicted a higher risk of recurrence in ATEMPT.
PubMed: 38935923
DOI: 10.1200/JCO.23.02170 -
PloS One 2024Mucosal-delivered drugs have to pass through the mucus layer before absorption through the epithelial cell membrane. Although there has been increasing interest in...
Mucosal-delivered drugs have to pass through the mucus layer before absorption through the epithelial cell membrane. Although there has been increasing interest in polymeric mucins, a major structural component of mucus, potentially acting as important physiological regulators of mucosal drug absorption, there are no reports that have systematically evaluated the interaction between mucins and drugs. In this study, we assessed the potential interaction between human polymeric mucins (MUC2, MUC5B, and MUC5AC) and various drugs with different chemical profiles by simple centrifugal method and fluorescence analysis. We found that paclitaxel, rifampicin, and theophylline likely induce the aggregation of MUC5B and/or MUC2. In addition, we showed that the binding affinity of drugs for polymeric mucins varied, not only between individual drugs but also among mucin subtypes. Furthermore, we demonstrated that deletion of MUC5AC and MUC5B in A549 cells increased the cytotoxic effects of cyclosporin A and paclitaxel, likely due to loss of mucin-drug interaction. In conclusion, our results indicate the necessity to determine the binding of drugs to mucins and their potential impact on the mucin network property.
Topics: Humans; Paclitaxel; Mucin 5AC; A549 Cells; Drug Interactions; Mucin-5B; Mucins; Mucin-2; Rifampin; Cyclosporine; Protein Binding
PubMed: 38935605
DOI: 10.1371/journal.pone.0306058 -
JAMA Oncology Jun 2024The optimal radiotherapy technique for unresectable locally advanced non-small cell lung cancer (NSCLC) is controversial, so evaluating long-term prospective outcomes of...
IMPORTANCE
The optimal radiotherapy technique for unresectable locally advanced non-small cell lung cancer (NSCLC) is controversial, so evaluating long-term prospective outcomes of intensity-modulated radiotherapy (IMRT) is important.
OBJECTIVE
To compare long-term prospective outcomes of patients receiving IMRT and 3-dimensional conformal radiotherapy (3D-CRT) with concurrent carboplatin/paclitaxel for locally advanced NSCLC.
DESIGN, SETTING, AND PARTICIPANTS
A secondary analysis of a prospective phase 3 randomized clinical trial NRG Oncology-RTOG 0617 assessed 483 patients receiving chemoradiotherapy (3D-CRT vs IMRT) for locally advanced NSCLC based on stratification.
MAIN OUTCOMES AND MEASURES
Long-term outcomes were analyzed, including overall survival (OS), progression-free survival (PFS), time to local failure, development of second cancers, and severe grade 3 or higher adverse events (AEs) per Common Terminology Criteria for Adverse Events, version 3. The percentage of an organ volume (V) receiving a specified amount of radiation in units of Gy is reported as V(radiation dose).
RESULTS
Of 483 patients (median [IQR] age, 64 [57-70] years; 194 [40.2%] female), 228 (47.2%) received IMRT, and 255 (52.8%) received 3D-CRT (median [IQR] follow-up, 5.2 [4.8-6.0] years). IMRT was associated with a 2-fold reduction in grade 3 or higher pneumonitis AEs compared with 3D-CRT (8 [3.5%] vs 21 [8.2%]; P = .03). On univariate analysis, heart V20, V40, and V60 were associated with worse OS (hazard ratios, 1.06 [95% CI, 1.04-1.09]; 1.09 [95% CI, 1.05-1.13]; 1.16 [95% CI, 1.09-1.24], respectively; all P < .001). IMRT significantly reduced heart V40 compared to 3D-CRT (16.5% vs 20.5%; P < .001). Heart V40 (<20%) had better OS than V40 (≥20%) (median [IQR], 2.5 [2.1-3.1] years vs 1.7 [1.5-2.0] years; P < .001). On multivariable analysis, heart V40 (≥20%), was associated with worse OS (hazard ratio, 1.34 [95% CI, 1.06-1.70]; P = .01), whereas lung V5 and age had no association with OS. Patients receiving IMRT and 3D-CRT had similar rates of developing secondary cancers (15 [6.6%] vs 14 [5.5%]) with long-term follow-up.
