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Cancer progression is driven in part by genomic alterations1. The genomic characterization of cancers has shown interpatient heterogeneity regarding driver alterations2, leading to the concept that generation of genomic profiling in patients with cancer could allow the selection of effective therapies3,4. Although DNA sequencing has been implemented in practice, it remains unclear how to use its results. A total of 1,462 patients with HER2-non-overexpressing metastatic breast cancer were enroled to receive genomic profiling in the SAFIR02-BREAST trial. Two hundred and thirty-eight of these patients were randomized in two trials (nos. NCT02299999 and NCT03386162) comparing the efficacy of maintenance treatment5 with a targeted therapy matched to genomic alteration. Targeted therapies matched to genomics improves progression-free survival when genomic alterations are classified as level I/II according to the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT)6 (adjusted hazards ratio (HR): 0.41, 90% confidence interval (CI): 0.27-0.61, P < 0.001), but not when alterations are unselected using ESCAT (adjusted HR: 0.77, 95% CI: 0.56-1.06, P = 0.109). No improvement in progression-free survival was observed in the targeted therapies arm (unadjusted HR: 1.15, 95% CI: 0.76-1.75) for patients presenting with ESCAT alteration beyond level I/II. Patients with germline BRCA1/2 mutations (n = 49) derived high benefit from olaparib (gBRCA1: HR = 0.36, 90% CI: 0.14-0.89; gBRCA2: HR = 0.37, 90% CI: 0.17-0.78). This trial provides evidence that the treatment decision led by genomics should be driven by a framework of target actionability in patients with metastatic breast cancer.
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Neoplasias da Mama , Tomada de Decisão Clínica , Genoma Humano , Genômica , Metástase Neoplásica , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Tomada de Decisão Clínica/métodos , Análise Mutacional de DNA , Progressão da Doença , Feminino , Genes BRCA1 , Genes BRCA2 , Genoma Humano/genética , Humanos , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Ftalazinas/uso terapêutico , Piperazinas/uso terapêuticoRESUMO
An Amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Metastasis is the main cause of death for patients with breast cancer. Many studies have characterized the genomic landscape of breast cancer during its early stages. However, there is evidence that genomic alterations are acquired during the evolution of cancers from their early to late stages, and that the genomic landscape of early cancers is not representative of that of lethal cancers1-7. Here we investigated the landscape of somatic alterations in 617 metastatic breast cancers. Nine driver genes (TP53, ESR1, GATA3, KMT2C, NCOR1, AKT1, NF1, RIC8A and RB1) were more frequently mutated in metastatic breast cancers that expressed hormone receptors (oestrogen and/or progesterone receptors; HR+) but did not have high levels of HER2 (HER2-; n = 381), when compared to early breast cancers from The Cancer Genome Atlas. In addition, 18 amplicons were more frequently observed in HR+/HER2- metastatic breast cancers. These cancers showed an increase in mutational signatures S2, S3, S10, S13 and S17. Among the gene alterations that were enriched in HR+/HER2- metastatic breast cancers, mutations in TP53, RB1 and NF1, together with S10, S13 and S17, were associated with poor outcome. Metastatic triple-negative breast cancers showed an increase in the frequency of somatic biallelic loss-of-function mutations in genes related to homologous recombination DNA repair, compared to early triple-negative breast cancers (7% versus 2%). Finally, metastatic breast cancers showed an increase in mutational burden and clonal diversity compared to early breast cancers. Thus, the genomic landscape of metastatic breast cancer is enriched in clinically relevant genomic alterations and is more complex than that of early breast cancer. The identification of genomic alterations associated with poor outcome will allow earlier and better selection of patients who require the use of treatments that are still in clinical trials. The genetic complexity observed in advanced breast cancer suggests that such treatments should be introduced as early as possible in the disease course.
