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1.
NPJ Breast Cancer ; 7(1): 144, 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34799582

RESUMO

Emerging data indicate that genomic alterations can shape immune cell composition in early breast cancer. However, there is a need for complementary imaging and sequencing methods for the quantitative assessment of combined somatic copy number alteration (SCNA) and immune profiling in pathological samples. Here, we tested the feasibility of three approaches-CUTseq, for high-throughput low-input SCNA profiling, multiplexed fluorescent immunohistochemistry (mfIHC) and digital-image analysis (DIA) for quantitative immuno-profiling- in archival formalin-fixed paraffin-embedded (FFPE) tissue samples from patients enrolled in the randomized SBG-2004-1 phase II trial. CUTseq was able to reproducibly identify amplification and deletion events with a resolution of 100 kb using only 6 ng of DNA extracted from FFPE tissue and pooling together 77 samples into the same sequencing library. In the same samples, mfIHC revealed that CD4 + T-cells and CD68 + macrophages were the most abundant immune cells and they mostly expressed PD-L1 and PD-1. Combined analysis showed that the SCNA burden was inversely associated with lymphocytic infiltration. Our results set the basis for further applications of CUTseq, mfIHC and DIA to larger cohorts of early breast cancer patients.

2.
Cancers (Basel) ; 13(18)2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34572882

RESUMO

We aimed to assess if the discrepant prognostic information between Programmed Death Ligand 1 (PD-L1) protein versus mRNA expression in early breast cancer (BC) could be attributed to heterogeneity in its expression. PD-L1 protein and mRNA expression in BC tissue microarrays from two clinical patient cohorts were evaluated (105 patients; cohort 1: untreated; cohort 2: neoadjuvant chemotherapy-treated). Immunohistochemistry (IHC) with SP142, SP263 was performed. PD-L1 mRNA was evaluated using bulk gene expression and RNA-FISH RNAscope®, the latter scored in a semi-quantitative manner and combined with immunofluorescence (IF) staining for the simultaneous detection of PD-L1 protein expression. PD-L1 expression was assessed in cores as a whole and in two regions of interest (ROI) from the same core. The cell origin of PD-L1 expression was evaluated using multiplex fluorescent IHC. IHC PD-L1 expression between SP142 and SP263 was concordant in 86.7% of cores (p < 0.001). PD-L1 IF/IHC was weakly correlated with spatial mRNA expression (concordance 54.6-71.2%). PD-L1 was mostly expressed by lymphocytes intra-tumorally, while its stromal expression was mostly observed in macrophages. Our results demonstrate only moderate concordance between the various methods of assessing PD-L1 expression at the protein and mRNA levels, which may be attributed to both analytical performance and spatial heterogeneity.

3.
Breast Cancer Res Treat ; 190(3): 451-462, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34570302

RESUMO

PURPOSE: Change in mammographic density has been suggested to be a proxy of tamoxifen response. We investigated the effect of additional adjuvant systemic therapy and CYP2D6 activity on MD change in a cohort of tamoxifen-treated pre- and postmenopausal breast cancer patients. METHODS: Swedish breast cancer patients (n = 699)  operated 2006-2014, genotyped for CYP2D6, having at least three months postoperative tamoxifen treatment, a baseline, and at least one follow-up digital mammogram were included in the study. Other systemic adjuvant treatment included chemotherapy, goserelin, and aromatase inhibitors. Change in MD, dense area, was assessed using the automated STRATUS method. Patients were stratified on baseline characteristics, treatments, and CYP2D6 activity (poor, intermediate, extensive, and ultrarapid). Relative density change was calculated at year 1, 2, and 5 during follow-up in relation to treatments and CYP2D6 activity. RESULTS: Mean relative DA decreased under the follow-up period, with a more pronounced MD reduction in premenopausal patients. No significant effect of chemotherapy, aromatase inhibitors, goserelin, or CYP2D6 activity on DA change was found. DA did not revert to baseline levels after tamoxifen discontinuation. CONCLUSION: Our results indicate that other systemic adjuvant therapy does not further reduce MD in tamoxifen-treated breast cancer patients. We could not confirm the previously suggested association between CYP2D6 activity and MD reduction in a clinical setting with multimodality adjuvant treatment. No rebound effect on MD decline after tamoxifen discontinuation was evident.


