Publications by authors named "Thomas Filleron"

154 Publications

Rucaparib in patients presenting a metastatic breast cancer with homologous recombination deficiency, without germline BRCA1/2 mutation.

Eur J Cancer 2021 Nov 24;159:283-295. Epub 2021 Nov 24.

Department of Medical Oncology, Gustave Roussy, Université Paris Saclay, 114 Rue Edouard Vaillant, 94805 Villejuif, France.

Background: Breast cancer may present genomic alterations leading to homologous recombination deficiency (HRD). PARP inhibitors have proven their efficacy in patients with HER2-negative (HER2-) metastatic breast cancer (mBC) harbouring germline (g) BRCA1/2 mutations in 3 phases III trials. The single-arm phase II RUBY trial included 42 patients, 40 of whom received at least one dose of rucaparib. RUBY study assessed the efficacy of rucaparib in HER2-mBC with either high genomic loss of heterozygosity (LOH) score or non-germline BRCA1/2 mutation.

Patients And Methods: The primary objective was the clinical benefit rate (CBR), and the study was powered to see 20% CBR using a 2-stage Simon design.

Results: The primary-end point was not reached with a CBR of 13.5%. Two LOH-high patients, without somatic BRCA1/2 mutation, presented a complete and durable response (12 and 28.5 months). Whole-genome analysis was performed on 24 samples, including 5 patients who presented a clinical benefit from rucaparib. HRDetect tended to be associated with response to rucaparib, without reaching statistical significance (median HRDetect responders versus non-responders: 0.465 versus 0.040; p = 0.2135). Finally, 220 of 711 patients with mBC screened for LOH upstream from RUBY presented a high LOH score associated with a higher likelihood of death (hazard ratio = 1.39; 95% CI: 1.11-1.75; p = 0.005).

Conclusion: Our data suggest that a small subset of patients with high LOH scores without germline BRCA1/2 mutation could derive benefit from PARP inhibitors. However, the RUBY study underlines the need to develop additional biomarkers to identify selectively potential responders.
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http://dx.doi.org/10.1016/j.ejca.2021.09.028DOI Listing
November 2021

Treatment strategies for unresectable locally advanced non-small cell lung cancer in the real-life ESME cohort.

Lung Cancer 2021 Nov 6;162:119-127. Epub 2021 Nov 6.

Centre Hospitalier Intercommunal de Créteil, Créteil, France.

Background: Cisplatin-based chemotherapy administered concurrently to thoracic radiation therapy is the recommended treatment for fit patients with unresectable stage III NSCLC. The aim of this study was to describe patient profiles and clinical outcomes for the different treatment strategies in a real-word setting.

Methods: The epidemio-strategy and medical economics (ESME) database for advanced and metastatic lung cancer is a French, national, multicenter, observational cohort. Out of 8514 Patients, 822 patients with unresectable locally advanced NSCLC in 2015-016 were selected (mean age, 65.3 years; male gender, 69%; performance status 0-1, 77%; smokers or former smokers, 89%).

Results: Treatment was initiated for 736 (90%) of patients (concurrent chemoradiotherapy, n = 283; sequential chemoradiotherapy, n = 121; chemotherapy alone, n = 194; radiotherapy alone, n = 121; targeted therapy alone, n = 8; other, n = 9). Compared to the other treatment strategy groups, patients with radiotherapy alone appeared the most fragile (e.g. higher age, lower body weight or higher frequency of chronic obstructive pulmonary disease). OS rates at 12 and 24 months were 79.5% (95% CI, 73.4-84.3) and 55.3% (95% CI, 44.9-64.5) for concurrent chemoradiotherapy, and 64.3% (95% CI, 52.8-73.8) and 53.2 (95% CI, 33.2-69.6) for sequential chemoradiotherapy.

Conclusions: Real-world evidence shows that concurrent chemoradiotherapy is administered to the most fit patients with non resectable locally-advanced NSCLC. Clinical outcomes are actually higher than those reported in landmark clinical trials, which suggests that an optimized and individualized selection of patients allows for prolonged survival. Long-term outcomes are similar after sequential or concurrent chemoradiotherapy.
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http://dx.doi.org/10.1016/j.lungcan.2021.10.017DOI Listing
November 2021

A Real-World Study of Patients with Advanced Non-squamous Non-small Cell Lung Cancer with EGFR Exon 20 Insertion: Clinical Characteristics and Outcomes.

Target Oncol 2021 Nov 18;16(6):801-811. Epub 2021 Oct 18.

Institut Régional du Cancer de Montpellier, Montpellier, France.

Background: In Europe, few data regarding the characteristics of EGFR exon 20 insertion (20ins) mutations in non-small cell lung cancer (NSCLC) are available.

Objective: Using a large real-world cohort, we assessed the incidence, characteristics, and outcomes of patients with non-squamous (nsq) NSCLC harboring EGFR exon 20ins.

Patients And Methods: The Epidemio-Strategy and Medical Economics advanced and metastatic lung cancer data platform including advanced/metastatic nsqNSCLC patients from January 2015 was analyzed (cut-off date: June 30, 2020). Characteristics, epidermal growth factor receptor (EGFR) mutation and other mutations, treatment patterns, and clinical outcomes were assessed for patients harboring EGFR exon 20ins, common EGFR mutations, other EGFR mutations, and wild-type EGFR. Survival parameters were estimated by the Kaplan-Meier method in these four groups.