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Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Evolução Molecular , Genoma Humano/genética , Genômica , Mutação , Metástase Neoplásica/genética , Análise Mutacional de DNA , Progressão da Doença , Feminino , Humanos , Masculino , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
BACKGROUND: Copy number alterations (CNA) are acquired during the evolution of cancers from their early stage to metastatic stage. This study aims at analysing the clinical value of the identified metastasis-associated CNAs both in metastatic breast cancers (mBCs) and early breast cancers (eBCs). METHODS: Single-nucleotide polymorphism (SNP)-array was performed on 926 biopsies from mBC patients, enrolled in SAFIR02-BREAST prospective trial. CNA profiles of eBCs from The Cancer Genome Atlas Breast Invasive Carcinoma (n = 770), Molecular Taxonomy of Breast Cancer International Consortium (n = 1620) and PACS04 trial (n = 243) cohorts were used as references for comparing mBCs and eBCs CNA profiles. Overall survival was the considered survival endpoint. RESULTS: Among the twenty-one genes frequently altered in ER + /HER2- mBCs: focal amplification of TERT was associated with poor outcome in the ER + /HER2- mBC population. Among the ER + /HER2- mBCs patients for whom CDK4/6 inhibitors information before biopsies collection was available: we identified seven genes on post-treatment biopsies, including the cyclin-dependent kinase 4 (CDK4), which was amplified in 9.8% of the ER + /HER2- mBCs pretreated population, as compared to 1.5% in the ER + /HER2- mBCs unpretreated population (P = 2.82E-04) as well as the 3 eBC populations. CDK4 amplification was associated with poor outcome in the ER + /HER2- eBCs. CONCLUSIONS: This study provides insights into the biology of mBCs and identifies clinically useful genomic features for future improvement of breast cancer patient management.
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PURPOSE: We aimed to determine the pattern of isolated local recurrences (ILR) in women with stage II-III hormone receptor-positive and human epidermal growth factor receptor 2 breast cancer (HR + /HER2-BC) after 10-year follow-up. METHODS: UNICANCER-PACS 01 and PACS 04 trials included 5,008 women with T1-T3 and N1-N3 to evaluate the efficacy of different anthracycline ± taxanes-containing regimens after modified mastectomy or lumpectomy plus axillary lymph node dissection. We analyzed the data from 2,932 women with HR + /HER2- BC to evaluate the cumulative incidence of ILR and describe the factors associated with ILR. RESULTS: After a median follow-up of 9.1 years (95% CI 9.0-9.2 years), the cumulative incidence of ILR increased steadily between 1 and 10 years from 0.2% to 2.5%. The multivariable analysis showed that older age (subhazard ratios [sHR] = 0.95, 95% CI 0.92-0.99) and mastectomy (sHR = 0.39, 95% CI 0.17-0.86) were associated with lower risk of ILR, and no adjuvant endocrine therapy (sHR = 2.73, 95% CI 1.32 7-5.67) with increased risk of ILR. CONCLUSION: In this population of high-risk patients with localized HR + /HER2- BC, the risk of ILR was low but remained constant over 10 years. Younger age at diagnosis, breast-conserving surgery, and adjuvant endocrine therapy were independent risk factors of ILR.
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Neoplasias da Mama , Feminino , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Neoplasias da Mama/metabolismo , Mastectomia , Seguimentos , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/cirurgia , Linfonodos/patologia , Fatores de RiscoRESUMO
BACKGROUND: Overall survival (OS) is the gold standard endpoint to assess treatment efficacy in cancer clinical trials. In metastatic breast cancer (mBC), progression-free survival (PFS) is commonly used as an intermediate endpoint. Evidence remains scarce regarding the degree of association between PFS and OS. Our study aimed to describe the individual-level association between real-world PFS (rwPFS) and OS according to first-line treatment in female patients with mBC managed in real-world setting for each BC subtype (defined by status for both hormone-receptor [HR] expression and HER2 protein expression/gene amplification). METHODS: We extracted data from the ESME mBC database (NCT03275311) which gathers deidentified data from consecutive patients managed in 18 French Comprehensive Cancer Centers. Adult women diagnosed with mBC between 2008 and 2017 were included. Endpoints (PFS, OS) were described using the Kaplan-Meier method. Individual-level associations between rwPFS and OS were estimated using the Spearman's correlation coefficient. Analyses were conducted by tumor subtype. RESULTS: 20,033 women were eligible. Median age was 60.0 years. Median follow-up duration was 62.3 months. Median rwPFS ranged from 6.0 months (95% CI 5.8-6.2) for HR-/HER2 - subtype to 13.3 months (36% CI 12.7-14.3) for HR + /HER2 + subtype. Correlation coefficients were highly variable across subtypes and first-line (L1) treatments. Among patients with HR - /HER2 - mBC, correlation coefficients ranged from 0.73 to 0.81, suggesting a strong rwPFS/OS association. For HR + /HER2 + mBC patients, the individual-level associations were weak to strong with coefficients ranging from 0.33 to 0.43 for monotherapy and from 0.67 to 0.78 for combined therapies. CONCLUSIONS: Our study provides comprehensive information on individual-level association between rwPFS and OS for L1 treatments in mBC women managed in real-life practice. Our results could be used as a basis for future research dedicated to surrogate endpoint candidates.