Assuntos
Neoplasias da Mama , Tamoxifeno , Antineoplásicos Hormonais/uso terapêutico , Densidade da Mama , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Quimioterapia Adjuvante , Citocromo P-450 CYP2D6/genética , Feminino , Genótipo , Humanos , Tamoxifeno/uso terapêutico
4.
Cancer Treat Rev ; 99: 102257, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34237488

RESUMO

INTRODUCTION: Programmed cell death ligand 1 (PD-L1) expression is predictive for benefit from immunotherapy in several human malignancies including triple negative breast cancer. Lower positivity rates but a larger relative benefit from atezolizumab has been implied when PD-L1 status is assessed at metastatic sites. We aimed to study the discordance of PD-L1 expression between primary tumor and metastasis in breast cancer due to its potential clinical utility. METHODS: Cochrane Library, Embase, Medline and Web of science were searched for studies reporting on PD-L1 expression in primary and metastatic breast cancer, followed by data extraction. Outcomes included pooled PD-L1 positivity rates in tumor cells, immune cells or both in primary tumor and metastasis, PD-L1 discordance between matched primary tumors and metastasis and direction of discordance. RESULTS: Of 2552 identified entries following de-duplication, 20 studies fulfilled the predefined inclusion criteria. Pooled PD-L1 positivity rate was higher in primary tumors compared to metastasis when assessed in immune cells (51.2% vs 37.1% p < 0.001) and tumor/immune cells (30.1% vs 14.6% p < 0.001), but not in tumor cells (18.7% vs 17.8% p = 0.65). PD-L1 positivity was lowest when assessed in bone metastases (12%) and highest in lymph nodes (60%). Discordance between primary tumors and metastasis was bidirectional, with higher pooled discordance rates when PD-L1 expression was assessed in immune compared to tumor cells (39.5% vs 13.6%, p < 0.001). CONCLUSION: The observed considerable discordance between PD-L1 status in primary and metastatic breast cancer emphasizes the importance of appropriate tissue sampling when selecting patients for immunotherapy.


Assuntos
Antígeno B7-H1/biossíntese , Neoplasias da Mama/metabolismo , Antígeno B7-H1/imunologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Feminino , Humanos , Metástase Neoplásica
5.
Breast Cancer Res Treat ; 189(1): 15-23, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34218359

RESUMO

PURPOSE: Endocrine therapy (ET) is an effective strategy to treat hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC) but nearly all patients eventually progress. Our goal was to develop and validate a web-based clinical calculator for predicting disease outcomes in women with HR+ABC who are candidates for receiving first-line single-agent ET. METHODS: The meta-database comprises 891 patient-level data from the control arms of five contemporary clinical trials where patients received first-line single-agent ET (either aromatase inhibitor or fulvestrant) for ABC. Risk models were constructed for predicting 24-months progression-free survival (PFS-24) and 24-months overall survival (OS-24). Final models were internally validated for calibration and discrimination using ten-fold cross-validation. RESULTS: Higher number of sites of metastases, measurable disease, younger age, lower body mass index, negative PR status, and prior endocrine therapy were associated with worse PFS. Final PFS and OS models were well-calibrated and associated with cross-validated time-dependent area under the curve (AUC) of 0.61 and 0.62, respectively. CONCLUSIONS: The proposed ABC calculator is internally valid and can accurately predict disease outcomes. It may be used to predict patient prognosis, aid planning of first-line treatment strategies, and facilitate risk stratification for future clinical trials in patients with HR+ABC. Future validation of the proposed models in independent patient cohorts is warranted.


Assuntos
Neoplasias da Mama , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama/tratamento farmacológico , Feminino , Fulvestranto/uso terapêutico , Humanos , Receptor ErbB-2 , Receptores de Estrogênio
6.
JAMA Oncol ; 7(9): 1360-1367, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34165503

