Murviel-lès-Montpellier, France
Murviel-lès-Montpellier, France

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Mazel M.,Montpellier University | Jacot W.,Montpellier Cancer Institute ICM | Pantel K.,University of Hamburg | Bartkowiak K.,University of Hamburg | And 8 more authors.
Molecular Oncology | Year: 2015

Immune checkpoint regulators such as PD-L1 have become exciting new therapeutic targets leading to long lasting remissions in patients with advanced malignancies. However, in view of the remarkable costs and the toxicity profiles of these therapies, predictive biomarkers able to discriminate responders from non-responders are urgently needed. In the present paper, we provide evidence that PD-L1 is frequently expressed on metastatic cells circulating in the blood of hormone receptor-positive, HER2-negative breast cancer patients. We performed western blot, flow cytometry and immunocytochemical analyses to demonstrate the specificity of the PDL1 antibody used in our study and established immunoscores for PDL1 expression on single tumor cells. We then selected sixteen patients with circulating tumor cells (CTCs) using the CellSearch® system and found PD-L1(+) CTCs in 11 patients (68.8%). The fraction of PD-L1(+) CTCs varied from 0.2 to 100% in individual patients. This is the first report demonstrating the expression of PD-L1 on CTCs. The established CTC/PD-L1 assay can be used for liquid biopsy in future clinical trials for stratification and monitoring of cancer patients undergoing immune checkpoint blockade. © 2015 Federation of European Biochemical Societies.


Azria D.,Montpellier Cancer Institute ICM | Azria D.,French Institute of Health and Medical Research | Riou O.,Montpellier Cancer Institute ICM | Rebillard X.,Clinique Beausoleil | And 5 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2014

Purpose Concomitant treatment with radiation therapy and cisplatin (CDDP) remains the gold standard for bladder preservation in the treatment of muscle-invasive bladder cancer (MIBC). We present the long-term results of a phase 1 clinical trial to assess the association of twice-weekly gemcitabine with CDDP and radiation therapy in this setting. Methods and Materials Patients with pT2-pT4N0M0 MIBC without hydronephrosis or diffuse carcinoma in situ were enrolled in this study. After maximal transurethral resection of the bladder tumor, patients received concomitant radiation therapy (63 Gy in 1.8 fractions) and chemotherapy (CDDP 20 mg/m2/day over 4 days every 21 days and gemcitabine twice a week). The starting dose of gemcitabine was 15 mg/m 2 with dose escalation to 20, 25, and 30 mg/m2. The primary endpoint was the maximum tolerated dose (MTD). Secondary endpoints included toxicity and tumor control. Results Fourteen patients were enrolled. Dose-limiting toxicity occurred in 2 patients treated with 30 mg/m2 gemcitabine (grade 4 thrombocytopenia and severe impairment of World Health Organization performance status, respectively). Nine patients received the complete chemoradiation therapy protocol. The recommended dose of gemcitabine was 25 mg/m2. The median follow-up time was 53 months, and the overall and disease-specific 5-year survival rates were 62% and 77%, respectively. Among the patients who received the complete treatment, bladder-intact survival was 76% at 5 years, and the median overall survival was 69.6 months. Conclusions This regimen was well tolerated. The gemcitabine MTD was 25 mg/m2. Bladder preservation and disease control were promising. A multicenter phase 2 randomized trial is ongoing. © 2014 Elsevier Inc. All rights reserved.


Martelotto L.G.,Sloan Kettering Cancer Center | De Filippo M.R.,Sloan Kettering Cancer Center | Ng C.K.,Sloan Kettering Cancer Center | Natrajan R.,Institute of Cancer Research | And 17 more authors.
Journal of Pathology | Year: 2015

Adenoid cystic carcinoma (AdCC) is a rare type of triple-negative breast cancer (TNBC) characterized by the presence of the MYB-NFIB fusion gene. The molecular underpinning of breast AdCCs other than the MYB-NFIB fusion gene remains largely unexplored. Here we sought to define the repertoire of somatic genetic alterations of breast AdCCs. We performed whole-exome sequencing, followed by orthogonal validation, of 12 breast AdCCs to determine the landscape of somatic mutations and gene copy number alterations. Fluorescence in situ hybridization and reverse-transcription PCR were used to define the presence of MYB gene rearrangements and MYB-NFIB chimeric transcripts. Unlike common forms of TNBC, we found that AdCCs have a low mutation rate (0.27 non-silent mutations/Mb), lack mutations in TP53 and PIK3CA and display a heterogeneous constellation of known cancer genes affected by somatic mutations, including MYB, BRAF, FBXW7, SMARCA5, SF3B1 and FGFR2. MYB and TLN2 were affected by somatic mutations in two cases each. Akin to salivary gland AdCCs, breast AdCCs were found to harbour mutations targeting chromatin remodelling, cell adhesion, RNA biology, ubiquitination and canonical signalling pathway genes. We observed that, although breast AdCCs had rather simple genomes, they likely display intra-tumour genetic heterogeneity at diagnosis. Taken together, these findings demonstrate that the mutational burden and mutational repertoire of breast AdCCs are more similar to those of salivary gland AdCCs than to those of other types of TNBCs, emphasizing the importance of histological subtyping of TNBCs. Furthermore, our data provide direct evidence that AdCCs harbour a distinctive mutational landscape and genomic structure, irrespective of the disease site of origin. © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