Results: Out of 9435 nsqNSCLC patients tested for EGFR, 1549 (16.4%) had a mutation, including 61 with EGFR exon 20ins (3.9% of all mutated EGFR). These 61 patients had a mean age of 63.6 years, were mostly female (68.9%) and non-smokers (55.7%), with de novo stage IV disease (73.8%) and performance status 0-1 (76.9%). Almost all patients (95.1%) with exon 20ins received systemic therapy (median, three lines). First-line systemic treatments consisted mainly of combination chemotherapy (70.7%), single-agent EGFR tyrosine kinase inhibitors (10.3%), and single-agent immunotherapy (5.2%). After a median follow-up of 25.0 (95% confidence interval [CI] 22.3-32.4) months, the median real-world overall survival was 24.3 (19.1-32.6) months in patients with exon 20ins compared to 35.4 (95% CI 32.6-37.5) in patients with common EGFR mutation (n = 1049) (p = 0.049) and 19.6 (95% CI 18.6-20.5) in patients with wild-type EGFR (n = 7866) (p = 0.2).

Conclusions: This large national study in nsqNSCLC patients confirms that EGFR exon 20ins is a rare condition (0.6%). The prognosis associated with exon 20ins appears to be in line with that of wild-type EGFR, but worse than common EGFR mutations, highlighting the need for advancements for this rare population.
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http://dx.doi.org/10.1007/s11523-021-00848-9DOI Listing
November 2021

Addressing the issue of bias in observational studies: Using instrumental variables and a quasi-randomization trial in an ESME research project.

PLoS One 2021 15;16(9):e0255017. Epub 2021 Sep 15.

Department of Biostatistics, DRCI, Centre Leon Berard, Lyon, France.

Purpose: Observational studies using routinely collected data are faced with a number of potential shortcomings that can bias their results. Many methods rely on controlling for measured and unmeasured confounders. In this work, we investigate the use of instrumental variables (IV) and quasi-trial analysis to control for unmeasured confounders in the context of a study based on the retrospective Epidemiological Strategy and Medical Economics (ESME) database, which compared overall survival (OS) with paclitaxel plus bevacizumab or paclitaxel alone as first-line treatment in patients with HER2-negative metastatic breast cancer (MBC).

Patients And Methods: Causal interpretations and estimates can be made from observation data using IV and quasi-trial analysis. Quasi-trial analysis has the same conceptual basis as IV, however, instead of using IV in the analysis, a "superficial" or "pseudo" randomized trial is used in a Cox model. For instance, in a multicenter trial, instead of using the treatment variable, quasi-trial analysis can consider the treatment preference in each center, which can be informative, and then comparisons of results between centers or clinicians can be informative.

Results: In the original analysis, the OS adjusted for major factors was significantly longer with paclitaxel and bevacizumab than with paclitaxel alone. Using the center-treatment preference as an instrument yielded to concordant results. For the quasi-trial analysis, a Cox model was used, adjusted on all factors initially used. The results consolidate those obtained with a conventional multivariate Cox model.

Conclusion: Unmeasured confounding is a major concern in observational studies, and IV or quasi-trial analysis can be helpful to complement analysis of studies of this nature.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255017PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8443058PMC
November 2021

Feasibility of comprehensive genotyping specimens from radial endobronchial ultrasonography and electromagnetic navigation bronchoscopy.

ERJ Open Res 2021 Jul 19;7(3). Epub 2021 Jul 19.

Pulmonology Dept, Larrey University Hospital, Toulouse, France.

Introduction: Mini-invasive bronchoscopic techniques (such as radial endobronchial ultrasonography (rEBUS) and electromagnetic navigation (EMN)) have been developed to reach the peripheral lung but result in small samples. The feasibility of an adequate molecular testing from these specimens has been very little studied.

Methods: We retrospectively reviewed EMN and rEBUS procedures performed in patients diagnosed with lung cancer in our institution in 2017 and 2018. We analysed the sensitivity for rEBUS and EMN and each sampling method, and the feasibility of a comprehensive molecular testing.

Results: In total, 317 rEBUS and 14 EMN were performed. Median sizes of tumours were 16 and 32 mm for EMN and rEBUS, respectively. Overall sensitivity for rEBUS and EMN was 84.3%. Cytology was found to be complementary with biopsies, with 13.3% of cancer diagnosed on cytology while biopsies were negative. Complication rate was 2.4% (pneumothorax 1.5%, mild haemoptysis 0.9%). Genotyping (immunohistochemistry for and followed by fluorescence hybridisation if positive and hybrid capture next-generation sequencing covering 48 genes), when ordered (n=188), was feasible in 69.1% ( 17.7%, 31.7%, 4.8%, 1.2%, 3.1%, 0.8%). PD-L1 (programmed death-ligand 1) expression, when ordered (n=232), could be analysed in 94% of cases. Overall, 56.9% (33 out of 58) of patients for whom genotyping was not feasible underwent a second sampling (12 pretreatment, 21 at progression), allowing for the detection of six actionable genotypes (five , one ).

Conclusion: rEBUS and EMN are sensitive and safe procedures that result in limited samples, often not suitable for genotyping, highlighting the importance of integrating liquid biopsy in routine testing.
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http://dx.doi.org/10.1183/23120541.00942-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287134PMC
July 2021

Immune microenvironment changes induced by neoadjuvant chemotherapy in triple-negative breast cancers: the MIMOSA-1 study.

Breast Cancer Res 2021 05 26;23(1):61. Epub 2021 May 26.

Department of Pathology, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse, IUCT-Oncopole, Toulouse, France.

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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http://dx.doi.org/10.1186/s13058-021-01437-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157437PMC
May 2021

Drug development in the era of precision medicine in oncology-Clues beyond randomization.

Chin Clin Oncol 2021 Jun 23;10(3):23. Epub 2021 Apr 23.

Department of Drug Development and Innovation (D3i), Institut Curie, Paris & Saint-Cloud, France; INSERM U900 Research Unit, Institut Curie, Saint-Cloud, France; Faculty of Medicine, Paris-Saclay University, Paris, France.