CONCLUSIONS AND RELEVANCE
These findings support the standard use of IMRT for locally advanced NSCLC. IMRT should aim to minimize lung V20 and heart V20 to V60, rather than constraining low-dose radiation bath. Lung V5 and age were not associated with survival and should not be considered a contraindication for chemoradiotherapy.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT00533949.
PubMed: 38935373
DOI: 10.1001/jamaoncol.2024.1841 -
Nanomedicine (London, England) Jun 2024Paclitaxel and imatinib mesylate are drugs used in the treatment of breast cancer. Conventional drug-delivery systems have limitations in the effective treatment of...
Paclitaxel and imatinib mesylate are drugs used in the treatment of breast cancer. Conventional drug-delivery systems have limitations in the effective treatment of breast cancer using the drugs. Combination index studies were used to identify the optimum ratio of both drugs showing maximum synergistic effect. Using a systematic quality-by-design approach, protamine-coated PLGA nanoparticles co-loaded with paclitaxel and imatinib mesylate were formulated. Further characterization and cell line evaluations were performed. Encapsulation efficiency obtained was 92.54% for paclitaxel and 75.12% for imatinib mesylate. A sustained (24 h) and controlled zero-order drug release was obtained. Formulated nanoparticles had a low IC value and enhanced cellular uptake.
PubMed: 38934510
DOI: 10.1080/17435889.2024.2353557 -
Scandinavian Journal of Clinical and... Jun 2024Neoadjuvant chemotherapy (NAC) is the preferred treatment option in locally advanced breast cancer (BC). The administration of NAC is associated with a wide range of...
Neoadjuvant chemotherapy (NAC) is the preferred treatment option in locally advanced breast cancer (BC). The administration of NAC is associated with a wide range of adverse effects. This pilot observational prospective study examined the effect of NAC using anthracycline + cyclophosphamide (AC) followed by paclitaxel (PTx) on a portfolio of 22 plasma and urinary amino acids, plasma proteins (albumin, prealbumin, transferrin), and products of nitrogen metabolism (urea, creatinine, uric acid) in plasma and urine. Plasma and 24-h urine samples were obtained from ten patients with early breast cancer (N1-3 N0-2 M0), at the following time points: before the start of NAC and during the AC/PTx treatment period (a total of 8 measurements at three-weekly intervals). Amino acids were analyzed using ion exchange chromatography. There were no significant differences in the measured parameters in plasma and urine between pre-NAC and during AC- and PTx-treatment. No trend was detected. A significant difference in the portfolio of plasma and urinary amino acids was found only in the pre-treatment period compared to the control group. Levels of eight plasma amino acids (8/22) were significantly reduced and those of nine urine amino acids were increased (9/22). Nitrogenous catabolites in plasma and urine were not indicative of increased protein catabolism during the anthracycline and taxane treatment periods. A slightly positive nitrogen balance was accompanied by an average weight gain of 3.3 kg (range 0-6 kg). The AC/PTx treatment regimen did not cause significant changes in the monitored laboratory parameters.
PubMed: 38934425
DOI: 10.1080/00365513.2024.2369982 -
Oncology Letters Aug 2024Adjuvant chemotherapy is usually not considered for pT1a pN0 human epidermal growth factor receptor 2 (HER2)-positive breast cancer due to its low recurrence rate. The...
Multiple metastases of human epidermal growth factor receptor 2‑positive, hormone receptor‑positive, pT1a pN0 breast cancer within 1 year after surgery: A case report.
Adjuvant chemotherapy is usually not considered for pT1a pN0 human epidermal growth factor receptor 2 (HER2)-positive breast cancer due to its low recurrence rate. The present report describes a case of pT1a hormone receptor-positive HER2-positive breast cancer with multiple recurrences in the axillary lymph nodes and liver within 1 year after radical surgery. A 58-year-old woman underwent left total mastectomy and sentinel lymph node biopsy for left breast cancer with pathological stage IA (pT1a pN0). The subtype corresponded to luminal B-like breast cancer with a nuclear grade of 3 and a Ki-67 labeling index of 37%. An aromatase inhibitor (letrozole) was planned to be administered for 5 years after surgery, but the patient was diagnosed with multiple liver and axillary lymph node metastases 11 months after surgery. After 1 year of chemotherapy (paclitaxel) in combination with anti-HER2 therapy (pertuzumab and trastuzumab), liver metastases resolved. A complete response of the liver lesion has been maintained 4 years after the anti-HER2 therapy initiation. The present case exhibited two poor prognostic factors: High Ki-67 labeling index and nuclear grade 3. Based on the 'Predict' tool, the present case would be expected to have a cancer-related mortality rate of 6% 10 years after surgery with adjuvant endocrine therapy. Although this value may be controversial for postoperative anti-HER2 therapy, the present case should not be considered to be a low-risk case. When the identification of high-risk pT1a pN0 HER2-positive breast cancer is possible, postoperative anti-HER2 therapy plus chemotherapy would be effective in decreasing the rate of recurrence.