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Neoplasias da Mama , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias da Mama/tratamento farmacológico , Intervalo Livre de Progressão , Bases de Dados Factuais , Expressão GênicaRESUMO
BACKGROUND: In case of locally advanced and/or non-metastatic unresectable esophageal cancer, definitive chemoradiotherapy (CRT) delivering 50 Gy in 25 daily fractions in combination with platinum-based regimen remains the standard of care resulting in a 2-year disease-free survival of 25% which deserves to be associated with new systemic strategies. In recent years, several immune checkpoint inhibitors (anti-PD1/anti-PD-L1, anti-Program-Death 1/anti-Program-Death ligand 1) have been approved for the treatment of various solid malignancies including metastatic esophageal cancer. As such, we hypothesized that the addition of an anti-PD-L1 to CRT would provide clinical benefit for patients with locally advanced oesophageal cancer. To assess the efficacy of the anti-PD-L1 durvalumab in combination with CRT and then as maintenance therapy we designed the randomized phase II ARION (Association of Radiochemotherapy with Immunotherapy in unresectable Oesophageal carciNoma- UCGI 33/PRODIGE 67). METHODS: ARION is a multicenter, open-label, randomized, comparative phase II trial. Patients are randomly assigned in a 1:1 ratio in each arm with a stratification according to tumor stage, histology and centre. Experimental arm relies on CRT with 50 Gy in 25 daily fractions in combination with FOLFOX regimen administrated during and after radiotherapy every two weeks for a total of 6 cycles and durvalumab starting with CRT for a total of 12 infusions. Standard arm is CRT alone. Use of Intensity Modulated radiotherapy is mandatory. The primary endpoint is to increase progression-free survival at 12 months from 50 to 68% (HR = 0.55) (power 90%; one-sided alpha-risk, 10%). Progression will be defined with central external review of imaging. ANCILLARY STUDIES ARE PLANNED: PD-L1 Combined Positivity Score on carcinoma cells and stromal immune cells of diagnostic biopsy specimen will be correlated to disease free survival. The study of gut microbiota will aim to determine if baseline intestinal bacteria correlates with tumor response. Proteomic analysis on blood samples will compare long-term responder after CRT with durvalumab to non-responder to identify biomarkers. CONCLUSION: Results of the present study will be of great importance to evaluate the impact of immunotherapy in combination with CRT and decipher immune response in this unmet need clinical situation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT: 03777813.Trial registration date: 5th December 2018.
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Carcinoma , Neoplasias Esofágicas , Humanos , Proteômica , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia , Neoplasias Esofágicas/terapia , Imunoterapia , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como Assunto , Ensaios Clínicos Fase II como AssuntoRESUMO
Immunotherapy cancer clinical trials routinely feature an initial period during which the treatment is given without evident therapeutic benefit, which may be followed by a period during which an effective therapy reduces the hazard for event occurrence. The nature of this treatment effect is incompatible with the proportional hazards assumption, which has prompted much work on the development of alternative effect measures of frameworks for testing. We consider tests based on individual and combination of early- and late-emphasis infimum and supremum logrank statistics, describe how they can be implemented, and evaluate their performance in simulation studies. Through this work and illustrative applications we conclude that this class of test statistics offers a new and powerful framework for assessing treatment effects in cancer clinical trials involving immunotherapies.