RESUMO

Importance: Trastuzumab emtansine (T-DM1) is presently approved for treatment of advanced breast cancer and after incomplete response to neoadjuvant therapy, but the potential of T-DM1 as monotherapy is so far unknown. Objective: To assess pathologic complete response (pCR) to standard neoadjuvant therapy of combination docetaxel, trastuzumab, and pertuzumab (DTP) vs T-DM1 monotherapy in patients with ERBB2 (formerly HER2)-positive breast cancer. Design, Setting, and Participants: This randomized phase 2 trial, conducted at 9 sites in Sweden, enrolled 202 patients between December 1, 2014, and October 31, 2018. Participants were 18 years or older, with ERBB2-positive tumors larger than 20 mm and/or verified lymph node metastases. Analysis was performed on an intention-to-treat basis. Interventions: Patients were randomized to receive 6 cycles of DTP (standard group) or T-DM1 (investigational group). Crossover was recommended at lack of response or occurrence of intolerable toxic effects. Assessment with fluorine 18-labeled fluorodeoxyglucose (18F-FDG) positron emission tomography combined with computed tomography (PET-CT) was performed at baseline and after 2 and 6 treatment cycles. Main Outcome and Measures: Pathologic complete response, defined as ypT0 or Tis ypN0. Secondary end points were clinical and radiologic objective response; event-free survival, invasive disease-free survival, distant disease-free survival, and overall survival; safety; health-related quality of life (HRQoL); functional and biological tumor characteristics; and frequency of breast-conserving surgery. Results: Overall, 202 patients were randomized; 197 (99 women in the standard group [median age, 51 years (range, 26-73 years)] and 98 women in the investigational group [median age, 53 years (range, 28-74 years)]) were evaluable for the primary end point. Pathologic complete response was achieved in 45 patients in the standard group (45.5%; 95% CI 35.4%-55.8%) and 43 patients in the investigational group (43.9%; 95% CI 33.9%-54.3%). The difference was not statistically significant (P = .82). In a subgroup analysis, the pCR rate was higher in hormone receptor-negative tumors than in hormone receptor-positive tumors in both treatment groups (45 of 72 [62.5%] vs 45 of 125 [36.0%]). Three patients in the T-DM1 group experienced progression during therapy. In an exploratory analysis, tumor-infiltrating lymphocytes at 10% or more (median) estimated pCR significantly (odds ratio, 2.76; 95% CI, 1.42-5.36; P = .003). Response evaluation with 18F-FDG PET-CT revealed a relative decrease of maximum standardized uptake value by equal to or greater than 68.7% (median) was associated with pCR (odds ratio, 6.74, 95% CI, 2.75-16.51; P < .001). Conclusions and Relevance: In this study, treatment with standard neoadjuvant combination DTP was equal to T-DM1. Trial Registrations: ClinicalTrials.gov Identifier: NCT02568839; EudraCT number: 2014-000808-10.

7.
Cardiooncology ; 7(1): 20, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34049593

RESUMO

BACKGROUND: Cancer treatment-related morbidity relevantly compromises health status in cancer survivors, and efforts to optimise health-related outcomes in this population are vital to maximising healthy survivorship. A pre-treatment assessment - and possibly preventive management strategies - of cancer patients at increased risk for cardiovascular disease (CVD) seems a rational approach in this regard. Definitive evidence for such strategies is largely lacking, thereby impeding the formulation of firm recommendations. RESULTS: The current scoping review aims to summarise and grade the evidence regarding strategies for prediction and prevention of CVD in adults in relation to oncological treatments. We conducted a scoping literature search for different strategies for primary prevention, such as medical and lifestyle interventions, as well as the use of predictive risk scores. We identified studies with moderate to good strength and up to now limited evidence to recommend primary preventive strategies in unselected patients treated with potentially cardiotoxic oncologic therapies. CONCLUSION: Efforts to minimize the CVD burden in cancer survivors are needed to accomplish healthy survivorship. This can be done by means of robust models predictive for CVD events or application of interventions during or after oncological treatments. Up to now there is insufficient evidence to implement preventive strategies in an unselected group of patients treated with potential cardiotoxic oncological treatments. We conclude that randomised controlled trials are needed that evaluate medical and lifestyle interventions in groups at increased risk for complications, in order to be able to influence chronic illness risks, such as cardiovascular complications, for cancer survivors.