PubMed: 38933808
DOI: 10.3892/ol.2024.14498 -
Frontiers in Pharmacology 2024Chemotherapy-induced peripheral neuropathy (CIPN) is a shared burden for 68.1% of oncological patients undergoing chemotherapy with Paclitaxel (PTX). The symptoms are...
Chemotherapy-induced peripheral neuropathy (CIPN) is a shared burden for 68.1% of oncological patients undergoing chemotherapy with Paclitaxel (PTX). The symptoms are intense and troublesome, patients reporting paresthesia, loss of sensation, and dysesthetic pain. While current medications focus on decreasing the symptom intensity, often ineffective, no medication is yet recommended by the guidelines for the prevention of CIPN. Cannabinoids are an attractive option, as their neuroprotective features have already been demonstrated in neuropathies with other etiologies, by offering the peripheral neurons protection against toxic effects, which promotes analgesia. We aim to screen several new cannabinoids for their potential use as neuroprotective agents for CIPN by investigating the cellular toxicity profile and by assessing the potential neuroprotective features against PTX using a primary dorsal root ganglion neuronal culture. Our study showed that synthetic cannabinoids JWH-007, AM-694 and MAB-CHMINACA and phytocannabinoids Cannabixir Medium dried flowers (NC1) and Cannabixir THC full extract (NC2) preserve the viability of fibroblasts and primary cultured neurons, in most of the tested dosages and time-points. The combination between the cannabinoids and PTX conducted to a cell viability of 70%-89% compared to 40% when PTX was administered alone for 48 h. When assessing the efficacy for neuroprotection, the combination between cannabinoids and PTX led to better preservation of neurite length at all tested time-points compared to controls, highly drug and exposure-time dependent. By comparison, the combination of the cannabinoids and PTX administered for 24 h conducted to axonal shortening between 23% and 44%, as opposed to PTX only, which shortened the axons by 63% compared to their baseline values. Cannabinoids could be potential new candidates for the treatment of paclitaxel-induced peripheral neuropathy; however, our findings need to be followed by additional tests to understand the exact mechanism of action, which would support the translation of the cannabinoids in the oncological clinical practice.
PubMed: 38933665
DOI: 10.3389/fphar.2024.1395951 -
Pharmaceutics Jun 2024This comprehensive review consolidates insights from two sources to emphasize the transformative impact of scaffold-based drug delivery systems in revolutionizing oral... (Review)
Review
This comprehensive review consolidates insights from two sources to emphasize the transformative impact of scaffold-based drug delivery systems in revolutionizing oral cancer therapy. By focusing on their core abilities to facilitate targeted and localized drug administration, these systems enhance therapeutic outcomes significantly. Scaffolds, notably those coated with anti-cancer agents such as cisplatin and paclitaxel, have proven effective in inhibiting oral cancer cell proliferation, establishing a promising avenue for site-specific drug delivery. The application of synthetic scaffolds, including Poly Ethylene Glycol (PEG) and poly(lactic-co-glycolic acid) (PLGA), and natural materials, like collagen or silk, in 3D systems has been pivotal for controlled release of therapeutic agents, executing diverse anti-cancer strategies. A key advancement in this field is the advent of smart scaffolds designed for sequential cancer therapy, which strive to refine drug delivery systems, minimizing surgical interventions, accentuating the significance of 3D scaffolds in oral cancer management. These systems, encompassing local drug-coated scaffolds and other scaffold-based platforms, hold the potential to transform oral cancer treatment through precise interventions, yielding improved patient outcomes. Local drug delivery via scaffolds can mitigate systemic side effects typically associated with chemotherapy, such as nausea, alopecia, infections, and gastrointestinal issues. Post-drug release, scaffolds foster a conducive environment for non-cancerous cell growth, adhering and proliferation, demonstrating restorative potential. Strategies for controlled and targeted drug delivery in oral cancer therapy span injectable self-assembling peptide hydrogels, nanocarriers, and dual drug-loaded nanofibrous scaffolds. These systems ensure prolonged release, synergistic effects, and tunable targeting, enhancing drug delivery efficiency while reducing systemic exposure. Smart scaffolds, capable of sequential drug release, transitioning to cell-friendly surfaces, and enabling combinatorial therapy, hold the promise to revolutionize treatment by delivering precise interventions and optimized outcomes. In essence, scaffold-based drug delivery systems, through their varied forms and functionalities, are reshaping oral cancer therapy. They target drug delivery efficiency, diminish side effects, and present avenues for personalization. Challenges like fabrication intricacy, biocompatibility, and scalability call for additional research. Nonetheless, the perspective on scaffold-based systems in oral cancer treatment is optimistic, as ongoing advancements aim to surmount current limitations and fully leverage their potential in cancer therapy.