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http://dx.doi.org/10.21037/cco-21-29DOI Listing
June 2021

Functional and oncological outcomes of salvage transoral robotic surgery: a comparative study.

Eur Arch Otorhinolaryngol 2021 Apr 20. Epub 2021 Apr 20.

Department of ENT Head and Neck Surgery, Institut Claudius Regaud, IUCT-Oncopole, 1 Av. Irène Joliot-Curie, 31059, Toulouse, France.

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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http://dx.doi.org/10.1007/s00405-021-06812-7DOI Listing
April 2021

Phenotypic discordance between primary and metastatic breast cancer in the large-scale real-life multicenter French ESME cohort.

NPJ Breast Cancer 2021 Apr 16;7(1):41. Epub 2021 Apr 16.

Gustave Roussy Cancer Campus, Villejuif, France.

Expression of hormone receptor (HR) for estrogens (ER) and progesterone (PR) and HER2 remains the cornerstone to define the therapeutic strategy for breast cancer patients. We aimed to compare phenotypic profiles between matched primary and metastatic breast cancer (MBC) in the ESME database, a National real-life multicenter cohort of MBC patients. Patients with results available on both primary tumour and metastatic disease within 6 months of MBC diagnosis and before any tumour progression were eligible for the main analysis. Among the 16,703 patients included in the database, 1677 (10.0%) had available biopsy results at MBC diagnosis and on matched primary tumour. The change rate of either HR or HER2 was 27.0%. Global HR status changed (from positive = either ER or PR positive, to negative = both negative; and reverse) in 14.2% of the cases (expression loss in 72.5% and gain in 27.5%). HER2 status changed in 7.8% (amplification loss in 45.2%). The discordance rate appeared similar across different biopsy sites. Metastasis to bone, HER2+ and RH+/HER2- subtypes and previous adjuvant endocrine therapy, but not relapse interval were associated with an HR discordance in multivariable analysis. Loss of HR status was significantly associated with a risk of death (HR adjusted = 1.51, p = 0.002) while gain of HR and HER2 discordance was not. In conclusion, discordance of HR and HER2 expression between primary and metastatic breast cancer cannot be neglected. In addition, HR loss is associated with worse survival. Sampling metastatic sites is essential for treatment adjustment.
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http://dx.doi.org/10.1038/s41523-021-00252-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052407PMC
April 2021

Nanobody-Based Quantification of GTP-Bound RHO Conformation Reveals RHOA and RHOC Activation Independent from Their Total Expression in Breast Cancer.

Anal Chem 2021 04 7;93(15):6104-6111. Epub 2021 Apr 7.

Centre de Recherche en Cancérologie de Toulouse (CRCT), INSERM, Université de Toulouse, CNRS, UPS, Toulouse 31037, France.

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.
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http://dx.doi.org/10.1021/acs.analchem.0c05137DOI Listing
April 2021

Neutral Sphingomyelinase 2 Heightens Anti-Melanoma Immune Responses and Anti-PD-1 Therapy Efficacy.

Cancer Immunol Res 2021 05 16;9(5):568-582. Epub 2021 Mar 16.

INSERM UMR 1037, Cancer Research Center of Toulouse (CRCT), Toulouse, France.

Dysregulation of lipid metabolism affects the behavior of cancer cells, but how this happens is not completely understood. Neutral sphingomyelinase 2 (nSMase2), encoded by , catalyzes the breakdown of sphingomyelin to produce the anti-oncometabolite ceramide. We found that this enzyme was often downregulated in human metastatic melanoma, likely contributing to immune escape. Overexpression of nSMase2 in mouse melanoma reduced tumor growth in syngeneic wild-type but not CD8-deficient mice. In wild-type mice, nSMase2-overexpressing tumors showed accumulation of both ceramide and CD8 tumor-infiltrating lymphocytes, and this was associated with increased level of transcripts encoding IFNγ and CXCL9. Overexpressing the catalytically inactive nSMase2 failed to alter tumor growth, indicating that the deleterious effect nSMase2 has on melanoma growth depends on its enzymatic activity. , small extracellular vesicles from melanoma cells overexpressing wild-type nSMase2 augmented the expression of IL12, CXCL9, and CCL19 by bone marrow-derived dendritic cells, suggesting that melanoma nSMase2 triggers T helper 1 (Th1) polarization in the earliest stages of the immune response. Most importantly, overexpression of wild-type nSMase2 increased anti-PD-1 efficacy in murine models of melanoma and breast cancer, and this was associated with an enhanced Th1 response. Therefore, increasing expression in melanoma may serve as an original therapeutic strategy to potentiate Th1 polarization and CD8 T-cell-dependent immune responses and overcome resistance to anti-PD-1.
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http://dx.doi.org/10.1158/2326-6066.CIR-20-0342DOI Listing
May 2021

VOTRAGE study: Phase I dose-escalation study of pazopanib in unfit older patients.

J Geriatr Oncol 2021 06 11;12(5):759-764. Epub 2021 Mar 11.

Laboratory of Phamacology, Institut Claudius Regaud, IUCT-Oncopole, and CRCT, Université de Toulouse, Inserm, 1, avenue Irène Joliot-Curie, 31059 Toulouse, France.

Background: Pazopanib is a tyrosine kinase inhibitor given at the approved dose of 800 mg orally once daily (OD), but often requiring individual dose adjustment due to toxicity. Limited data is available to guide prescription in older patients especially the unfit according to geriatric assessment.

Patients And Methods: VOTRAGE is a 3 + 3 dose-escalation, open-label phase I trial of continuous OD oral administration of pazopanib to evaluate safety, PK and PD data in unfit older patients with advanced solid tumors. The primary objective was to determine the maximum tolerated dose (MTD). PK data were compared with those obtained in younger adult patients in a population PK analysis.

