Publications by authors named "Yann Vano"

21 Publications

  • Page 1 of 1

MET alterations in biphasic squamoid alveolar papillary renal cell carcinomas and clinicopathological features.

Mod Pathol 2021 03 7;34(3):647-659. Epub 2020 Aug 7.

Assistance Publique-Hôpitaux de Paris (AP-HP) Paris-Centre, Hôpital Européen Georges Pompidou, Service de Pathologie, F-75015, Paris, France.

Biphasic squamoid alveolar papillary renal cell carcinoma (BSA-PRCC) is a recently studied lesion considered a morphologic variant of papillary renal cell carcinoma (RCC), more closely related to type 1. Considering the role of proto-oncogene MET in both sporadic type 1 papillary RCC and hereditary papillary RCC, we aimed to explore the role of MET activation in the oncogenesis of BSA-PRCC. We identified 17 patients with either unique (n = 14) or multiple (n = 3) BSA-PRCC, all localized, and performed an integrative analysis of MET status in 18 formalin-fixed paraffin-embedded tumors combining next-generation sequencing analysis, fluorescent in situ hybridization and immunohistochemistry. Trisomy 7 was found in 86% of tumors (14/16) without MET amplification at 7q31 (15/15). A pathogenic MET genetic variant was identified in 60% (9/15) of cases, at the germline level in 57% (4/7) of tested patients or at the somatic level (5/11). MET expression was observed in all tumors with a higher value of combined score in large cells (mean 97%, range 80-100%) than in small cells (mean 74%, range 10-100%) and was lower in two cases without MET copy number gain. In conclusion, our study provides additional evidence to consider biphasic squamoid alveolar papillary RCC as a morphological variant of type 1 papillary renal RCC. Our data strongly suggest that MET represents a major oncogenic driver gene in BSA-PRCC, harboring a higher frequency of MET mutation that encourages to further explore the benefice of anti-MET targeted therapies for aggressive BSA-PRCC.
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http://dx.doi.org/10.1038/s41379-020-0645-6DOI Listing
March 2021

Comparative Efficacy of First-Line Immune-Based Combination Therapies in Metastatic Renal Cell Carcinoma: A Systematic Review and Network Meta-Analysis.

Cancers (Basel) 2020 Jun 24;12(6). Epub 2020 Jun 24.

Department of Medical Oncology, Hôpital Européen Georges Pompidou, 75015 Paris, France.

Three drug combinations, ipilimumab-nivolumab (Ipi-Nivo), pembrolizumab-axitinib (Pembro-Axi), and avelumab-axitinib (Ave-Axi), have received regulatory approval in the USA and Europe for the treatment of metastatic renal cell carcinoma with clear cell component (mRCC). However, no head-to-head comparison data are available to identify the best option. Therefore, we aimed to compare these new treatments in a first-line setting. We conducted a systematic search in PubMed, the Cochrane Library, and clinicaltrials.gov for any randomized controlled trials of treatment-naïve patients with mRCC, from January 2015 to October 2019. The process was performed according to PRISMA guidelines. We performed a Bayesian network meta-analysis with two different approaches, a contrast-based model comparing HRs and ORs between studies and arm-based using parametric modeling. The outcomes for the analysis were overall survival, progression-free survival (PFS), and objective response rate. Our search identified 3 published phase 3 randomized clinical trials (2835 patients). In the contrast-based model, Ave-Axi (SUCRA = 83%) and Pembro-Axi (SUCRA = 80%) exhibited the best ranking probabilities for PFS. For overall survival (OS), Pembro-Axi (SUCRA = 96%) was the most preferable option against Ave-Axi and Ipi-Nivo. Objective response rate analysis showed Ave-Axi as the best (SUCRA: 94%) and Pembro-Axi as the second best option. In the parametric models, the risk of progression was comparable for Ave-Axi and Ipi-Nivo, whereas Pembro-Axi exhibited a lower risk during the first 6 months of treatment and a higher risk afterwards. Furthermore, Pembro-Axi exhibited a net advantage in terms of OS over the two other regimens, while Ave-Axi was the least preferable option. Overall evidence suggests that pembrolizumab plus axitinib seems to have a slight advantage over the other two combinations.
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http://dx.doi.org/10.3390/cancers12061673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352474PMC
June 2020

Clear-cell Renal Cell Carcinoma: Molecular Characterization of IMDC Risk Groups and Sarcomatoid Tumors.

