PURPOSE: The CD47 molecule, often referred to as the "do not eat me" signal, is frequently overexpressed in tumor cells. This signaling pathway limits phagocytosis by macrophages. Our objective was to determine CD47 abundance in various soft tissue sarcomas (STS) to investigate whether it could serve as a potential evasion mechanism for tumor cells. Additionally, we aimed to assess the prognostic value of CD47 expression by examining its association with different clinicopathological factors. This study aimed to elucidate the significance of CD47 in the context of emerging anti-tumor targeting approaches. METHODS: In this retrospective study, formalin-fixed paraffine-embedded (FFPE) tumor tissues of 55 treatment-naïve patients were evaluated by immunohistochemistry for the abundance of CD47 molecule on tumor cells. The categorization of CD47 positivity was as follows: 0 (no staining of tumor cells), 1 + (less than 1/3 of tumor area positive), 2 + (between 1/3 and 2/3 of tumor area positive), and 3 + (more than 2/3 of tumor area positive for CD47). Next, we compared CD47 abundance between different tumor grades (G1-3). We used Kaplan-Meier survival curves with log-rank test to analyze the differences in survival between patients with different CD47 expression. Moreover, we performed Cox proportional hazards regression model to evaluate the clinical significance of CD47. RESULTS: CD47 is widely prevalent across distinct STS subtypes. More than 80% of high grade undifferentiated pleiomorphic sarcoma (UPS), 70% of myxofibrosarcoma (MFS) and more than 60% of liposarcoma (LPS) samples displayed a pattern of moderate-to-diffuse positivity. This phenomenon remains consistent regardless of the tumor grade. However, there was a tendency for higher CD47 expression levels in the G3 group compared to the combined G1 + G2 groups when all LPS, MFS, and UPS were analyzed together. No significant associations were observed between CD47 abundance, death, and metastatic status. Additionally, high CD47 expression was associated with a statistically significant increase in progression-free survival in the studied cohort of patients. CONCLUSION: This study highlights the potential of the CD47 molecule as a promising immunotherapeutic target in STS, particularly given its elevated expression levels in diverse sarcoma types. Our data showed a notable trend linking CD47 expression to tumor grade, while also suggesting an interesting correlation between enhanced abundance of CD47 expression and a reduced hazard risk of disease progression. Although these findings shed light on different roles of CD47 in STS, further research is crucial to assess its potential in clinical settings.
- MeSH
- antigeny CD47 metabolismus MeSH
- dospělí MeSH
- lidé MeSH
- lipopolysacharidy MeSH
- makrofágy patologie MeSH
- nádory měkkých tkání * patologie MeSH
- prognóza MeSH
- retrospektivní studie MeSH
- sarkom * terapie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Selpercatinib, a highly selective, potent RET inhibitor, has shown efficacy in advanced RET-mutant medullary thyroid cancer in a phase 1-2 trial, but its efficacy as compared with approved multikinase inhibitors is unclear. METHODS: We conducted a phase 3, randomized trial comparing selpercatinib as first-line therapy with the physician's choice of cabozantinib or vandetanib (control group). Eligible patients had progressive disease documented within 14 months before enrollment. The primary end point in the protocol-specified interim efficacy analysis was progression-free survival, assessed by blinded independent central review. Crossover to selpercatinib was permitted among patients in the control group after disease progression. Treatment failure-free survival, assessed by blinded independent central review, was a secondary, alpha-controlled end point that was to be tested only if progression-free survival was significant. Among the other secondary end points were overall response and safety. RESULTS: A total of 291 patients underwent randomization. At a median follow-up of 12 months, median progression-free survival as assessed by blinded independent central review was not reached in the selpercatinib group and was 16.8 months (95% confidence interval [CI], 12.2 to 25.1) in the control group (hazard ratio for disease progression or death, 0.28; 95% CI, 0.16 to 0.48; P<0.001). Progression-free survival at 12 months was 86.8% (95% CI, 79.8 to 91.6) in the selpercatinib group and 65.7% (95% CI, 51.9 to 76.4) in the control group. Median treatment failure-free survival as assessed by blinded independent central review was not reached in the selpercatinib group and was 13.9 months in the control group (hazard ratio for disease progression, discontinuation due to treatment-related adverse events, or death, 0.25; 95% CI, 0.15 to 0.42; P<0.001). Treatment failure-free survival at 12 months was 86.2% (95% CI, 79.1 to 91.0) in the selpercatinib group and 62.1% (95% CI, 48.9 to 72.8) in the control group. The overall response was 69.4% (95% CI, 62.4 to 75.8) in the selpercatinib group and 38.8% (95% CI, 29.1 to 49.2) in the control group. Adverse events led to a dose reduction in 38.9% of the patients in the selpercatinib group, as compared with 77.3% in the control group, and to treatment discontinuation in 4.7% and 26.8%, respectively. CONCLUSIONS: Selpercatinib treatment resulted in superior progression-free survival and treatment failure-free survival as compared with cabozantinib or vandetanib in patients with RET-mutant medullary thyroid cancer. (Funded by Loxo Oncology, a subsidiary of Eli Lilly; LIBRETTO-531 ClinicalTrials.gov number, NCT04211337.).