Results: Eighteen patients with a median age of 82.5 years (range 75-91) were included in three dosing cohorts (400, 600, and 800 mg daily). Three dose-limiting toxicities (DLT) were observed in five patients at 800 mg and one DLT at 600 mg in six evaluable patients. MTD was defined as level 2 dose (600 mg). Individual oral clearance was not correlated with age. A relationship was observed between the occurrence of DLT and pazopanib plasma exposure. Decreased oral bioavailability of pazopanib when given with proton-pump inhibitors was confirmed in this group of patients.

Conclusion: We recommend performing geriatric assessment in patients older than 75 and starting pazopanib at 600 mg per day in unfit older patients. Therapeutic drug monitoring appears very helpful in this population.
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http://dx.doi.org/10.1016/j.jgo.2021.02.006DOI Listing
June 2021

Multicentric phase II trial of TI-CE high-dose chemotherapy with therapeutic drug monitoring of carboplatin in patients with relapsed advanced germ cell tumors.

Cancer Med 2021 04 5;10(7):2250-2258. Epub 2021 Mar 5.

Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France.

Background: High-dose chemotherapy (HDCT) with TI-CE regimen is a valid option for the treatment of relapsed advanced germ cell tumors (GCT). We report a phase II trial with therapeutic drug monitoring of carboplatin for optimizing area under the curve (AUC) of this drug.

Methods: Patients with unfavorable relapsed GCT were treated according to TI-CE regimen: two cycles combining paclitaxel and ifosfamide followed by three cycles of HD carboplatin plus etoposide administered on 3 days. Carboplatin dose was adapted on day 3 based on carboplatin clearance (CL) at day 1 in order to reach a target AUC of 24 mg.min/mL per cycle. The primary endpoint was the complete response (CR) rate.

Results: Eighty-nine patients who received HDCT were included in the modified intent-to-treat (mITT) analysis. Measured mean AUC was 24.4 mg.min/mL per cycle (22.4 and 26.8 mg.min/mL for 10th and 90th percentiles). Thirty-five (44.3%) patients achieved a CR with or without surgery of residual masses and 20 patients achieved a partial response with negative tumor markers. With a median follow-up of 44 months (m), median PFS was 12.3 m (95% CI: 7.5-25.9) and OS was 46.3 m (95% CI: 18.6-not reached). For high- and very high-risk patients, according to the International Prognostic Score at first relapse or treated after at least one salvage treatment (n = 51), 2-year PFS rate was 41.1%.

Conclusion: The rates of complete and favorable responses were clinically relevant in this very poor risk population. Individual monitoring of carboplatin plasma concentration permitted to control more accurately the target AUC and avoided both underexposure and overexposure to the drug.
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http://dx.doi.org/10.1002/cam4.3687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982623PMC
April 2021

Durvalumab compared to maintenance chemotherapy in metastatic breast cancer: the randomized phase II SAFIR02-BREAST IMMUNO trial.

Nat Med 2021 02 18;27(2):250-255. Epub 2021 Jan 18.

Unicancer, Paris, France.

The impact of single-agent antibodies against programmed death-ligand 1 (PD-L1) as maintenance therapy is unknown in patients with metastatic breast cancer. The SAFIR02-BREAST IMMUNO substudy included patients with human epidermal growth factor receptor type 2 (Her2)-negative metastatic breast cancer whose disease did not progress after six to eight cycles of chemotherapy. Patients (n = 199) were randomized to either durvalumab (10 mg kg every 2 weeks) or maintenance chemotherapy. In the overall population, durvalumab did not improve progression-free survival (adjusted hazard ratio (HR): 1.40, 95% confidence interval (CI): 1.00-1.96; P = 0.047) or overall survival (OS; adjusted HR: 0.84, 95% CI: 0.54-1.29; P = 0.423). In an exploratory subgroup analysis, durvalumab improved OS in patients with triple-negative breast cancer (TNBC; n = 82; HR: 0.54, 95% CI: 0.30-0.97, P = 0.0377). Exploratory analysis showed that the HR of death was 0.37 (95% CI: 0.12-1.13) for patients with PD-L1 TNBC (n = 32) and 0.49 (95% CI: 0.18-1.34) for those with PD-L1 TNBC (n = 29). In patients with TNBC, exploratory analyses showed that the HR for durvalumab efficacy (OS) was 0.18 (95% CI: 0.05-0.71; log-rank test, P = 0.0059) in patients with CD274 gain/amplification (n = 23) and 1.12 (95% CI: 0.42-2.99; log-rank test, P = 0.8139) in patients with CD274 normal/loss (n = 32). Tumor infiltration by lymphocytes (CD8, FoxP3 and CD103 expressions) and homologous recombination deficiency did not predict sensitivity to durvalumab in exploratory analyses. This latter finding should be interpreted with caution since only one patient presented a germline BRCA mutation. The present study provides a rationale to evaluate single-agent durvalumab in maintenance therapy in patients with TNBC. Exploratory analyses identified CD274 amplification as a potential biomarker of sensitivity. Maintenance chemotherapy was more effective than durvalumab in patients with hormone receptor-positive and Her2-negative disease.
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http://dx.doi.org/10.1038/s41591-020-01189-2DOI Listing
February 2021

Impact of a comprehensive geriatric assessment on decision-making in older patients with hematological malignancies.

Eur J Haematol 2021 May 14;106(5):616-626. Epub 2021 Feb 14.

Geriatric Department, Internal Medicine and Oncogeriatry Unit, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.

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.
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http://dx.doi.org/10.1111/ejh.13570DOI Listing
May 2021

Combining Nivolumab and Ipilimumab with Infliximab or Certolizumab in Patients with Advanced Melanoma: First Results of a Phase Ib Clinical Trial.