Clin Genitourin Cancer 2019 10 25;17(5):e981-e994. Epub 2019 May 25.

Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium; Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium; Inserm, UMR-1162, Génomique fonctionnelle des tumeurs solides, IUH, Paris, France. Electronic address:

Introduction: Recent trials have suggested predictive biomarkers in advanced clear-cell renal cell carcinoma (accRCC): International Metastatic RCC Database Consortium (IMDC) good risk or angiogenic gene signature for sunitinib and IMDC intermediate/poor risk for ipilimumab-nivolumab and T-effector cell signature or sarcomatoid dedifferentiation for atezolizumab-bevacizumab. We hypothesized that earlier described molecular subtypes, ccrcc1 to ccrcc4, could provide similar information as a single generic biomarker and molecularly characterize the heterogeneous intermediate-risk group.

Patients And Methods: Patients with accRCC treated with systemic therapies were included. We assessed associations between the 5 biomarkers and their impact on progression-free survival (PFS) and response rate (RR) on first-line sunitinib or pazopanib. The cutoff percentage of sarcomatoid dedifferentiation with optimal discriminative value was determined.

Results: In total, 430 patients were included (163 with molecular data). The molecular ccrcc2 subtype identified tumors with higher angiogenic gene expression across IMDC risk groups: prevalence was high in IMDC good risk and low in IMDC poor risk (P < .001). Molecular subtype, IMDC, and angiogenic gene expression had comparable C-indices to predict PFS and RR (range, 60%-66%). The ccrcc2 subtype and angiogenic gene expression were positive predictors of PFS in IMDC intermediate-risk patients (P = .006; P = .04). Immune signature did not differ between IMDC groups, but was strongly correlated with molecular subtype (P = .8 and P = .0007). A cutoff value of 25% sarcomatoid differentiation discriminated tumors with distinct molecular characteristics and therapeutic sensitivity.

Conclusion: In accRCC, molecular subtypes can explain differences in IMDC risk group, expression of angiogenesis and immune response genes, and sarcomatoid dedifferentiation. They can identify molecularly different patient populations within the heterogeneous IMDC intermediate group and select patients for systemic therapies.
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http://dx.doi.org/10.1016/j.clgc.2019.05.009DOI Listing
October 2019

Tumor Cells Hijack Macrophage-Produced Complement C1q to Promote Tumor Growth.

Cancer Immunol Res 2019 07 4;7(7):1091-1105. Epub 2019 Jun 4.

Sorbonne Paris Cite, Cordeliers Research Center, University Paris Descartes Paris 5, Paris, France.

Clear-cell renal cell carcinoma (ccRCC) possesses an unmet medical need, particularly at the metastatic stage, when surgery is ineffective. Complement is a key factor in tissue inflammation, favoring cancer progression through the production of complement component 5a (C5a). However, the activation pathways that generate C5a in tumors remain obscure. By data mining, we identified ccRCC as a cancer type expressing concomitantly high expression of the components that are part of the classical complement pathway. To understand how the complement cascade is activated in ccRCC and impacts patients' clinical outcome, primary tumors from three patient cohorts ( = 106, 154, and 43), ccRCC cell lines, and tumor models in complement-deficient mice were used. High densities of cells producing classical complement pathway components C1q and C4 and the presence of C4 activation fragment deposits in primary tumors correlated with poor prognosis. The orchestrated production of C1q by tumor-associated macrophages (TAM) and C1r, C1s, C4, and C3 by tumor cells associated with IgG deposits, led to C1 complex assembly, and complement activation. Accordingly, mice deficient in C1q, C4, or C3 displayed decreased tumor growth. However, the ccRCC tumors infiltrated with high densities of C1q-producing TAMs exhibited an immunosuppressed microenvironment, characterized by high expression of immune checkpoints (i.e., PD-1, Lag-3, PD-L1, and PD-L2). Our data have identified the classical complement pathway as a key inflammatory mechanism activated by the cooperation between tumor cells and TAMs, favoring cancer progression, and highlight potential therapeutic targets to restore an efficient immune reaction to cancer.
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http://dx.doi.org/10.1158/2326-6066.CIR-18-0891DOI Listing
July 2019

[Treatment of metastatic prostate cancer: what recent progress?]