- MeSH
- antitumorózní látky * škodlivé účinky terapeutické užití MeSH
- chinazoliny škodlivé účinky terapeutické užití MeSH
- lidé MeSH
- nádory štítné žlázy * farmakoterapie genetika MeSH
- piperidiny škodlivé účinky terapeutické užití MeSH
- progrese nemoci MeSH
- protoonkogenní proteiny c-ret genetika MeSH
- pyridiny * škodlivé účinky terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- randomizované kontrolované studie MeSH
- srovnávací studie MeSH
OBJECTIVES: This article estimates the cost-effectiveness of adding pertuzumab to the combination of trastuzumab and docetaxel within the first-line treatment for metastatic breast cancer with the amplification of HER2+. METHODS: Data from Czech clinical practice recorded in the BREAST register are used. A semi-Markov model with states derived based on the treatment phases (first-line medication, no medication, next-line medication, death) is defined to estimate costs from the healthcare payers' perspective. The benefits are estimated as patient survival until death. The Kaplan-Meier estimates are supplemented by the Cox proportional hazard and the accelerated failure time models to control for patient characteristics. Health-related quality-of-life indicators are derived from relevant literature. RESULTS: Based on the used data, adding pertuzumab does not result in statistically significantly longer survival while inducing higher treatment costs (€163 360 compared with €90 112 per patient in 2018 prices). Statistically longer survival was not supported by the log-rank test (P = .97), the Cox proportional hazard model, or the accelerated failure time model using the Gompertz distribution. The incremental cost-effectiveness ratio (€87 200) substantially exceeds the willingness to pay for 1 quality-adjusted life-year (€46 500). CONCLUSIONS: This analysis indicates that adding pertuzumab cannot be considered cost-effective in Czechia. However, the observed phenomenon may be attributed to the limited duration of patient follow-up periods at the time of the study's execution (mean of 20-21 months). Importantly, we find that using states connected to specific treatment phases is appropriate for a retrospective analysis of patient-level clinical data.
- MeSH
- analýza nákladů a výnosů MeSH
- lidé MeSH
- nádory prsu * farmakoterapie MeSH
- receptor erbB-2 terapeutické užití MeSH
- retrospektivní studie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
Oxysterols, oxidized derivatives of cholesterol, act in breast cancer (BC) as selective estrogen receptor modulators and affect cholesterol homeostasis, drug transport, nuclear and cell receptors, and other signaling proteins. Using data from three highly overlapping sets of patients (N = 162 in total) with early-stage estrogen-receptor-positive luminal BC-high-coverage targeted DNA sequencing (113 genes), mRNA sequencing, and full micro-RNA (miRNA) transcriptome microarrays-we describe complex oxysterol-related interaction (correlation) networks, with validation in public datasets (n = 538) and 11 databases. The ESR1-CH25H-INSIG1-ABCA9 axis was the most prominent, interconnected through miR-125b-5p, miR-99a-5p, miR-100-5p, miR-143-3p, miR-199b-5p, miR-376a-3p, and miR-376c-3p. Mutations in SC5D, CYP46A1, and its functionally linked gene set were associated with multiple differentially expressed oxysterol-related genes. STARD5 was upregulated in patients with positive lymph node status. High expression of hsa-miR-19b-3p was weakly associated with poor survival. This is the first study of oxysterol-related genes in BC that combines DNA, mRNA, and miRNA multiomics with detailed clinical data. Future studies should provide links between intratumoral oxysterol signaling depicted here, circulating oxysterol levels, and therapy outcomes, enabling eventual clinical exploitation of present findings.