Clin Cancer Res 2021 02 3;27(4):1037-1047. Epub 2020 Dec 3.

INSERM UMR 1037, Cancer Research Center of Toulouse (CRCT), Toulouse, France.

Purpose: TNF blockers can be used to manage gastrointestinal inflammatory side effects following nivolumab and/or ipilimumab treatment in patients with advanced melanoma. Our preclinical data showed that anti-TNF could promote the efficacy of immune checkpoint inhibitors.

Patients And Methods: TICIMEL (NTC03293784) is an open-label, two-arm phase Ib clinical trial. Fourteen patients with advanced and/or metastatic melanoma (stage IIIc/IV) were enrolled. Patients were treated with nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) combined to infliximab (5 mg/kg, = 6) or certolizumab (400/200 mg, = 8). The primary endpoint was safety and the secondary endpoint was antitumor activity. Adverse events (AEs) were graded according to the NCI Common Terminology Criteria for Adverse Events and response was assessed following RECIST 1.1.

Results: Only one dose-limiting toxicity was observed in the infliximab cohort. The two different combinations were found to be safe. We observed lower treatment-related AEs with infliximab as compared with certolizumab. In the certolizumab cohort, one patient was not evaluable for response. In this cohort, four of eight patients exhibited hepatobiliary disorders and seven of seven evaluable patients achieved objective response including four complete responses (CRs) and three partial responses (PRs). In the infliximab cohort, we observed one CR, two PRs, and three progressive diseases. Signs of activation and maturation of systemic T-cell responses were seen in patients from both cohorts.

Conclusions: Our results show that both combinations are safe in human and provide clinical and biological activities. The high response rate in the certolizumab-treated patient cohort deserves further investigations.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3449DOI Listing
February 2021

Improving patient selection for immuno-oncology phase 1 trials: External validation of six prognostic scores in a French Cancer Center.

Int J Cancer 2020 Nov 24. Epub 2020 Nov 24.

Department of Biostatistics, Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse-Oncopole (IUCT-O), Toulouse, France.

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.
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http://dx.doi.org/10.1002/ijc.33409DOI Listing
November 2020

Model-Based Quantification of Impact of Genetic Polymorphisms and Co-Medications on Pharmacokinetics of Tamoxifen and Six Metabolites in Breast Cancer.

Clin Pharmacol Ther 2021 05 10;109(5):1244-1255. Epub 2020 Nov 10.

Cancer Research Center of Toulouse (CRCT), Inserm U1037, Université Paul Sabatier, Toulouse, France.

Variations in clinical response to tamoxifen (TAM) may be related to polymorphic cytochromes P450 (CYPs) involved in forming its active metabolite endoxifen (ENDO). We developed a population pharmacokinetic (PopPK) model for tamoxifen and six metabolites to determine clinically relevant factors of ENDO exposure. Concentration-time data for TAM and 6 metabolites come from a prospective, multicenter, 3-year follow-up study of adjuvant TAM (20 mg/day) in patients with breast cancer, with plasma samples drawn every 6 months, and genotypes for 63 genetic polymorphisms (PHACS study, NCT01127295). Concentration data for TAM and 6 metabolites from 928 patients (n = 27,433 concentrations) were analyzed simultaneously with a 7-compartment PopPK model. CYP2D6 phenotype (poor metabolizer (PM), intermediate metabolizer (IM), normal metabolizer (NM), and ultra-rapid metabolizer (UM)), CYP3A4*22, CYP2C19*2, and CYP2B6*6 genotypes, concomitant CYP2D6 inhibitors, age, and body weight had a significant impact on TAM metabolism. Formation of ENDO from N-desmethyltamoxifen was decreased by 84% (relative standard error (RSE) = 14%) in PM patients and by 47% (RSE = 9%) in IM patients and increased in UM patients by 27% (RSE = 12%) compared with NM patients. Dose-adjustment simulations support an increase from 20 mg/day to 40 and 80 mg/day in IM patients and PM patients, respectively, to reach ENDO levels similar to those in NM patients. However, when considering Antiestrogenic Activity Score (AAS), a dose increase to 60 mg/day in PM patients seems sufficient. This PopPK model can be used as a tool to predict ENDO levels or AAS according to the patient's CYP2D6 phenotype for TAM dose adaptation.
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http://dx.doi.org/10.1002/cpt.2077DOI Listing
May 2021

Impact of TP53 mutations in acute myeloid leukemia patients treated with azacitidine.

PLoS One 2020 1;15(10):e0238795. Epub 2020 Oct 1.

Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France.

Hypomethylating agents are a classical frontline low-intensity therapy for older patients with acute myeloid leukemia. Recently, TP53 gene mutations have been described as a potential predictive biomarker of better outcome in patients treated with a ten-day decitabine regimen., However, functional characteristics of TP53 mutant are heterogeneous, as reflected in multiple functional TP53 classifications and their impact in patients treated with azacitidine is less clear. We analyzed the therapeutic course and outcome of 279 patients treated with azacitidine between 2007 and 2016, prospectively enrolled in our regional healthcare network. By screening 224 of them, we detected TP53 mutations in 55 patients (24.6%), including 53 patients (96.4%) harboring high-risk cytogenetics. The identification of any TP53 mutation was associated with worse overall survival but not with response to azacitidine in the whole cohort and in the subgroup of patients with adverse karyotype. Stratification of patients according to three recent validated functional classifications did not allow the identification of TP53 mutated patients who could benefit from azacitidine. Systematic TP53 mutant classification will deserve further exploration in the setting of patients treated with conventional therapy and in the emerging field of therapies targeting TP53 pathway.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238795PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529302PMC
November 2020

Value of peri-operative chemotherapy in patients with CINSARC high-risk localized grade 1 or 2 soft tissue sarcoma: study protocol of the target selection phase III CHIC-STS trial.