Rev Prat 2018 Sep;68(7):707-712

Service de cancérologie médicale, Hôpital européen Georges-Pompidou, AP-HP, université René-Descartes Paris-5, groupe hospitalier Ouest Parisien, Paris, France.

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September 2018

The clinical role of the TME in solid cancer.

Br J Cancer 2019 01 9;120(1):45-53. Epub 2018 Nov 9.

INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, Team "Cancer, immune control and escape", F-75006, Paris, France.

The highly complex and heterogenous ecosystem of a tumour not only contains malignant cells, but also interacting cells from the host such as endothelial cells, stromal fibroblasts, and a variety of immune cells that control tumour growth and invasion. It is well established that anti-tumour immunity is a critical hurdle that must be overcome for tumours to initiate, grow and spread and that anti-tumour immunity can be modulated using current immunotherapies to achieve meaningful anti-tumour clinical responses. Pioneering studies in melanoma, ovarian and colorectal cancer have demonstrated that certain features of the tumour immune microenvironment (TME)-in particular, the degree of tumour infiltration by cytotoxic T cells-can predict a patient's clinical outcome. More recently, studies in renal cell cancer have highlighted the importance of assessing the phenotype of the infiltrating T cells to predict early relapse. Furthermore, intricate interactions with non-immune cellular players such as endothelial cells and fibroblasts modulate the clinical impact of immune cells in the TME. Here, we review the critical components of the TME in solid tumours and how they shape the immune cell contexture, and we summarise numerous studies evaluating its clinical significance from a prognostic and theranostic perspective.
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http://dx.doi.org/10.1038/s41416-018-0327-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325164PMC
January 2019

Imaging Response of Antiangiogenic and Immune-Oncology Drugs in Metastatic Renal Cell Carcinoma (mRCC): Current Status and Future Challenges.

Kidney Cancer 2017 Nov 27;1(2):107-114. Epub 2017 Nov 27.

Université Paris Descartes Sorbonne Paris Cité, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Radiology Department, Paris, France.

This report aims to review criteria which have been proposed for treatment evaluation in mRCC under anti-angiogenic and immune-oncologic therapies and discuss future challenges for imagers. RECIST criteria seem to only partially reflect the clinical benefit derived from anti-angiogenic drugs in mRCC. New methods of analysis propose to better evaluate response to these drugs, including a new threshold for size criteria (-10%), attenuation (Choi and modified Choi criteria), functional imaging techniques (perfusion CT, ultrasound or MRI), and new PET radiotracers. Imaging of progression is one of the main future challenges facing imagers. It is progression and not response that will trigger changes in therapy, therefore it is tumour progression that should be identified by imaging techniques to guide the oncologist on the most appropriate time to change therapy. Yet little is known on dynamics of tumour progression, and much data still needs to be accrued to understand it. Finally, as immunotherapies develop, flare or pseudo-progression phenomena are observed. Studies need to be performed to determine whether imaging can distinguish between patients undergoing pseudo-progression for which therapy should be continued, or true progression for which the treatment must be changed.
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http://dx.doi.org/10.3233/KCA-170011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6179123PMC
November 2017

Immune checkpoint inhibitors myocarditis: not all cases are clinically patent.

Eur Heart J 2018 10;39(38):3553

INSERM U970, Paris Cardiovascular Research Centre -PARCC, Paris, France.

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http://dx.doi.org/10.1093/eurheartj/ehy485DOI Listing
October 2018

[Tim-3: a novel biomarker and therapeutic target in oncology].

Med Sci (Paris) 2018 Mar 16;34(3):231-237. Epub 2018 Mar 16.

Inserm U970, université Paris Descartes Sorbonne Paris-Cité, Paris, France - Équipe labellisée Ligue contre le cancer, Paris, France - Hôpital européen Georges Pompidou, service d'immunologie biologique, 20, rue Leblanc, 75015 Paris, France.