- MeSH
- lidé MeSH
- messenger RNA genetika MeSH
- mikro RNA * genetika metabolismus MeSH
- nádory prsu * patologie MeSH
- oxysteroly * MeSH
- transkriptom genetika MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Anti-CD19 immunotherapy tafasitamab is used in combination with lenalidomide in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are ineligible for autologous stem cell transplant. Open-label, phase 1b, First-MIND study assessed safety and preliminary efficacy of tafasitamab + R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) ± lenalidomide as first-line therapy in patients with DLBCL. From December 2019 to August 2020, 83 adults with untreated DLBCL (International Prognostic Index 2-5) were screened and 66 were randomly assigned (33 per arm) to R-CHOP-tafasitamab (arm T) or R-CHOP-tafasitamab-lenalidomide (arm T/L) for 6 cycles. Primary end point was safety; secondary end points included end-of-treatment (EoT) overall response rate (ORR) and complete response (CR) rate. All patients had ≥1 treatment-emergent adverse event, mostly grade 1 or 2. Grade ≥3 neutropenia and thrombocytopenia occurred, respectively, in 57.6% and 12.1% (arm T) and 84.8% and 36.4% (arm T/L) of patients. Nonhematologic toxicities occurred at similar rates among arms. R-CHOP mean relative dose intensity was ≥89% in both arms. EoT ORR was 75.8% (CR 72.7%) in arm T and 81.8% (CR 66.7%) in arm T/L; best ORR across visits was 90.0% and 93.9%. Eighteen-month duration of response and of CR rates were 72.7% and 74.5% (arm T) and 78.7% and 86.5% (arm T/L); 24-month progression-free and overall survival rates were 72.7% and 90.3% (arm T) and 76.8% and 93.8% (arm T/L). Manageable safety and promising signals of efficacy were observed in both arms. Potential benefit of adding tafasitamab + lenalidomide to R-CHOP is being investigated in phase 3 frontMIND (NCT04824092). This study is registered at www.clinicaltrials.gov as #NCT04134936.
- MeSH
- cyklofosfamid škodlivé účinky MeSH
- difúzní velkobuněčný B-lymfom * patologie MeSH
- dospělí MeSH
- doxorubicin škodlivé účinky MeSH
- lenalidomid terapeutické užití MeSH
- lidé MeSH
- myší monoklonální protilátky škodlivé účinky MeSH
- prednison škodlivé účinky MeSH
- protokoly antitumorózní kombinované chemoterapie škodlivé účinky MeSH
- rituximab škodlivé účinky MeSH
- vinkristin škodlivé účinky MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze I MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- Publikační typ
- abstrakt z konference MeSH
- Publikační typ
- abstrakt z konference MeSH
CONTEXT: The chemo-free immunotherapy tafasitamab + lenalidomide has been granted FDA accelerated approval and EU conditional marketing authorization for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) treatment in autologous stem cell transplant-ineligible adults. Treatment schedule optimization aims to reduce the frequency of hospital visits and decrease treatment burden and healthcare utilization. MINDway (NCT05222555) will investigate if tafasitamab administration at levels higher than the approved 12 mg/kg dose at a reduced dosing frequency maintains the benefit-risk relationship of tafasitamab + lenalidomide for patients with R/R DLBCL. OBJECTIVE: To assess an optimized tafasitamab treatment schedule in patients with R/R DLBCL. DESIGN: Open-label, multicenter, Phase Ib/II study. SETTING: Currently enrolling; the planned sample size is 51 patients. PATIENTS: Eligible patients are aged 18-80 years with histologically confirmed R/R DLBCL and 1-3 prior systemic regimens, including CD20-targeted therapy. Patients previously treated with CD19-targeted therapy or immunomodulatory imide drugs, such as lenalidomide, are excluded. INTERVENTIONS: The modified dosing regimen will be investigated in a stepwise design: two sequential dose-finding cohorts (planned n=6 each) followed by an expansion cohort (planned n=39). Lenalidomide 25 mg will be administered in all cohorts on Days 1-21 of each 28-day cycle for up to 12 cycles. After Cycle 12, patients will continue tafasitamab monotherapy at the assigned dosing regimen until progression. After reviewing safety and pharmacokinetic data from Cohorts 1 and 2, patients will be enrolled in an expansion cohort to receive tafasitamab + lenalidomide (tafasitamab dose: 24 or 30 mg/kg) for further evaluation. No intra-patient dose escalation from 24 to 30 mg/kg is permitted. MAIN OUTCOME MEASURES: The primary endpoints are the incidence and severity of treatment-emergent adverse events. Key secondary endpoints are tafasitamab serum concentration after 3 and 12 cycles, best objective response rate, duration of response, and progression-free survival. RESULTS: Not yet available. CONCLUSIONS: MINDway will evaluate an optimized tafasitamab dosing regimen to reduce the frequency of hospital/clinic visits for tafasitamab-treated patients with R/R DLBCL. Reducing the frequency of visits by half is expected to reduce patient burden and support long-term treatment compliance. Fewer visits may result in less exposure to hospital infections in this already susceptible population. FUNDING: MorphoSys AG.