PubMed: 38931923
DOI: 10.3390/pharmaceutics16060802 -
Pharmaceutics May 2024Dendrimers are potent nanocarriers in drug delivery systems because their structure can be precisely controlled. We previously reported that polyamidoamine (PAMAM)...
Dendrimers are potent nanocarriers in drug delivery systems because their structure can be precisely controlled. We previously reported that polyamidoamine (PAMAM) dendrimers that were modified with 1,2-cyclohexanedicarboxylic acid (CHex) and phenylalanine (Phe), PAMAM-CHex-Phe, exhibited an effective association with various immune cells, including T-cells. In this study, we synthesized various carboxy-terminal Phe-modified dendrimers with different linkers using phthalic acid and linear dicarboxylic acids to determine the association of these dendrimers with Jurkat cells, a T-cell model. PAMAM--hexyl-Phe demonstrated the highest association with Jurkat T-cells. In addition, dendri-graft polylysine (DGL) with CHex and Phe, DGL-CHex-Phe, was synthesized, and its association with Jurkat cells was investigated. The association of DGL-CHex-Phe with T-cells was higher than that of PAMAM-CHex-Phe. However, it was insoluble in water and thus it is unsuitable as a drug carrier. Model drugs, such as protoporphyrin IX and paclitaxel, were loaded onto these dendrimers, and the most model drug molecules could be loaded into PAMAM-CHex-Phe. PTX-loaded PAMAM-CHex-Phe exhibited cytotoxicity against Jurkat cells at a similar level to free PTX. These results suggest that PAMAM-CHex-Phe exhibited both efficient T-cell association and drug loading properties.
PubMed: 38931839
DOI: 10.3390/pharmaceutics16060715 -
Pharmaceuticals (Basel, Switzerland) May 2024Investigating pharmacovigilance (PV) practices among oncology healthcare providers (HCPs) is crucial for patient safety in oncology settings. This study aimed to assess...
Investigating pharmacovigilance (PV) practices among oncology healthcare providers (HCPs) is crucial for patient safety in oncology settings. This study aimed to assess the awareness, attitudes, and practices towards PV and identify barriers to effective adverse drug reaction (ADR) reporting for HCPs working in oncology-related settings. Employing a cross-sectional survey design, we collected data from 65 HCPs, focusing on their experiences with ADR reporting, education on ADR management, and familiarity with PV protocols. The results showed that about half of the responders were pharmacists. Around 58.9% of the respondents reported ADRs internally, and 76.9% had received some form of ADR-related education. However, only 38.5% were aware of formal ADR review procedures. Methotrexate and paclitaxel emerged as the drugs most frequently associated with ADRs. The complexity of cancer treatments was among the common reasons for the low reporting of ADRs by the study participants. The findings highlight the need for enhanced PV education and standardized reporting mechanisms to improve oncology care. We conclude that reinforcing PV training and streamlining ADR-reporting processes are critical to optimizing patient outcomes and safety in oncology, advocating for targeted educational interventions and the development of unified PV guidelines.
PubMed: 38931351
DOI: 10.3390/ph17060683