T cells harboring multiple co-inhibitory molecules lose their anti-tumoral functionality. PD-1 is a clinically approved target in cancer therapy, but its expression alone does not mean dysfunctionality. The expression of Tim-3 on numerous cell types (T cell, Treg, dendritic cell, myeloid cells) favors tumor escape to immune cells. Within many tumors, PD-1/Tim-3 coexpressing CD8-T cells lose their ability to secrete cytokines (IFNγ, IL-2, TNFα) and their intratumoral infiltration correlates with a bad prognosis. Tim-3 recently appeared as a potential biomarker of anti-PD-1 resistance. Combined blockade of PD-1 and Tim-3 axis demonstrated potent clinical efficacy in preclinical models and reinforced the rationale of using an anti-Tim-3 to override tumor resistance.
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http://dx.doi.org/10.1051/medsci/20183403011DOI Listing
March 2018

Transcriptomic analysis of the tumor microenvironment to guide prognosis and immunotherapies.

Cancer Immunol Immunother 2018 06 7;67(6):981-988. Epub 2017 Sep 7.

INSERM, UMR_S 1138, Cordeliers Research Center, Team Cancer, Immune Control and Escape, 75006, Paris, France.

Tumors are highly heterogeneous tissues where malignant cells are surrounded by and interact with a complex tumor microenvironment (TME), notably composed of a wide variety of immune cells, as well as vessels and fibroblasts. As the dialectical influence between tumor cells and their TME is known to be clinically crucial, we need tools that allow us to study the cellular composition of the microenvironment. In this focused research review, we report MCP-counter, a methodology based on transcriptomic markers that assesses the proportion of several immune and stromal cell populations in the TME from transcriptomic data, and we highlight how it can provide a way to decipher the complex mechanisms at play in tumors. In several malignancies, MCP-counter scores have been used to show various prognostic impacts of the TME, which we also show to be linked with the mutational burden of tumors. We also compared established molecular classifications of colorectal cancer and clear-cell renal cell carcinoma with the output of MCP-counter, and show that molecular subgroups have different TME profiles, and that these profiles are consistent within a given subgroup. Finally, we provide insights as to how knowing the TME composition may shape patient care in the near future.
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http://dx.doi.org/10.1007/s00262-017-2058-zDOI Listing
June 2018

PD-L1 Expression and CD8 T-cell Infiltrate are Associated with Clinical Progression in Patients with Node-positive Prostate Cancer.

Eur Urol Focus 2019 03 21;5(2):192-196. Epub 2017 Jun 21.

NET-IMPACT, IRCCS Ospedale San Raffaele, Milan, Italy; Cellular Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS Ospedale San Raffaele, Milan, Italy. Electronic address:

Prostate cancer (PCa) patients with lymph node invasion at radical prostatectomy are at higher risk of tumor recurrence and receive immediate androgen deprivation therapy (ADT). While approximately 30% of these patients do not experience recurrence, others experience disease recurrence despite ADT, and currently no biomarkers can accurately identify them. We analyzed tumors from 51 patients with node-positive prostate cancer using immunohistochemistry to investigate whether expression of the immune checkpoint ligand PD-L1 by tumor cells or the density of CD8 or CD20 cells are associated with clinical progression. Patients with at least 1% PD-L1 tumor cells had shorter metastasis-free survival than those with PD-L1 tumors (p=0.008, log-rank test). Univariate Cox regression showed that patients with PD-L1 tumors had almost four times the risk of experiencing distant metastases than those with PD-L1 tumors (hazard ratio 3.90). In addition, we found that PD-L1 expression was significantly associated with CD8 T-cell density, but not with CD20 B-cell density. While these results need to be confirmed in larger studies, they show that PD-L1 and CD8 may be used as biomarkers for node-positive patients at high risk of progression. The study also provides a rationale for selecting patients with node-positive PCa who might benefit the most from adjuvant immunotherapies. PATIENT SUMMARY: None of the available biomarkers can identify node-positive prostate cancer that will recur after surgery. We found that expression of PD-L1 by tumor cells and a high density of CD8 T cells in tumor are associated with a higher risk of clinical progression in men with node-positive prostate cancer.
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http://dx.doi.org/10.1016/j.euf.2017.05.013DOI Listing
March 2019

Safety and efficacy of 2-weekly cabazitaxel in metastatic castration-resistant prostate cancer.