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Neoplasias , Humanos , Modelos de Riscos Proporcionais , Simulação por Computador , Neoplasias/tratamento farmacológico , Oncologia , Análise de SobrevidaRESUMO
BACKGROUND: Positron emission tomography/computed tomography (PET/CT) fails to detect approximately 25% of aortic lymph node metastasis in patients with PET/CT stage IIIC1 cervical cancer. Surgical staging could lead to treatment modification and to improved para-aortic and distant control. PRIMARY OBJECTIVES: To demonstrate if chemoradiation with tailored external beam radiation field based on surgical staging and pathologic examination of the para-aortic lymph node is associated with improved 3-year disease-free survival compared with patients staged with PET/CT staging only. STUDY HYPOTHESIS: Surgical staging followed by tailored chemoradiation will improve disease-free survival while avoiding unnecessary prophylactic extended-field chemoradiation in patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIIC1 cervical cancer. TRIAL DESIGN: This is an international multicenter, randomized, phase III study. Eligible patients will be randomized 1:1 between PET/CT staging followed by chemoradiation (control arm), or surgical staging followed by tailored chemo-radiation (experimental arm). Randomization will be stratified by tumor stage according to TNM classification, center, and adjuvant treatment. MAJOR INCLUSION/EXCLUSION CRITERIA: Main inclusion criteria are histologically proven PET/CT FIGO stage IIIC1 cervical cancer. Main exclusion criteria include unequivocal positive common iliac or para-aortic lymph node at pre-therapeutic imaging PET/CT. PRIMARY ENDPOINTS: The primary endpoint is disease-free survival defined as the time from randomization until first relapse (local, regional, or distant), or death from any cause. SAMPLE SIZE: 510 eligible patients ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: The estimated date for completing accrual will be Q2 2027. The estimated date for presenting results will be Q4 2030. TRIAL REGISTRATION NUMBER: NCT05581121.
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Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias do Colo do Útero , Feminino , Humanos , Neoplasias do Colo do Útero/cirurgia , Neoplasias do Colo do Útero/patologia , Metástase Linfática/patologia , Recidiva Local de Neoplasia/patologia , Excisão de Linfonodo/métodos , Linfonodos/cirurgia , Linfonodos/patologia , Estadiamento de Neoplasias , Estudos RetrospectivosRESUMO
Even though male breast cancer (MBC) risk encompasses both genetic and environmental aetiologies, the primary risk factor is a germline pathogenic variant (PV) or likely pathogenic variant (LPV) in BRCA2, BRCA1 and/or PALB2 genes. To identify new potential MBC-specific predisposition genes, we sequenced a panel of 585 carcinogenesis genes in an MBC cohort without BRCA1/BRCA2/PALB2 PV/LPV. We identified 14 genes carrying rare PVs/LPVs in the MBC population versus noncancer non-Finnish European men, predominantly coding for DNA repair and maintenance of genomic stability proteins. We identified for the first time PVs/LPVs in PRCC (pre-mRNA processing), HOXA9 (transcription regulation), RECQL4 and WRN (maintenance of genomic stability) as well as in genes involved in other cellular processes. To study the specificity of this MBC PV/LPV profile, we examined whether variants in the same genes could be detected in a female breast cancer (FBC) cohort without BRCA1/BRCA2/PALB2 PV/LPV. Only 5/109 women (4.6%) carried a PV/LPV versus 18/85 men (21.2%) on these genes. FBC did not carry any PV/LPV on 11 of these genes. Although 5.9% of the MBC cohort carried PVs/LPVs in PALLD and ERCC2, neither of these genes were altered in our FBC cohort. Our data suggest that in addition to BRCA1/BRCA2/PALB2, other genes involved in DNA repair/maintenance or genomic stability as well as cell adhesion may form a specific MBC PV/LPV signature.