8.
Clin Cancer Res ; 27(12): 3469-3477, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33952629

RESUMO

PURPOSE: This study analyzes the potential of stromal platelet-derived growth factor receptor-beta (PDGFRb) expression as biomarker for radiotherapy (RT) benefit on ipsilateral breast events (IBE) in ductal carcinoma in situ (DCIS). Improved identification of DCIS patients refractory to adjuvant whole-breast RT is needed. Predictive biomarker studies in DCIS have focused on tumor cell features rather than the tumor-associated stroma, despite growing evidence of its influence on therapy efficiency. EXPERIMENTAL DESIGN: Samples from the Swedish randomized radiotherapy DCIS trial (SweDCIS) were subjected to IHC analysis for stromal PDGFRb expression. IBE incidence at 10 years after breast-conserving surgery was the primary endpoint. Interactions between marker and treatment were analyzed. RESULTS: PDGFRb score was predictive for RT benefit with regard to IBE (P interaction = 0.002 and P interaction = 0.008 adjusted multivariably). Patients of the PDGFRblow group had a strong benefit from RT regarding IBE risk [HR, 0.23; 95% confidence interval (CI), 0.12-0.45; P < 0.001] with an absolute risk reduction of 21% (cumulative risk 7% vs. 28%) at 10 years. No significant risk reduction by RT was observed for patients of the PDGFRbhigh group (HR, 0.83; 0.51-1.34; P = 0.444; cumulative risk 22% vs. 25%). The RT response-predictive effect of stromal PDGFRb was equally strong in analyses for in situ and invasive IBE when analyzed separately (in situ IBE: P = 0.029; invasive IBE: P = 0.044). CONCLUSIONS: Results suggest high stromal PDGFRb expression as a novel biomarker identifying DCIS patients who are refractory to standard whole-breast adjuvant RT. The data imply previously unrecognized fibroblast-mediated modulation of radiosensitivity of DCIS, which should be further explored from mechanistic and targeting perspectives.

9.
Cancers (Basel) ; 13(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803148

RESUMO

We compared estrogen receptor (ER), progesterone receptor (PR), human epidermal growth-factor receptor 2 (HER2), Ki67, and grade scores among the pathology departments in Sweden. We investigated how ER and HER2 positivity rates affect the distribution of endocrine and HER2-targeted treatments among oncology departments. All breast cancer patients diagnosed between 2013 and 2018 in Sweden were identified in the National Quality Register for Breast Cancer. Cases with data on ER, PR, HER2, Ki67, grade, and treatment were selected (43,261 cases from 29 departments following the guidelines for biomarker testing). The ER positivity rates ranged from 84.2% to 97.6% with 6/29 labs out of the overall confidence intervals (CIs), while PR rates varied between 64.8% and 86.6% with 7/29 labs out of the CIs. HER2 positivity rates ranged from 9.4% to 16.3%, with 3/29 labs out of the overall CIs. Median Ki67 varied between 15% and 30%, where 19/29 labs showed significant intra-laboratory variability. The proportion of grade-II cases varied between 42.9% and 57.1%, and 13/29 labs were outside of the CI. Adjusting for patient characteristics, the proportion of endocrine and anti-HER2 treatments followed the rate of ER and HER2 positivity, illustrating the clinical effect of inter- and intra-laboratory variability. There was limited variability among departments in ER, PR, and HER2 testing. However, even a few outlier pathology labs affected endocrine and HER2-targeted treatment rates in a clinically relevant proportion, suggesting the need for improvement. High variability was found in grading and Ki67 assessment, illustrating the need for the adoption of new technologies in practice.

10.
Cancers (Basel) ; 13(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803245

RESUMO

Checkpoint inhibitors are slowly being introduced in the care of specific sarcoma subtypes such as undifferentiated pleomorphic sarcoma, alveolar soft part sarcoma, and angiosarcoma even though formal indication is lacking. Proper biomarkers to unravel potential immune reactivity in the tumor microenvironment are therefore expected to be highly warranted. In this study, intratumoral spatial cross presentation was investigated as a novel concept where immune cell composition in the tumor microenvironment was suggested to act as a proxy for immune surveillance. Double immunohistochemistry revealed a prognostic role of direct spatial interactions between CD11c+ antigen-presenting cells (APCs) and CD8+ cells in contrast to each marker alone in a soft tissue sarcoma (STS) cohort of 177 patients from the Karolinska University Hospital (MFS p = 0.048, OS p = 0.025). The survival benefit was verified in multivariable analysis (MFS p = 0.012, OS p = 0.004). Transcriptomics performed in the TCGA sarcoma cohort confirmed the prognostic value of combining CD11c with CD8 (259 patients, p = 0.005), irrespective of FOXP3 levels and in a CD274 (PD-LI)-rich tumor microenvironment. Altogether, this study presents a histopathological approach to link immune surveillance and patient survival in STS. Notably, spatial cross presentation as a prognostic marker is distinct from therapy response-predictive biomarkers such as immune checkpoint molecules of the PD-L1/PD1 pathway.