BJU Int 2018 02 27;121(2):203-208. Epub 2017 Apr 27.

Department of Medical Oncology, Hôpital Européen Georges Pompidou, Paris, France.

Objectives: To evaluate the safety and efficacy of a 2-weekly cabazitaxel schedule in patients with metastatic castration-resistant prostate cancer (mCRPC).

Materials And Methods: During the period October 2013 to February 2016, 43 patients with mCRPC were treated with cabazitaxel (16 mg/m , on days 1 and 15 of a 4-week cycle) together with prophylactic granulocyte colony-stimulating factor (G-CSF). The safety profile and efficacy (prostate-specific antigen [PSA] response; biological, clinical or radiological progression-free survival [PFS] and overall survival [OS]) of the treatment were analysed.

Results: All patients had received prior docetaxel and 79.1% abiraterone acetate. At inclusion, 46.5% were aged >70 years and 27.9% had an Eastern Cooperative Oncology Group performance status ≥2. Six patients stopped treatment because of toxicity. Grade ≥3 toxicities were: asthenia (16.3%); neutropenia (11.6%); thrombocytopenia (9.3%); diarrhoea (7%), anaemia (4.7%), febrile neutropenia (4.7%) and haematuria (2.3%). In all, 52.4% achieved a ≥30% PSA response and 40.5% had a ≥50% PSA response. The median OS was 15.2 months.

Conclusion: This prospective pilot study suggests that cabazitaxel 16 mg/m² given 2-weekly has a manageable toxicity profile in docetaxel- and abiraterone acetate-pretreated patients with mCRPC. A prospective phase III trial comparing this regimen with the standard cabazitaxel regimen is planned to confirm these results.
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http://dx.doi.org/10.1111/bju.13855DOI Listing
February 2018

Tumor-Infiltrating and Peripheral Blood T-cell Immunophenotypes Predict Early Relapse in Localized Clear Cell Renal Cell Carcinoma.

Clin Cancer Res 2017 Aug 17;23(15):4416-4428. Epub 2017 Feb 17.

INSERM, UMR_S 1138, Cordeliers Research Center, Team "Cancer, immune control and escape", Paris, France.

The efficacy of PD-1 checkpoint blockade as adjuvant therapy in localized clear cell renal cell carcinoma (ccRCC) is currently unknown. The identification of tumor microenvironment (TME) prognostic biomarkers in this setting may help define which patients could benefit from checkpoint blockade and uncover new therapeutic targets. We performed multiparametric flow cytometric immunophenotypic analysis of T cells isolated from tumor tissue [tumor-infiltrating lymphocytes (TIL)], adjacent non-malignant renal tissue [renal-infiltrating lymphocytes (RIL)], and peripheral blood lymphocytes (PBL), in a cohort of patients ( = 40) with localized ccRCC. Immunophenotypic data were integrated with prognostic and histopathologic variables, T-cell receptor (TCR) repertoire analysis of sorted CD8PD-1 TILs, tumor mRNA expression, and digital quantitative immunohistochemistry. On the basis of TIL phenotypic characterization, we identified three dominant immune profiles in localized ccRCC: (i) immune-regulated, characterized by polyclonal/poorly cytotoxic CD8PD-1Tim-3Lag-3 TILs and CD4ICOS cells with a Treg phenotype (CD25CD127Foxp3/HeliosGITR), that developed in inflamed tumors with prominent infiltrations by dysfunctional dendritic cells and high PD-L1 expression; (ii) immune-activated, enriched in oligoclonal/cytotoxic CD8PD-1Tim-3 TILs, that represented 22% of the tumors; and (iii) immune-silent, enriched in TILs exhibiting RIL-like phenotype, that represented 56% of patients in the cohort. Only immune-regulated tumors displayed aggressive histologic features, high risk of disease progression in the year following nephrectomy, and a CD8PD-1Tim-3 and CD4ICOS PBL phenotypic signature. In localized ccRCC, the infiltration with CD8PD-1Tim-3Lag-3 exhausted TILs and ICOS Treg identifies the patients with deleterious prognosis who could benefit from adjuvant therapy with TME-modulating agents and checkpoint blockade. This work also provides PBL phenotypic markers that could allow their identification. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-2848DOI Listing
August 2017

Immunothérapie dans les cancers de la prostate.