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BACKGROUND: The efficacy and added benefit of platinum-based chemotherapy (PtCT) for metastatic breast cancer (MBC) remain unclear in patients with and without germline BRCA1 or BRCA2 mutations (gBRCA1/2m and gBRCA1/2wt, respectively). METHODS: We selected from the French national real-world multicentre ESME cohort (2008-2016) all patients with HER2-negative MBC with known gBRCA1/2 status at first-line chemotherapy initiation. Using multivariable Cox models, we compared the outcome (progression-free (PFS) and overall survival (OS)) of first-line PtCT and non-PtCT regimens based on the patients' gBRCA1/2 status and tumour subtype. RESULTS: Patients who received PtCT had more aggressive tumour features. In the multivariable analysis, first-line PtCT was associated with better adjusted PFS and OS in gBRCA1/2m carriers (N = 300), compared with non-PtCT (HR 0.54, 95% CI 0.4-0.73, P < 0.001, and HR 0.70, 95% CI 0.49-0.99, P = 0.047, respectively). Conversely, outcomes were similar in gBRCA1/2wt patients (N = 922) treated with PtCT and non-PtCT, whatever the tumour subtype. Landmark analyses at months 3 and 6 post treatment initiation supported these results. CONCLUSIONS: In this pre-PARP inhibitor real-world cohort, PFS and OS were better after PtCT than non-PtCT in patients with gBRCA1/2m, but not in those with gBRCA1/2wt. These results emphasise the need of early gBRCA1/2 testing in patients with MBC. CLINICAL TRIAL NUMBER: NCT03275311.
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Antineoplásicos , Neoplasias da Mama , Feminino , Humanos , Antineoplásicos/uso terapêutico , Proteína BRCA1/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Células Germinativas , Mutação , Platina/uso terapêuticoRESUMO
The outcome of stage II-III colorectal cancer (CRC) is highly variable and therapeutic choice is currently based on TNM staging with a few additional biomarkers. However, studies show that some stage III patients have a better prognosis than some stage II patients. A promising consensus molecular (CMS) classification with prognostic relevance has been developed, but it is not used in daily practice. Our team developed CINSARC, a 67-gene expression prognostic signature, whose prognostic value has been demonstrated in many cancer types. It is applicable to formalin-fixed, paraffin-embedded (FFPE) blocks using NanoString® technology. We investigated whether it could predict outcome in stage II-III CRC. We established the CINSARC classification on the TCGA retrospective cohort comprising 297 stage II-III CRC patients using RNA sequencing and on a second independent cohort comprising 169 cases using NanoString® technology. We compared its recurrence-free and overall survival prognostic value with TNM staging and CMS classification. In the TCGA cohort, we showed that CINSARC significantly splits the population of stage II-III CRC into two groups with different progression-free interval (P = 1.68 × 10-2; HR = 1.87 [1.11-3.16]) and overall survival (P = 3.73 × 10-3; HR = 2.45 [1.31-4.59]) and is a strong prognostic factor in multivariate analysis, outperforming TNM staging and CMS classification. We validated these results in the second cohort by applying CINSARC on FFPE samples with Nanostring® technology. CINSARC is a ready-to-use tool with a robust independent prognostic value in stage II-III CRC.
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Neoplasias Colorretais , Humanos , Estadiamento de Neoplasias , Estudos Retrospectivos , Neoplasias Colorretais/patologia , Prognóstico , Transcriptoma , Biomarcadores Tumorais/genéticaRESUMO
BACKGROUND: Neuropathic pain is common in cancer survivorship and is one of the most distressing symptoms for patients previously treated for head and neck cancer. Persistent neuropathic pain, when it is ongoing and uncontrolled, has a detrimental effect and erodes patients' quality of life. Patients treated for head and neck cancer are chronic opioid users to manage their post-treatment pain, which may entail an increased risk of addiction and overdose. We propose to evaluate the analgesic activity of high-concentration capsaicin patches for the treatment of head and neck cancer survivors presenting with neuropathic pain sequelae. METHODS: TEC-ORL is a parallel, multicenter randomized comparative phase II study evaluating whether Capsaïcin patches (Qutenza®) reduce neuropathic pain when compared to Amitriptyline (Laroxyl®) in head and neck cancer survivors presenting with neuropathic pain sequelae. The primary efficacy outcome is the rate of patients with a pain reduction of at least two points at 9 months compared to baseline. Assuming that 5% of patients become lost to follow-up, 130 patients will need to be randomized to detect a 25% improvement (i.e., standard: 25%, experimental: 50%) using a one-sided chi-square test with an alpha of 0.05%. According to the recommendations for comparative phase II trials, the target differences and type I error rates are relaxed. Randomized patients will either be treated with a capsaicin 8% (Qutenza®) patch applied at three time intervals in the experimental arm or with Amitriptyline (Laroxyl®) (oral solution 40 mg/ml) taken for 9 months at the recommended daily dose of 25 mg to 75 mg in the control arm. DISCUSSION: TEC-ORL is a randomized comparative phase II trial designed to comprehensively evaluate the analgesic activity of capsaicin compared to Laroxyl in Head and Neck Cancer survivors presenting with neuropathic pain sequelae. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04704453 Date of registration: 2021/01/13.