BMC Cancer 2020 Jul 31;20(1):716. Epub 2020 Jul 31.

INSERM U1037, Cancer Research Center of Toulouse (CRCT), Toulouse, France.

Background: The value of chemotherapy in soft tissue sarcoma (STS) remains controversial. Several expert teams consider that chemotherapy provides a survival advantage and should be proposed in high-risk (HR) patients. However, the lack of accuracy in identifying HR patients with conventional risk factors (large, deep, FNCLCC grade 3, extremity STS) is an issue that cannot be neglected. For example, while the FNCLCC grading system is a powerful tool, it has several limitations. CINSARC, a 67-gene signature, has proved to be an additional independent factor for predicting metastatic spread and outperforms histological grade. Regardless of FNCLCC grade, CINSARC stratifies patients into two separate prognostic groups: one with an excellent prognosis (low-risk (LR) CINSARC) and the other with a worse outcome (HR-CINSARC) in terms of metastatic relapse. Here we evaluate the role of chemotherapy in grade 1-2 STS patients with HR-CINSARC and assess the prognostic value of CINSARC in patients treated with standard of care.

Methods: CHIC is a parallel, randomized, open-label, multicenter study evaluating the effect on metastasis-free survival of adding perioperative chemotherapy to standard of care in patients with grade ½ STS sarcoma defined as HR by CINSARC. In this target selection design, 600 patients will be screened with CINSARC to randomize 250 HR-CINSARC patients between standard of care and standard of care plus chemotherapy (4 cycles of 3 weeks of intravenous chemotherapy with doxorubicin in combination with dacarbazine or ifosfamide according to histologic subtype). LR-CINSARC patients will be treated by standard of care according to the investigator. The primary endpoint is metastasis-free survival. Secondary endpoints include overall survival, disease-free survival and safety. Furthermore, the prognostic value of CINSARC will be evaluated by comparing LR-CINSARC patients to HR-CINSARC patients randomized in standard of care.

Discussion: CHIC is a prospective randomized phase III trial designed to comprehensively evaluate the benefit of chemotherapy in HR-CINSARC patients and to prospectively validate the prognostic value of CINSARC in grade ½ STS sarcoma patients.

Trial Registration: ClinicalTrials.gov identifier: NCT04307277 Date of registration: 13 March 2020.
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http://dx.doi.org/10.1186/s12885-020-07207-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395339PMC
July 2020

Pharmacokinetic and Pharmacogenetic Study of Etoposide in High-Dose Protocol (TI-CE) for Advanced Germ Cell Tumors.

Pharm Res 2020 Jul 16;37(7):147. Epub 2020 Jul 16.

Institut Claudius-Regaud, IUCT-Oncopole, Toulouse, France.

Background: Etoposide dosing is based on body surface area. We evaluated if further dose individualization would be required for high dose (HD) etoposide within the TI-CE (taxol, ifosfamide, carboplatin, and etoposide) protocol.

Methods: Eighty-eight patients received 400 mg/m/day of etoposide as a 1-hour IV infusion on 3 consecutive days over 3 cycles as part of a phase II trial evaluating efficacy of therapeutic drug monitoring (TDM) of carboplatin in the TI-CE HD protocol. Pharmacokinetic (PK) data were analyzed using population PK model on NONMEM to quantify inter- and intra-individual variabilities. Relationship between etoposide exposure and pharmacodynamic (PD) endpoints, and between selected genetic polymorphisms and tumor response or toxicity were evaluated.

Results: The inter-patient, inter- and intra-cycle variabilities of clearance were 16%, 9% and 0.1%, respectively. The PK-PD relationship was not significant despite a trend toward higher etoposide exposure in patients responding to treatment. A significant correlation was found between exposure and extended neutropenia at cycle 3. A significant association between UGT1A1*28 polymorphism and late neutropenia was observed but needs further evaluation.

Conclusions: The present study suggests that neither a priori dose individualization nor dose adaptation using TDM is required validating body surface area dosing of etoposide in the TI-CE protocol.
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http://dx.doi.org/10.1007/s11095-020-02861-5DOI Listing
July 2020

Comparison of Variable Selection Methods for Time-to-Event Data in High-Dimensional Settings.

Comput Math Methods Med 2020 1;2020:6795392. Epub 2020 Jul 1.

Department of Biostatistics, Institut Claudius Regaud, IUCT-O, Toulouse, France.

Over the last decades, molecular signatures have become increasingly important in oncology and are opening up a new area of personalized medicine. Nevertheless, biological relevance and statistical tools necessary for the development of these signatures have been called into question in the literature. Here, we investigate six typical selection methods for high-dimensional settings and survival endpoints, including LASSO and some of its extensions, component-wise boosting, and random survival forests (RSF). A resampling algorithm based on data splitting was used on nine high-dimensional simulated datasets to assess selection stability on training sets and the intersection between selection methods. Prognostic performances were evaluated on respective validation sets. Finally, one application on a real breast cancer dataset has been proposed. The false discovery rate (FDR) was high for each selection method, and the intersection between lists of predictors was very poor. RSF selects many more variables than the other methods and thus becomes less efficient on validation sets. Due to the complex correlation structure in genomic data, stability in the selection procedure is generally poor for selected predictors, but can be improved with a higher training sample size. In a very high-dimensional setting, we recommend the LASSO-pcvl method since it outperforms other methods by reducing the number of selected genes and minimizing FDR in most scenarios. Nevertheless, this method still gives a high rate of false positives. Further work is thus necessary to propose new methods to overcome this issue where numerous predictors are present. Pluridisciplinary discussion between clinicians and statisticians is necessary to ensure both statistical and biological relevance of the predictors included in molecular signatures.
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http://dx.doi.org/10.1155/2020/6795392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350178PMC
May 2021

Modernizing adverse events analysis in oncology clinical trials using alternative approaches: rationale and design of the MOTIVATE trial.