11.
JNCI Cancer Spectr ; 5(1): pkaa084, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33442658

RESUMO

Background: Although small, node-negative breast cancer (ie, T1abN0) constitutes 20% of all newly diagnosed breast cancers, data on prognosis and prognostic factors are limited. Methods: We conducted a population-based cohort study including 20 114 Swedish women treated for T1abN0 breast cancer from 1977 onward. Patient and tumor data were collected from Swedish breast cancer registries. Cohort subjects were followed through linkage to the Cause of Death Register. We calculated the cumulative incidence of breast cancer-specific and overall death and used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: During a median follow-up of 9.1 years (range = 0-38), 915 women died of breast cancer and 5416 of any cause. The 10-, 20-, and 30-year cumulative incidences of breast cancer death were 3.4% (95% CI = 3.1% to 3.7%), 7.6% (95% CI = 7.1% to 8.2%), and 10.5% (95% CI = 9.6% to 11.4%), respectively. The multivariable hazard ratios and 95% confidence intervals of breast cancer death were 0.92 (95% CI = 0.88 to 0.97) for each additional calendar year of diagnosis, 4.38 (95% CI = 2.79 to 6.87) for grade 3 vs grade 1 tumors, 0.43 (95% CI = 0.31 to 0.62) for progesterone receptor-positive vs progesterone receptor-negative disease, and 2.01 (95% CI = 0.99 to 4.07) for HER2-positive vs HER2-negative disease. Women with grade 3 vs grade 1 tumors had a 56% increased risk of death from any cause (HR = 1.56, 95% CI = 1.30 to 1.88). Conclusions: The risk of breast cancer death in T1abN0 disease continues to increase steadily beyond 10 years after diagnosis, has improved over time, and varies substantially by tumor characteristics.

12.
Breast Cancer Res ; 23(1): 8, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33451345

RESUMO

BACKGROUND: Xentuzumab-a humanised IgG1 monoclonal antibody-binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling and suppressing AKT activation by everolimus. This phase Ib/II exploratory trial evaluated xentuzumab plus everolimus and exemestane in hormone receptor-positive, locally advanced and/or metastatic breast cancer (LA/MBC). METHODS: Patients with hormone receptor-positive/HER2-negative LA/MBC resistant to non-steroidal aromatase inhibitors were enrolled. Maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of xentuzumab/everolimus/exemestane were determined in phase I (single-arm, dose-escalation). In phase II (open-label), patients were randomised 1:1 to the RP2D of xentuzumab/everolimus/exemestane or everolimus/exemestane alone. Randomisation was stratified by the presence of visceral metastases. Primary endpoint was progression-free survival (PFS). RESULTS: MTD was determined as xentuzumab 1000 mg weekly plus everolimus 10 mg/day and exemestane 25 mg/day. A total of 140 patients were enrolled in phase II (70 to each arm). Further recruitment was stopped following an unfavourable benefit-risk assessment by the internal Data Monitoring Committee appointed by the sponsor. Xentuzumab was discontinued; patients could receive everolimus/exemestane if clinically indicated. Median PFS was 7.3 months (95% CI 3.3-not calculable) in the xentuzumab/everolimus/exemestane group and 5.6 months (3.7-9.1) in the everolimus/exemestane group (hazard ratio 0.97, 95% CI 0.57-1.65; P = 0.9057). In a pre-specified subgroup of patients without visceral metastases at screening, xentuzumab/everolimus/exemestane showed evidence of PFS benefit versus everolimus/exemestane (hazard ratio 0.21 [0.05-0.98]; P = 0.0293). Most common any-cause adverse events in phase II were diarrhoea (29 [41.4%] in the xentuzumab/everolimus/exemestane group versus 20 [29.0%] in the everolimus/exemestane group), mucosal inflammation (27 [38.6%] versus 21 [30.4%]), stomatitis (24 [34.3%] versus 24 [34.8%]), and asthenia (21 [30.0%] versus 24 [34.8%]). CONCLUSIONS: Addition of xentuzumab to everolimus/exemestane did not improve PFS in the overall population, leading to early discontinuation of the trial. Evidence of PFS benefit was observed in patients without visceral metastases when treated with xentuzumab/everolimus/exemestane, leading to initiation of the phase II XENERA™-1 trial (NCT03659136). TRIAL REGISTRATION: ClinicalTrials.gov, NCT02123823 . Prospectively registered, 8 March 2013.