- MeSH
- difúzní velkobuněčný B-lymfom * MeSH
- dospělí MeSH
- humanizované monoklonální protilátky terapeutické užití MeSH
- lenalidomid MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- nehodgkinský lymfom * farmakoterapie MeSH
- protokoly antitumorózní kombinované chemoterapie škodlivé účinky MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze I MeSH
- klinické zkoušky, fáze II MeSH
- multicentrická studie MeSH
CONTEXT: The chemo-free immunotherapy tafasitamab + lenalidomide was granted accelerated approval in the United States (2020) and conditional approval in Canada and Europe (2021) for relapsed/refractory diffuse large B-cell lymphoma (DLBCL) in autologous stem cell transplant-ineligible adult patients. We report pharmacokinetics, pharmacodynamics, and immunogenicity in patients with newly diagnosed DLBCL after adding tafasitamab ± lenalidomide to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as first-line treatment. OBJECTIVE: To study the pharmacokinetics, pharmacodynamics, and immunogenicity of tafasitamab. DESIGN: Open-label, randomized, multicenter. SETTING: Fifty sites in North America and Europe. PATIENTS: Eligible patients were ≥18 years with treatment-naïve DLBCL, IPI 2-5, and ECOG PS 0-2. INTERVENTIONS: Patients were randomized 1:1 to six 21-day (D) cycles (C) of either R-CHOP (R-CHO, D1; P, D1-5) + tafasitamab (12 mg/kg IV, D1, 8, 15) (Arm A) or R-CHOP + tafasitamab + lenalidomide (25 mg orally, D1-10) (Arm B). OUTCOME MEASURES: Tafasitamab serum concentration and the number and percentage of patients developing anti-tafasitamab antibodies were secondary endpoints. NK-cell, T-cell, and B-cell counts in peripheral blood were exploratory endpoints. RESULTS: Tafasitamab serum concentrations reached steady state by C3 (geometric mean trough concentrations: Arm A, 186.40-216.55 μg/mL; Arm B, 171.77-201.54 μg/mL) and steadily declined after treatment completion. Anti-tafasitamab antibodies were detected in 1/65 (1.5%) patients and decreased during treatment. Median NK-cell counts decreased from baseline at C1D8 but were at baseline or higher levels by end-of-treatment (EoT) visit (Arm A) and C1D15 (Arm B). T-cell counts decreased from baseline at C1D8 in both arms but were at baseline or higher by C1D15 (Arm A) and EoT visit (Arm B). Median B-cell counts decreased from baseline to 0 cells/μL (Arm A, C1D15; Arm B, C1D8); at 6-month follow-up after EoT visit, B-cell counts recovered to measurable levels in ~50% of patients. CONCLUSIONS: Tafasitamab serum concentration reached and maintained a therapeutic dose level and declined after treatment completion. No patients developed treatment-induced or treatment-boosted anti-tafasitamab antibodies. Median cell counts for NK cells, T cells, and B cells were comparable between treatment arms in all cycles. FUNDING: MorphoSys AG.
- MeSH
- cyklofosfamid farmakologie terapeutické užití MeSH
- difúzní velkobuněčný B-lymfom * patologie MeSH
- dospělí MeSH
- doxorubicin farmakologie terapeutické užití MeSH
- lenalidomid farmakologie terapeutické užití MeSH
- lidé MeSH
- myší monoklonální protilátky terapeutické užití MeSH
- prednison farmakologie terapeutické užití MeSH
- protokoly antitumorózní kombinované chemoterapie * farmakologie terapeutické užití MeSH
- rituximab farmakologie terapeutické užití MeSH
- vinkristin farmakologie terapeutické užití MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze I MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
INTRODUCTION: Human kinesin 14 (KIF14) is one of the 70 prognostic marker genes (so-called Amsterdam profile) previously identified by the microarray of breast carcinomas, and its high transcript expression in tumor specimens indicates a poor prognosis for patients. We performed a pilot study to explore the prognostic and predictive meaning of KIF14 germline genetic variability in breast cancer patients. METHODS: KIF14 coding sequence, including 5' and 3' untranslated regions and overlaps to introns for identification of splicing sites, was analyzed using next-generation sequencing in the testing set of blood DNA samples from 105 breast cancer patients with clinical follow-up. After rigorous evaluation of major allele frequency, haplotype blocks, in silico predicted functional aspects, expression quantitative trait loci, and clinical associations, eight single nucleotide variants were subsequently validated in the evaluation set of 808 patients. RESULTS: Carriers of minor alleles G (rs17448931) or T (rs3806362) had significantly shorter overall survival than wild type homozygotes (p = 0.010 and p = 0.023, respectively) thus successfully replicating the results of the testing set. Both associations remained significant in the multivariate Cox regression analysis, including molecular subtype and stage as covariates (hazard ratio, HR = 1.7, 95% confidence interval (CI) = 1.1-2.8 for rs17448931 and HR = 1.9, CI 1.2-3.0 for rs3806362). DISCUSSION: In conclusion, our preliminary data suggest that minor alleles in rs17448931 and rs3806362 of KIF14 represent candidate biomarkers of poor prognosis of breast cancer patients. After pending validation in independent populations and eventual functional characterization, these candidates might become useful biomarkers in the clinics.