Invest New Drugs 2020 12 7;38(6):1879-1887. Epub 2020 May 7.

Department of Biostatistics, Institut Claudius Regaud - IUCT-O, 1 avenue Irène Joliot-Curie, 31059, Toulouse Cedex 9, France.

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).
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http://dx.doi.org/10.1007/s10637-020-00938-xDOI Listing
December 2020

Resistance of melanoma to immune checkpoint inhibitors is overcome by targeting the sphingosine kinase-1.

Nat Commun 2020 01 23;11(1):437. Epub 2020 Jan 23.

Inserm UMR1037, Cancer Research Center of Toulouse, 31037, Toulouse, France.

Immune checkpoint inhibitors (ICIs) have dramatically modified the prognosis of several advanced cancers, however many patients still do not respond to treatment. Optimal results might be obtained by targeting cancer cell metabolism to modulate the immunosuppressive tumor microenvironment. Here, we identify sphingosine kinase-1 (SK1) as a key regulator of anti-tumor immunity. Increased expression of SK1 in tumor cells is significantly associated with shorter survival in metastatic melanoma patients treated with anti-PD-1. Targeting SK1 markedly enhances the responses to ICI in murine models of melanoma, breast and colon cancer. Mechanistically, SK1 silencing decreases the expression of various immunosuppressive factors in the tumor microenvironment to limit regulatory T cell (Treg) infiltration. Accordingly, a SK1-dependent immunosuppressive signature is also observed in human melanoma biopsies. Altogether, this study identifies SK1 as a checkpoint lipid kinase that could be targeted to enhance immunotherapy.
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http://dx.doi.org/10.1038/s41467-019-14218-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978345PMC
January 2020

Radiation therapy to the primary tumor for de novo metastatic breast cancer and overall survival in a retrospective multicenter cohort analysis.

Radiother Oncol 2020 04 10;145:109-116. Epub 2020 Jan 10.

Medical Oncology Department, Claudius Regaud Institute, IUCT-Oncopole, Toulouse, France.

Background: The impact of locoregional treatment (LRT) on overall survival (OS) in de novo metastatic breast cancer (dnMBC) is still under debate, with very few data available regarding exclusive radiotherapy (ERT) as a therapeutic modality.

Methods: We evaluated the impact of ERT, exclusive surgery, or a combination of surgery plus radiotherapy (bimodality therapy, BMT) on survival outcomes in a national real-life dnMBC cohort. The primary and secondary end points were OS and progression free survival (PFS) according to LRT (ERT, exclusive surgery, BMT) and no LRT. Sensitivity analyses were performed using propensity score matched analyses.

Results: From 2008 to 2014, 4507 dnMBC patients were identified. Only patients alive and free from progression under systemic therapy at least 1 year after diagnosis were included (n = 1965). Forty-five percent of patients (891/1965) underwent LRT: 41.1% (n = 366) ERT, 13.7% (n = 122) exclusive surgery, and 45.2% (n = 403) BMT. OS adjusted for major prognostic factors was significantly longer in the ERT and BMT group compared with no-LRT group, but not exclusive surgery (hazard ratio (HR) = 0.63, 95% confidence interval (CI) [0.49, 0.80], p < 0.001, HR = 0.61, 95%CI [0.47, 0.78], p < 0.001 and HR = 0.87, 95%CI [0.61, 1.26], p = 0.466 respectively). Results were similar after matching on a propensity score. ERT, surgery and BMT were all associated with a significantly better PFS in multivariable analysis.

Conclusion: ERT was significantly associated with better OS in dnMBC, in the same magnitude as BMT, compared with no-LRT. However, even with statistical models adjusted for known prognostic factors and propensity score analysis, selection biases cannot be eliminated from observational studies.
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http://dx.doi.org/10.1016/j.radonc.2019.12.019DOI Listing
April 2020

Low lean mass and chemotherapy toxicity risk in the elderly: the Fraction study protocol.

BMC Cancer 2019 Nov 27;19(1):1153. Epub 2019 Nov 27.

Geriatric Department, Internal Medicine and Oncogeriatry Unit, University Hospital, Place du Docteur Baylac, TSA 40031, 31059, Toulouse Cedex 9, France.

Background: Half of cancer cases occur in patients aged 70 and above. Majority of older patients are eligible for chemotherapy but evidence for treating this population is sparse and severe toxicities affect more than half of them. Determining prognostic biomarkers able to predict poor chemotherapy tolerance remains one of the major issues in geriatric oncology. Ageing is associated with body composition changes (increase of fat mass and loss of lean mass) independently of weight-loss. Previous studies suggest that body composition parameters (particularly muscle mass) may predict poor chemotherapy tolerance. However, studies specifically including older adults on this subject remain sparse and the majority of them study body composition based on computed tomography (CT) scanner (axial L3 section) muscle mass estimation. This method is to date not validated in elderly cancer patients.

Methods: This trial (Fraction) will evaluate the discriminative ability of appendicular lean mass measured by dual-energy X-ray absorptiometry (DXA) to predict severe toxicity incidence in older cancer-patients treated with first-line chemotherapy. DXA is considered the gold standard in body composition assessment in older adults. Patient's aged ≥70 diagnosed with solid neoplasms or lymphomas at a locally advanced or metastatic stage treated for first-line chemotherapy were recruited. Patients completed a pre-chemotherapy assessment that recorded socio-demographics, tumor/treatment variables, laboratory test results, geriatric assessment variables (function, comorbidity, cognition, social support and nutritional status), oncological risk scores and body composition with DXA. Appendicular lean mass was standardized using evidence based international criteria. Participants underwent short follow-up geriatric assessments within the first 3 months, 6 months and a year after inclusion. Grade 3 to 5 chemotherapy-related toxicities, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) were assessed at each chemotherapy cycle.