Bull Cancer 2016 Nov;103 Suppl 1:S144-S150

Service de cancérologie médicale, hôpital européen Georges-Pompidou, 20, rue Leblanc, 75015 Paris, France; CRC UMRS1138 EQ13, 15, rue de l'École-de-Médecine, 75006 Paris, France.

Immunotherapy In Uro-oncology: Immunotherapy is moving forward in prostate cancer. The autologous vaccine, Sipuleucel-T has been the first vaccine to be approved by FDA. First results with GVAX, tasquinimob or anti-PD-1 have been disappointing. Ipilimumab seen to be more active at an earlier stage of prostate disease. Identifying predictive factor or surrogate markers of activity of immunotherapy and which agents are clinically effective alone or in combination with others therapies such as hormonal or bone targeted therapies are warranted.
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http://dx.doi.org/10.1016/S0007-4551(16)30372-1DOI Listing
November 2016

Sunitinib in kidney cancer: 10 years of experience and development.

Expert Rev Anticancer Ther 2017 Feb 27;17(2):129-142. Epub 2016 Dec 27.

a Oncology Department , Georges Pompidou European Hospital , Paris , France.

Introduction: Sunitinib is a multi-target, anti-angiogenic tyrosine kinase inhibitor and a key molecule in the treatment of metastatic renal cell carcinoma (mRCC). Since it first demonstrated its efficacy ten years ago, overall survival of mRCC has more than doubled, in part due to sunitinib. In most recent years, progress has been made in the comprehension of its mechanism of action and resistance. Areas Covered: In this article, clinical trials involving sunitinib in kidney cancer have been reviewed, defining its different indications in metastatic and localized RCC. The rationale of sunitinib's efficacy, preclinical trials, past-clinical trials and ongoing clinical trials are summarized. Dose and scheme base are discussed, as the recommended dosage is frequently not well tolerated. Combination therapies appear to be toxic. Novel immunotherapies are changing the landscape of mRCC treatment and challenging sunitinib. Special attention has been paid towards cancer cell biology and immunity involved in treatment response. Expert Commentary: Sunitinib's place in the therapeutic arsenal is being redefined with the arrival of major challengers. Dosage and scheduling of sunitinib remains a major challenge.
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http://dx.doi.org/10.1080/14737140.2017.1272415DOI Listing
February 2017

Clinical Benefit of Everolimus as Second-Line Therapy in Metastatic Renal Cell Carcinoma: The French Retrospective SECTOR Study.

Clin Genitourin Cancer 2016 12 2;14(6):e595-e607. Epub 2016 May 2.

Gustave Roussy, Oncology Department, Villejuif, France.

Background: Real-world data of everolimus after vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitor (TKI) therapy in metastatic renal cell carcinoma (mRCC) are limited.

Patients And Methods: The retrospective, noninterventional SECTOR (SECond line with afiniTOR) study (N = 165) assessed outcomes of second-line everolimus after initial VEGFR-TKI (TKI-everolimus, n = 144) and of third-line VEGFR-TKI after everolimus (TKI-everolimus-TKI, n = 59) in patients with mRCC. The primary end point was duration of everolimus therapy for both populations.

Results: Median duration was 4.0 months (range, 0.0-33.0 months) for second-line everolimus and 18.0 months (range, 2-78 months) for sequential VEGFR-TKI and everolimus. Median overall survival (OS) for this sequence was 36.0 months (95% confidence interval [CI], 27.0-56.0 months) and was longer for patients who received a first-line TKI for ≥ 9 months (not reached) than for < 9 months (28.0 months; P < .001). During second-line everolimus treatment, commonly reported adverse events (all grades) were fatigue (n = 66, 40.7%), anemia (n = 58, 35.8%), and stomatitis (n = 41, 25.3%). Median duration from initiation of first-line TKI to the end of the third-line TKI was 24.0 months (95% CI, 19.0-29.0 months). Median OS for this sequence was 41.0 months (95% CI, 25.0-57.0 months) and was significantly longer for patients who received the first-line TKI for ≥ 9 months (37.5 months) than for < 9 months (19.0 months; P < .0001).