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Amitriptilina , Analgésicos , Capsaicina , Neoplasias de Cabeça e Pescoço , Neuralgia , Humanos , Amitriptilina/farmacologia , Analgésicos/farmacologia , Capsaicina/farmacologia , Ensaios Clínicos Fase II como Assunto , Neoplasias de Cabeça e Pescoço/complicações , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Estudos Multicêntricos como Assunto , Neuralgia/etiologia , Neuralgia/prevenção & controle , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , SobreviventesRESUMO
BACKGROUND: Given the inherent challenges of conducting randomized phase III trials in older cancer patients, single-arm phase II trials which assess the feasibility of a treatment that has already been shown to be effective in a younger population may provide a compelling alternative. Such an approach would need to evaluate treatment feasibility based on a composite endpoint that combines multiple clinical dimensions and to stratify older patients as fit or frail to account for the heterogeneity of the study population to recommend an appropriate treatment approach. In this context, stratified adaptive two-stage designs for binary or composite endpoints, initially developed for biomarker studies, allow to include two subgroups whilst maintaining competitive statistical performances. In practice, heterogeneity may indeed affect more than one dimension and incorporating co-primary endpoints, which independently assess each individual clinical dimension, would therefore appear quite pertinent. The current paper presents a novel phase II design for co-primary endpoints which takes into account the heterogeneity of a population. METHODS: We developed a stratified adaptive Bryant & Day design based on the Jones et al. and Parashar et al. algorithm. This two-stage design allows to jointly assess two dimensions (e.g. activity and toxicity) in two different subgroups. The operating characteristics of this new design were evaluated using examples and simulation comparisons with the Bryant & Day design in the context where the study population is stratified according to a pre-defined criterion. RESULTS: Simulation results demonstrated that the new design minimized the expected and maximum sample sizes as compared to parallel Bryant & Day designs (one in each subgroup), whilst controlling type I error rates and maintaining a competitive statistical power as well as a high probability of detecting heterogeneity. CONCLUSIONS: In a heterogeneous population, this two-stage stratified adaptive phase II design provides a useful alternative to classical one and allows to identify a subgroup of interest without dramatically increasing sample size. As heterogeneity is not limited to older populations, this new design may also be relevant to other study populations such as children or adolescents and young adults or the development of targeted therapies based on a biomarker.
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Oncologia , Neoplasias , Idoso , Humanos , Biomarcadores , Oncologia/métodos , Neoplasias/terapia , Projetos de Pesquisa , Tamanho da AmostraRESUMO
PURPOSE: Transoral robotic surgery (TORS) as a first-line therapy has been well-documented but evidence is missing regarding salvage therapy. The aim of this study is to compare the oncological and functional outcomes of TORS as a primary and salvage therapy. METHODS: This retrospective monocentric study included 74 patients operated by a single surgeon and sorted out into two groups: primary treatment (PT) or Salvage treatment (ST) in case of previous history of radiation therapy. Patients were further stratified by tumour location: larynx and pharynx (lST vs lPT and pST vs pPT). RESULTS: Forty-eight patients were included in PT group (64.9%) and 26 in ST group (35.1%). ST patients had more frequent cTis/T1 tumours (57.7% vs 29.2%, p = 0.0164) and no clinical lymph disease (3.8% vs 37.5%, p = 0.0016). Tracheostomy was more often performed in the ST group (57.7% vs 16.7%, p = 0.0003) and the lST subgroup (88.9% vs 9.1%, p < 0.0001). Gastric feeding tube placement was more frequent in the ST group (76.9% vs 33.3%, p = 0.0003), the pST subgroup (64.7% vs 15.4%, p = 0.0009) and the lST subgroup (100% vs 54.5%, p = 0.0297). We observed a trend for more postoperative complications in the ST group (69.2% vs 47.9%, p = 0.0783). The overall survival was lower in the ST group (p = 0.0004), and in the pST subgroup (p < 0.0001). The disease-free survival rate was lower in the ST group (p = 0.0001), the pST subgroup (p = 0.0002) and the lST subgroup (p = 0.0328). CONCLUSION: This study confirms that survival and functional outcomes after salvage TORS are worse than in first line surgery.