13.
Br J Clin Pharmacol ; 87(3): 1243-1252, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32713032

RESUMO

AIMS: Tamoxifen is bioactivated to endoxifen by polymorphic CYP2D6-dependent metabolism. Here, endoxifen levels were compared to CYP2D6 diplotypes, tentative target concentrations and side effects. METHODS: In total, 118 Swedish premenopausal breast cancer patients diagnosed 2006-2014, with on-going postoperative tamoxifen treatment January 2017, were included. Biobanked DNA from peripheral blood was used for CYP2D6 genotyping by TaqMan real-time polymerase chain reaction (CYP2D6*1, *3, *4, *5, *6, *9, *10, *41, *1xN). Plasma levels of tamoxifen and 3 major metabolites were quantified by liquid chromatography-tandem mass spectrometry. Clinical information on treatment and side effects was retrospectively obtained from medical records. RESULTS: In the final analysis of 114 patients, a clear relationship between CYP2D6 genotype and plasma endoxifen levels was evident. Low endoxifen (1.6-5.2 ng/mL), i.e. below the suggested threshold for clinical efficacy, was found in all patients with 2 reduced-function alleles, 2 null-alleles, or a null/reduced-function combination. CYP2D6*41 was the most common reduced-function allele (82%) and 17 of 21 CYP2D6*41-carriers exhibited a lower CYP2D6 activity than predicted from published guidelines. No difference in endoxifen levels was observed between carriers of 2 null-alleles vs patients homozygous for CYP2D6*41 or the corresponding heterozygous combination (P = .338). In patients with endoxifen levels <5.9 ng/mL (36/114), side effects were either mild or absent. At higher endoxifen levels moderate-to-severe side effects were reported in a concentration-dependent manner. CONCLUSION: Significantly reduced endoxifen levels were observed not only in all homozygous carriers of CYP2D6 null-alleles, but also in carriers of 2 reduced-function alleles. This finding may be highly relevant for future, genotype-based dose considerations.


Assuntos
Neoplasias da Mama , Citocromo P-450 CYP2D6 , Alelos , Antineoplásicos Hormonais/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Citocromo P-450 CYP2D6/genética , Feminino , Genótipo , Humanos , Estudos Retrospectivos , Tamoxifeno/análogos & derivados , Tamoxifeno/uso terapêutico
14.
Semin Musculoskelet Radiol ; 24(6): 692-709, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33307585

RESUMO

Musculoskeletal (MSK) image-guided oncologic intervention is an established field within radiology. Numerous studies have described its clinical benefits, safety, cost effectiveness, patient satisfaction, and improved quality of life, thereby establishing image-guided oncologic intervention as a preferred pathway in treating patients presenting with specific benign MSK tumors. But there is a paradigm shift on the horizon because these techniques may also support established pillars (surgery, systemic treatment, radiotherapy) in the treatment of malignant MSK tumors. Unlike benign tumors, where they are used as primary therapy lines with curative intent, such interventions can be selected for malignant tumors as adjuvant treatment in painful or unstable bone or soft tissue lesions or as more palliative therapy strategies. Using examples from our clinical practices, we elaborate on the benefits of applying a multidisciplinary approach (traditionally involving MSK radiologists, oncologists, orthopaedic surgeons, microbiologists, pathologists, physiotherapists, and pain management experts), ideally within a sarcoma treatment center to deliver a patient-specific therapy plan and illustrate methods to assess the benefits of this model of care.In this article, we review the current repertoire of ablation techniques, demonstrate why such procedures offer value-based alternatives to conventional treatments of specific tumors, and reflect on future directions. Additionally, we review the advantages and limitations of each technique and offer guidance to improve outcomes.


Assuntos
Técnicas de Ablação , Neoplasias Ósseas/cirurgia , Radiologia Intervencionista , Neoplasias de Tecidos Moles/cirurgia , Neoplasias Ósseas/patologia , Humanos , Equipe de Assistência ao Paciente , Neoplasias de Tecidos Moles/patologia
15.
Semin Musculoskelet Radiol ; 24(6): 710-725, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33307586

RESUMO

Percutaneous image-guided oncologic interventions have rapidly evolved over the last two decades as an independent strategy or used within a first-, second-, or even third-line strategy in the treatment of musculoskeletal (MSK) tumors. Abundant mostly nonrandomized publications have described the safety, efficacy, and reproducibility of implementing percutaneous therapies both with curative and palliative intent. In this article, we continue to share our experience in bone and MSK soft tissue interventions focusing on stabilization and combined ablation and stabilization. We propose a pathway and explore future directions of image-guided interventional oncology related to skeletal disease. We reflect on the advantages and limitations of each technique and offer guidance and pearls to improve outcomes. Representing patterns from our practices, we demonstrate the role of collaborative working within a multidisciplinary team, ideally within a dedicated tumor treatment center, to deliver patient-specific therapy plans that are value based and favored by patients when given the choice.