Conclusion: These results reflect clinical use of sequential TKI-everolimus and TKI-everolimus-TKI and provide additional evidence that everolimus could be an option in second-line therapy in mRCC. Results of the CheckMate-025 (Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma) and METEOR (Metastatic RCC Phase 3 Study Evaluating Cabozantinib versus Everolimus) studies might change the treatment landscape.
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http://dx.doi.org/10.1016/j.clgc.2016.04.019DOI Listing
December 2016

Prognostic and theranostic impact of molecular subtypes and immune classifications in renal cell cancer (RCC) and colorectal cancer (CRC).

Oncoimmunology 2015 Dec 7;4(12):e1049804. Epub 2015 Aug 7.

INSERM UMR_S 1138 Cancer; Immune Control and Escape; Cordeliers Research Centre ; Paris, France ; Université Paris Descartes; Sorbonne Paris Cité; UMR_S 1338; Cordeliers Research Centre ; Paris, France ; Sorbonne Universités; UPMC Univ Paris 06; UMR_S 1138; Cordeliers Research Centre ; Paris, France ; Assistance Publique-Hôpitaux de Paris; Hôpital Européen Georges Pompidou, Department of Biology , Paris, France.

Molecular and immune classifications powerfully predict cancer patient's survival and response to therapies. We herein describe the immune tumor microenvironment of molecular subgroups of colorectal and renal cell cancers, revealing a strong correlation between tumor subtypes and distinct immune profiles.
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http://dx.doi.org/10.1080/2162402X.2015.1049804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4635888PMC
December 2015

The role of rechallenge with targeted therapies in metastatic renal-cell carcinoma.

Curr Opin Urol 2015 Sep;25(5):402-10

aOncology Department, European Hospital Georges Pompidou bOncology Department, Paris Descartes University, Paris, France.

Purpose Of Review: To explore the accumulating evidence and feasibility of rechallenge with agents targeting the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways for incorporation into the evolving management algorithm for metastatic renal-cell carcinoma (mRCC).

Recent Findings: The current standard of care after the development of resistance to first-line targeted therapies in mRCC is sequential treatment with subsequent lines of alternative anti-VEGF agents or mTOR inhibitors, with optimal sequencing being the focus of ongoing research. Recent evidence from case study and retrospective reports suggests that mRCC patients can achieve important clinical benefits from rechallenge at later lines of therapy with the same targeted therapy used for previous line treatment. Further, the results of REchallenge with SUnitinib in MEtastatic, the first study of sunitinib rechallenge to include a prospective component, reinforce the potential for prolonged survival with this treatment approach for mRCC patients.

Summary: Rechallenge represents an important and feasible therapeutic option for the future treatment of mRCC patients. The results of ongoing prospective studies are expected to further evaluate the benefits of rechallenge and better inform wherein this approach fits in the treatment algorithm for mRCC.
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http://dx.doi.org/10.1097/MOU.0000000000000206DOI Listing
September 2015

The immune response in cancer: from immunology to pathology to immunotherapy.

Virchows Arch 2015 Aug 16;467(2):127-35. Epub 2015 Jun 16.

Cordeliers Research Center, Team 13 Cancer, immune control and escape, INSERM, UMR_S 1138, 75006, Paris, France,

In the recent years, breakthrough advances in the characterization of the tumor-infiltrating immune cells and in the understanding of their influence on tumor invasion and metastasis have been accomplished. These studies have allowed the development of assays quantifying immune infiltrates to predict patient's clinical outcome. Increasing evidence supports their utility as prognostic and potentially teragnostic markers. The in-depth characterization of the tumor's immune profile and the standard histopathological criteria are becoming the optimal method of tumor classification in the era of personalized medicine. This review describes the major concepts in the anti-tumor immunity field, with particular focus on the tumor immune microenvironment and the delicate balance between inflammatory and anti-tumor immune responses, its importance as a prognostic tool, and its utility as a teragnostic marker for patients receiving new-generation immunotherapies.
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http://dx.doi.org/10.1007/s00428-015-1787-7DOI Listing
August 2015

Orchestration and Prognostic Significance of Immune Checkpoints in the Microenvironment of Primary and Metastatic Renal Cell Cancer.