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Neoplasias Orofaríngeas , Procedimentos Cirúrgicos Robóticos , Intervalo Livre de Doença , Humanos , Estudos Retrospectivos , Terapia de Salvação , Resultado do TratamentoRESUMO
BACKGROUND: The immune microenvironment (IME) of triple-negative breast cancers (TNBCs) and its modulation by neoadjuvant chemotherapy (NACT) remain to be fully characterized. Our current study aims to evaluate NACT-induced IME changes and assess the prognostic value of specific immune biomarkers. METHODS: Tumor-infiltrating lymphocytes (TILs) were identified from hematoxylin-eosin-stained sections of paired pre- and post-NACT tumor samples from a TNBC cohort (n = 66) and expression of PD-L1, TIM-3, and LAG-3 evaluated by immunohistochemistry. RESULTS: Overall TIL counts and PD-L1 expression did not differ pre- and post-NACT, but there was a response-specific statistically significant difference. TIL counts decreased in 65.5% of patients who achieved a pathological complete response (pCR) and increased in 56.8% of no-pCR patients (p = 0.0092). PD-L1 expression was significantly more frequently lost after NACT in pCR than in no-pCR patients (41.4% vs 16.2%, p = 0.0020). TIM-3 positivity (≥ 1%) was significantly more frequent after NACT (p < 0.0001) with increases in expression levels occurring more frequently in no-pCR than in pCR patients (51.4% vs 31%). LAG-3 expression significantly decreased after NACT, but there was no difference between response groups. Before NACT, a high TIL count (> 10%) was significantly associated with better overall survival (OS), p = 0.0112. After NACT, PD-L1 positivity and strong TIM-3 positivity (≥ 5%) were both associated with significantly worse OS (p = 0.0055 and p = 0.0274, respectively). Patients positive for both PD-L1 and TIM-3 had the worst prognosis (p = 0.0020), even when only considering patients who failed to achieve a pCR, p = 0.0479. CONCLUSIONS: NACT induces significant IME changes in TNBCs. PD-L1 and TIM-3 expression post-NACT may yield important prognostic information for TNBC patients.
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Terapia Neoadjuvante , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Adulto , Idoso , Antígenos CD/metabolismo , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/imunologia , Biomarcadores Tumorais/metabolismo , Feminino , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Linfócitos do Interstício Tumoral/metabolismo , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/patologia , Adulto Jovem , Proteína do Gene 3 de Ativação de LinfócitosRESUMO
We compared the performance of six prognostic scores (Royal Marsden Hospital, MDACC: MD Anderson Clinical Center and MDACC + NLR: neutrophil-to-lymphocyte ratio, MD Anderson - immune checkpoint inhibitors (MDA-ICI), GRIm: Gustave Roussy Immune Score and LIPI: Lung Immune Prognostic Index) in predicting overall survival (OS) in phase I trial patients treated with immune checkpoint inhibitors (ICI). Medical records of patients with advanced solid tumors enrolled in ICI phase I trials between 2015 and 2018 at Institut Universitaire du Cancer de Toulouse-Oncopole were reviewed. The performance of prognostic scores on OS was compared using different criteria. A total of 259 patients were included. Median age was 63 years (range: 18-83). Main primary cancers were melanoma (19%), head and neck (16%), lung (13%) and bladder (10%). With a median follow-up of 15 months (95% confidence interval [CI] = [11.6;17.5]), median OS was 12.5 months (95% CI = [10.3;16.0]). All scores were associated with OS. The MDACC, LIPI and GRIm scores performed better than the others. Concordance of risk group assignment between the scoring systems was poor. According to our results, the MDACC, GRIm and LIPI scores better suited to ICI phase I settings. Adequate scoring would allow better patient selection in early ICI trials, especially during the critical period of dose escalation, and in proof-of-concept expansion cohorts.