Discussion: The finding that body composition is associated with poor tolerance of chemotherapy could lead to consider these parameters as well as improve current decision-making algorithms when treating older adults.

Trial Registration: ClinicalTrials.gov Identifier: NCT02806154 registered on October 2016.
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http://dx.doi.org/10.1186/s12885-019-6377-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882112PMC
November 2019

Anti-TNF, a magic bullet in cancer immunotherapy?

J Immunother Cancer 2019 11 14;7(1):303. Epub 2019 Nov 14.

INSERM UMR 1037, Cancer Research Center of Toulouse (CRCT), 2 avenue Hubert Curien, CS 53717, 31037, Toulouse Cedex 1, France.

Immune checkpoint blockers (ICB) have revolutionized cancer therapy. However, complete response is observed in a minority of patients and most patients develop immune-related adverse events (irAEs). These include colitis, which can be treated with anti-tumor necrosis factor (TNF) antibodies such as Infliximab. In a recent issue of the Journal for ImmunoTherapy of Cancer, Badran et al. reported that co-administering Infliximab together with ICB to five cancer patients prevents colitis recurrence, with four of them exhibiting overall disease stability. The basis for this treatment strategy stemmed from our pre-clinical demonstration that TNF contributes to resistance to anti-PD-1 therapy. In agreement with this concept, we have shown that TNF blockers improve the anti-tumor therapeutic activity of ICB in mice and based on these findings we are currently evaluating the combination in melanoma patients enrolled in the TICIMEL clinical trial. Herein, (i) we discuss the scientific rationale for combining anti-TNF and ICB in cancer patients, (ii) comment on the paper published by Badran et al. and (iii) provide the TICIMEL clinical trial design.
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http://dx.doi.org/10.1186/s40425-019-0802-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857159PMC
November 2019

Prognostic role of CD4 T-cell depletion after frontline fludarabine, cyclophosphamide and rituximab in chronic lymphocytic leukaemia.

BMC Cancer 2019 Aug 14;19(1):809. Epub 2019 Aug 14.

Department of Haematology, Toulouse-Oncopole University Cancer Institute (IUCT-O), 1 Avenue Irene Joliot-Curie, 31059, Toulouse, France.

Background: Eradication of minimal residual disease (MRD), at the end of Fludarabine-Cyclophosphamide-Rituximab (FCR) treatment, is a validated surrogate marker for progression-free and overall survival in chronic lymphocytic leukaemia. But such deep responses are also associated with severe immuno-depletion, leading to infections and the development of secondary cancers.

Methods: We assessed, blood MRD and normal immune cell levels at the end of treatment, in 162 first-line FCR patients, and analysed survival and adverse event.

Results: Multivariate Landmark analysis 3 months after FCR completion identified unmutated IGHV status (HR, 2.03, p = 0.043), the level of MRD reached (intermediate versus low, HR, 2.43, p = 0.002; high versus low, HR, 4.56, p = 0.002) and CD4 > 200/mm (HR, 3.30, p <  0.001) as factors independently associated with progression-free survival (PFS); neither CD8 nor NK counts were associated with PFS. The CD4 count was associated with PFS irrespective of IGHV mutational status, but only in patients with detectable MRD (HR, 3.51, p = 0.0004, whereas it had no prognostic impact in MRD < 10 patients: p = 0.6998). We next used a competitive risk model to investigate whether immune cell subsets could be associated with the risk of infection and found no association between CD4, CD8 and NK cells and infection.

Conclusions: Consolidation/maintenance trials based on detectable MRD after FCR should investigate CD4 T-cell numbers both as a selection and a response criterion, and consolidation treatments should target B-cell/T-cell interactions.
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http://dx.doi.org/10.1186/s12885-019-5971-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694602PMC
August 2019

Cutaneous Squamous Cell Carcinoma Tumour Size is Associated with Sentinel Lymph Node Metastasis in a Cohort of 69 Patients.

Acta Derm Venereol 2019 Dec;99(13):1241-1245

Department of ENT-Head and Neck Surgery, University Cancer Institute Toulouse and Toulouse University Hospital, Hôpital Larrey, FR-31400 Toulouse, France.

Ten to fifty percent of high-risk cutaneous squamous cell carcinoma may potentially metastasize. However, the concept of sentinel lymph node biopsy remains controversial for cutaneous squamous cell carcinoma. The aim of this study was to identify prognostic factors associated with sentinel lymph node positivity. A bicentric retrospective analysis was conducted between January 2006 and January 2018. All patients undergoing sentinel lymph node biopsy for high-risk cutaneous squamous cell carcinoma were included, based on the criteria of the prognostic classification of the French Society of Dermatology. Seventy-four patients were included. Five (6.8%) procedures failed. Of the 69 patients assessed, the positive sentinel lymph node biopsy rate was 11.6% (n = 8) with a false negative rate of 5.7% (n = 4). The positivity of sentinel lymph node biopsy was associated with tumour size (p = 0.0194). Sentinel lymph node biopsy is an effective staging procedure for clinically N0 high-risk cutaneous squamous cell carcinoma, with an acceptable morbidity. To date, 2 risk factors of sentinel lymph node positivity have been identified with statistical significance: tumour size and poor tumour differentiation.
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http://dx.doi.org/10.2340/00015555-3293DOI Listing
December 2019
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