Clin Cancer Res 2015 Jul 16;21(13):3031-40. Epub 2015 Feb 16.

INSERM, UMRS 1138, Cordeliers Research Center, Team 13 Cancer, Immune Control and Escape, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France. UPMC Univ Paris 06, Sorbonne Universités, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France.

Purpose: Clear cell renal cell carcinoma (ccRCC) has shown durable responses to checkpoint blockade therapies. However, important gaps persist in the understanding of its immune microenvironment. This study aims to investigate the expression and prognostic significance of immune checkpoints in primary and metastatic ccRCC, in relation with mature dendritic cells (DC) and T-cell densities.

Experimental Design: We investigated the infiltration and the localization of CD8(+) T cells and mature DC, and the expression of immune checkpoints (PD-1, LAG-3, PD-L1, and PD-L2) in relation with prognosis, in 135 primary ccRCC tumors and 51 ccRCC lung metastases. RNA expression data for 496 primary ccRCC samples were used as confirmatory cohort.

Results: We identify two groups of tumors with extensive CD8(+) T-cell infiltrates. One group, characterized by high expression of immune checkpoints in the absence of fully functional mature DC, is associated with increased risk of disease progression. The second group, characterized by low expression of immune checkpoints and localization of mature DC in peritumoral immune aggregates (tertiary lymphoid structures), is associated with good prognosis.

Conclusions: The expression of the immune checkpoints and the localization of DC in the tumor microenvironment modulate the clinical impact of CD8(+) T cells in ccRCC.
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http://dx.doi.org/10.1158/1078-0432.CCR-14-2926DOI Listing
July 2015

Multicentre randomised phase II trial of gemcitabine+platinum, with or without trastuzumab, in advanced or metastatic urothelial carcinoma overexpressing Her2.

Eur J Cancer 2015 Jan 15;51(1):45-54. Epub 2014 Nov 15.

Department of Medical Oncology, Curie Institute, Paris, France.

Aim: To investigate the efficacy and safety of gemcitabine and platinum salt, with or without trastuzumab, in patients with locally advanced or metastatic urothelial carcinoma overexpressing Her2.

Methods: The main eligibility criterion was Her2 overexpression on immunohistochemistry (IHC 2+ or 3+) of primary tumour tissue confirmed by fluorescence in situ hybridisation (FISH). Patients were randomised to Arm A: gemcitabine 1000mg/m(2) (days 1 and 8) plus either cisplatin (70mg/m(2)) or carboplatin (AUC=5) (day 1 every 3 weeks) or Arm B: added trastuzumab (8mg/kg loading dose, then 6 mg/kg every 21 days until progression). The primary end-point was progression-free survival (PFS).

Results: Among 563 screened patients, 75 (13.3%) were Her2 positive (IHC 2+/3+ and FISH+) and 61 met all eligibility criteria (median age, 64 years; 54/61 males; 50/61 baseline ECOG-PS 0-1; 11 locally advanced and 50 metastatic). There was no significant difference between Arms A and B in median PFS (10.2 versus 8.2 months, respectively, p=0.689), objective response rate (65.5% versus 53.2%, p=0.39), and median overall survival (15.7 versus 14.1 months, respectively, p=0.684). In an exploratory analysis, trastuzumab-treated patients receiving cisplatin rather than carboplatin-based chemotherapy fared better (PFS: 10.6 versus 8.0; OS: 33.1 versus 9.5 months). Myelosuppression was the main grade 3/4 toxicity. A case of grade 3 cardiotoxicity and one death from febrile neutropenia occurred in arm B.

Conclusion: The unexpectedly low incidence of Her2 overexpression precluded the detection of a significant difference in efficacy on addition of trastuzumab to platinum-based chemotherapy with gemcitabine. However, the satisfactory tolerance of the combination warrants further studies, especially of the cisplatin-based combination, in well-defined patient subsets.
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http://dx.doi.org/10.1016/j.ejca.2014.10.009DOI Listing
January 2015