RESUMO
As key regulators of the actin cytoskeleton, RHO GTPase expression and/or activity are deregulated in tumorigenesis and metastatic progression. Nevertheless, the vast majority of experiments supporting this conclusion was conducted on cell lines but not on human tumor samples that were mostly studied at the expression level only. Up to now, the activity of RHO proteins remains poorly investigated in human tumors. In this article, we present the development of a robust nanobody-based ELISA assay, with a high selectivity that allows an accurate quantification of RHO protein GTP-bound state in the nanomolar range (1 nM; 20 µg/L), not only in cell lines after treatment but also in tumor samples. Of note, we present here a fine analysis of RHOA-like and RAC1 active state in tumor samples with the most comprehensive study of RHOA-GTP and RHOC-GTP levels performed on human breast tumor samples. We revealed increased GTP-bound RHOA and RHOC protein activities in tumors compared to normal tissue counterparts, and demonstrated that the RHO active state and RHO expression are two independent parameters among different breast cancer subtypes. Our results further highlight the regulation of RHO protein activation in tumor samples and the relevance of directly studying RHO GTPase activities involvement in molecular pathways.
Assuntos
Neoplasias da Mama , Proteína rhoA de Ligação ao GTP , Proteína de Ligação a GTP rhoC , Transformação Celular Neoplásica , Feminino , Guanosina Trifosfato , Humanos , Proteína rhoA de Ligação ao GTP/metabolismo , Proteína de Ligação a GTP rhoC/metabolismoRESUMO
OBJECTIVE: Hematological treatment decisions in older adults with hematological malignancies are complex. Our objective is to study the impact of a comprehensive geriatric assessment on hematological treatment decision in older patients and the factors associated with change in treatment plan. METHODS: We conducted a cross-sectional analysis of patients aged 65 years and above with hematological malignancies, hospitalized between 2008 and 2019 at the University Cancer Institute of Toulouse. They were assessed by a geriatrician/nurse team using a comprehensive geriatric assessment (CGA). A penalized logistic regression model with elastic net regularization was used to identify factors associated with change in hematological treatment plan. RESULTS: A total of 424 patients were included. Main hematological malignancies were lymphoma (36.1 %), acute myeloid leukemia (26.9 %) and myelodysplastic syndrome (19.8%). Change in hematological treatment plan was suggested after CGA for 92 patients (21.7%). Factors associated with change in treatment plan were functional impairment according to ADL and IADL scale, mobility impairment, the presence of comorbidity defined by the Charlson score >1 and increasing age. CONCLUSION: A CGA has a significant impact on hematological treatment decision in older patients. Functional and mobility impairment, comorbidities and age are predictive factors of change in treatment plan.
Assuntos
Tomada de Decisão Clínica , Avaliação Geriátrica , Avaliação do Impacto na Saúde , Neoplasias Hematológicas/epidemiologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Estudos Transversais , Gerenciamento Clínico , Avaliação Geriátrica/métodos , Avaliação Geriátrica/estatística & dados numéricos , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/terapia , Humanos , PrognósticoRESUMO
In oncology clinical research, the analysis and reporting of adverse events is of major interest. A consistent depiction of the safety profile of a new treatment is as crucial in establishing how to use it as its antitumor activity. The advent of new therapeutics has led to major changes in the management of patients and targeted therapies or immune checkpoint inhibitors are administered continuously for months or even years. However, the classical methods of adverse events analysis are no longer adequate to properly assess their safety profile. Indeed, the worst grade method and time-to-event analysis cannot capture the duration or the evolution of adverse events induced by extended treatment durations. Many authors have highlighted this issue and argue that the analysis of safety data from clinical trials should be modernized by considering the dimension of time and the recurrent nature of adverse events. This paper aims to illustrate the limitations of current methods and discusses the value of alternative approaches such as the prevalence function, Q-TWiST, the ToxT and the recurrent event approaches. The rationale and design of the MOTIVATE trial, which aims to model the evolution of toxicities over time using the prevalence function in patients treated by immunotherapy, is also presented ( ClinicalTrials.gov Identifier: NCT03447483; Date of registration: 27 February 2018).