Assuntos
Neoplasias Ósseas/terapia , Radiologia Intervencionista , Neoplasias de Tecidos Moles/terapia , Técnicas de Ablação , Neoplasias Ósseas/patologia , Previsões , Humanos , Cuidados Paliativos , Equipe de Assistência ao Paciente , Neoplasias de Tecidos Moles/patologia
16.
ESMO Open ; 5(6): e001032, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33172959

RESUMO

BACKGROUND: There is a paucity of data on the prognostic value of programmed cell death protein 1 (PD-1) protein and gene expression in early breast cancer (BC) and the present study's aim was to comprehensively investigate it. METHODS: The study consisted of three parts: a correlative analysis of PD-1 protein and gene expression from an original patient cohort of 564 patients with early BC; a systematic review and trial-level meta-analysis on the association between PD-1 protein expression and disease-free survival/overall survival (OS) in early BC; and a pooled gene expression analysis from publicly available transcriptomic datasets regarding PDCD1 expression. RESULTS: In the study cohort, PD-1 protein, but not gene expression, was associated with improved OS (HRadj=0.73, 95% CI 0.55 to 0.97, p=0.027 and HRadj=0.88, 95% CI 0.68 to 1.13, p=0.312, respectively). In the trial-level meta-analysis, PD-1 protein expression was not found to be statistically significantly associated with outcomes in the overall population. Finally, in the pooled gene expression analysis, higher PDCD1 expression was associated with better OS in multivariable analysis in the entire population (HRadj=0.89, 95% CI 0.80 to 0.99, p=0.025) and in basal-like tumours. CONCLUSIONS: PD-1 protein and gene expression seem to be promising prognostic factors in early BC. Standardisation of detection and assessment methods is of utmost importance.


Assuntos
Neoplasias da Mama , Receptor de Morte Celular Programada 1 , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Intervalo Livre de Doença , Feminino , Humanos , Prognóstico , Receptor de Morte Celular Programada 1/genética , Transcriptoma
17.
ESMO Open ; 5(6): e000798, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33188050

RESUMO

On the 15 November 2018, the Committee for Medicinal Products for Human Use adopted an extension to an existing indication for the use of nivolumab (Opdivo) in combination with ipilimumab (Yervoy) for the first-line treatment of adult patients with intermediate/poor-risk advanced renal cell carcinoma (RCC). The approval was based on results from the Pivotal CA209214 study, a randomised, open-label, phase III study, comparing nivolumab +ipilimumab with sunitinib in subjects≥18 years of age with previously untreated advanced RCC (not amenable for surgery or radiotherapy) or metastatic RCC, with a clear-cell component. A total of 1096 patients were randomised in the trial, of which 847 patients had intermediate/poor-risk RCC and received either nivolumab (n=425) in combination with ipilimumab administered every 3 weeks for 4 doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks or sunitinib (n=422) administered orally for 4 weeks followed by 2 weeks off, every cycle. A statistically significant difference in overall survival (OS) was observed in the nivolumab + ipilimumab group compared with the sunitinib group in intermediate/poor-risk subjects (HR 0.63 (99.8% CI 0.44 to 0.89); stratified log-rank 2-sided p-value<0.0001). The median OS was not reached for the nivolumab + ipilimumab group and was 25.95 months for the sunitinib group. The OS rates were 89.5% and 86.2% at 6 months, and 80.1% and 72.1% at 12 months in the nivolumab +ipilimumab and the sunitinib groups, respectively. K-M curves separated after approximately 3 months, favouring nivolumab + ipilimumab. This was not mirrored in the favourable-risk patients where no statistically significant difference was observed between nivolumab + ipilimumab and sunitinib in favourable-risk patients (HR 1.45 (descriptive 99.8% CI 0.51 to 4.12), p =0.2715).


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Células Renais/tratamento farmacológico , Humanos , Imunoterapia , Ipilimumab/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Nivolumabe/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
18.
Proc Natl Acad Sci U S A ; 117(44): 27556-27565, 2020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-33077599

RESUMO

Tumor-associated macrophages (TAMs) continuously fine tune their immune modulatory properties, but how gene expression programs coordinate this immune cell plasticity is largely unknown. Selective mRNA translation, controlled by MNK1/MNK2 and mTOR pathways impinging on eIF4E, facilitates reshaping of proteomes without changes in abundance of corresponding mRNAs. Using polysome profiling developed for small samples we show that, during tumor growth, gene expression in TAMs is predominately modulated via mRNA-selective changes in translational efficiencies. These alterations in gene expression paralleled accumulation of antiinflammatory macrophages with augmented phosphorylation of eIF4E, a target of the MNK1 and MNK2 kinases, known to selectively modulate mRNA translation. Furthermore, suppression of the MNK2, but not the mTOR signaling pathway, reprogrammed antiinflammatory macrophages toward a proinflammatory phenotype with the ability to activate CD8+ T cells. Thus, selective changes of mRNA translation depending on MNK2 signaling represents a key node regulating macrophage antiinflammatory functions.


Assuntos
Macrófagos/imunologia , Neoplasias/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Técnicas de Cocultura , Modelos Animais de Doenças , Fator de Iniciação 4E em Eucariotos/genética , Fator de Iniciação 4E em Eucariotos/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Técnicas de Silenciamento de Genes , Humanos , Células MCF-7 , Macrófagos/metabolismo , Camundongos , Camundongos Transgênicos , Naftiridinas/farmacologia , Neoplasias/genética , Neoplasias/patologia , Fosforilação/genética , Fosforilação/imunologia , Cultura Primária de Células , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Evasão Tumoral/genética
19.
Acta Oncol ; 59(11): 1382-1387, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32783667

RESUMO

BACKGROUND: Randomized trials have shown survival gains for patients with metastatic breast cancer (BC) treated with CDK4/6 inhibitors (CDK4/6i) in combination with endocrine agents. It is not unlikely that there may be discrepancies between the generally fit clinical study population and the real-world setting that could affect adherence to treatment guidelines, tolerance to treatment and outcome. MATERIAL AND METHODS: Consecutive patients with metastatic or locally advanced and unresectable BC that were treated between July 2017 and January 2020 at Karolinska University Hospital, Stockholm, Sweden and that had received at least one dose of CDK4/6i were included in this retrospective study. The primary endpoint was safety, including toxicity according to CTCAE 5 and rates of treatment interruptions, dose reductions and discontinuations. The secondary endpoint was efficacy based on the treating physicians' assessments in terms of progression free (PFS) and overall survival (OS), as well as the factors associated with patient outcome. RESULTS: Eighty-eight patients were included in the analysis, with a median age of 67.2 years. Grade 4 neutropenia occurred in 9.1% of patients and one episode of neutropenic infection was observed. Dose reductions were made in 38.6% of patients, while 11.4% discontinued treatment due to toxicity, most commonly non-hematologic. After a median follow-up of 18.33 months, median PFS was 13.30 months (95% CI, 11.39-15.21) and median OS could yet not be estimated. In multivariable analysis, number of prior chemotherapy lines was an independent predictor for shorter PFS (HR = 3.28, 95% CI 1.50-7.16, p = .003). CONCLUSIONS: CDK4/6i administered in a real-world setting exhibits a similar toxicity profile but higher incidence of treatment discontinuation compared to randomized trials. Efficacy of CDK4/6i among patients pretreated with multiple therapy lines is markedly reduced.


Assuntos
Neoplasias da Mama , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Quinases Ciclina-Dependentes/uso terapêutico , Feminino , Humanos , Estudos Retrospectivos , Suécia
20.
ESMO Open ; 5(4)2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32847837

RESUMO

The therapeutic landscape in the treatment of advanced/metastatic renal cell cancer has evolved over the last 2 years with the advent of immune checkpoint inhibitors. In 2018 and 2019, marketing authorisations valid throughout the European Union were issued for nivolumab and ipilimumab dual checkpoint inhibition and pembrolizumab or avelumab in combination with the tyrosine kinase inhibitor axitinib. These applications presented numerous regulatory challenges.In this paper, we summarise the main regulatory considerations, originating from the assessment of the dossiers submitted from the applicants for the three combinations. The regulatory issues are grouped in four sections: clinical pharmacology, efficacy, biomarkers and safety. In each section, we describe the issues raised during the regulatory evaluation performed by the Committee for Medicinal Products for Human Use (CHMP) assessors. The CHMP assessments determine whether the medicines concerned meet the necessary quality, safety and efficacy requirements, and whether the benefit-risk balance is positive.In summary, although the overall benefit-risk was considered positive for the three combinations, the immaturity of the outcome data and the absence of long-term safety data remain issues to be addressed. Postauthorisation efficacy studies have been required to confirm the effects of the new combinations.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Axitinibe , Humanos , Ipilimumab , Nivolumabe
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