PubMed | Sloan Kettering Cancer Center, Cancer Research UK Research Institute, Montpellier Cancer Institute ICM, Gothenburg University and University Pierre and Marie Curie
Type: Journal Article | Journal: The Journal of pathology | Year: 2016

Adenoid cystic carcinoma (AdCC) is a rare type of triple-negative breast cancer (TNBC) characterized by the presence of the MYB-NFIB fusion gene. The molecular underpinning of breast AdCCs other than the MYB-NFIB fusion gene remains largely unexplored. Here we sought to define the repertoire of somatic genetic alterations of breast AdCCs. We performed whole-exome sequencing, followed by orthogonal validation, of 12 breast AdCCs to determine the landscape of somatic mutations and gene copy number alterations. Fluorescence in situ hybridization and reverse-transcription PCR were used to define the presence of MYB gene rearrangements and MYB-NFIB chimeric transcripts. Unlike common forms of TNBC, we found that AdCCs have a low mutation rate (0.27 non-silent mutations/Mb), lack mutations in TP53 and PIK3CA and display a heterogeneous constellation of known cancer genes affected by somatic mutations, including MYB, BRAF, FBXW7, SMARCA5, SF3B1 and FGFR2. MYB and TLN2 were affected by somatic mutations in two cases each. Akin to salivary gland AdCCs, breast AdCCs were found to harbour mutations targeting chromatin remodelling, cell adhesion, RNA biology, ubiquitination and canonical signalling pathway genes. We observed that, although breast AdCCs had rather simple genomes, they likely display intra-tumour genetic heterogeneity at diagnosis. Taken together, these findings demonstrate that the mutational burden and mutational repertoire of breast AdCCs are more similar to those of salivary gland AdCCs than to those of other types of TNBCs, emphasizing the importance of histological subtyping of TNBCs. Furthermore, our data provide direct evidence that AdCCs harbour a distinctive mutational landscape and genomic structure, irrespective of the disease site of origin.


PubMed | Sloan Kettering Cancer Center, Montpellier Cancer Institute ICM and University Pierre and Marie Curie
Type: Journal Article | Journal: Histopathology | Year: 2016

The aims of this study were to perform a whole-exome sequencing analysis of a breast cylindroma and to investigate the role of molecular analyses in the differentiation between breast cylindroma, a benign tumour that displays MYB expression, and CYLD gene mutations, and its main differential diagnosis, the breast solid-basaloid adenoid cystic carcinoma, a malignant tumour that is characterized by the presence of the MYB-NFIB fusion gene and MYB overexpression.A 66-year-old female underwent quadrantectomy after an irregular dense shadow was discovered in the right breast at the screening mammogram. Histologically, the tumour displayed features suggestive of a solid-basaloid variant of adenoid cystic carcinoma with a differential diagnosis of cylindroma. Fluorescence in situ hybridization, reverse transcription-polymerase chain reaction, immunohistochemistry and whole-exome sequencing revealed absence of the MYB-NFIB fusion gene, low levels of MYB protein expression and a clonal somatic CYLD splice site mutation associated with loss of heterozygosity of the wild-type allele.The results of the histological, immunohistochemical and molecular analyses were consistent with a diagnosis of breast cylindroma, providing a proof-of-principle that the integration of histopathological and molecular approaches can help to differentiate between a low-malignant potential and a benign breast tumour of triple-negative phenotype.


PubMed | University of Nimes, Toulouse University Hospital Center, Montpellier Cancer Institute ICM and Montpellier University
Type: | Journal: European journal of radiology | Year: 2016

This was a single center, retrospective observational study.to investigate-in a cancer population-the prevalence and hallmarks of intravertebral enhancement (IVE) detected on contrast-enhanced CT.Intravertebral enhancements secondary to iodinated contrast stagnation have been described. Cancer patients have an increased risk of perivertebral venous thrombosis or stenosis secondary to several risk factors (cancer or drug induced hypercoagulability, deterioration of venous flow linked to catheter insertion, prolonged immobilization). In case of a high density lesion identified on CT, the diagnostic choice between metastasis and contrast media within bone marrow vessels may be an issue, especially as oncologic follow-up CT scans are usually performed with contrast medium injection.2572 contrast-enhanced body CT scans performed in cancer patients over 3 months in the medical imaging department of a university hospital were retrospectively reviewed. IVE was sought when paravertebral venous collateral circulation was detected and bone metastasis ruled out and classified as linear or nodular. Their locations within vertebra, their relation to the injection side and the predominant collateral venous network side were evaluated.Sixty-seven (2.8%) patients had a collateral paravertebral venous system and among them 21 had IVE (37%). There were 208 IVE locations involving 75 vertebrae. 199 IVE were linear-shaped (95.7%) and 9 nodular-shaped (4.3%). 80.8% were located between C6 and T4. 88.9% were localized in the vertebral body. 73.1% were located medially or ipsilateral to the injection side.Intravertebral enhancement is found in 37% of the patients with paraspinal collateral venous circulation when a CT scan is performed for cancer. The ipsilateral or medial position of the IVE relative to the injection side and the side of the dominant perivertebral venous system, and the possibility of connecting the IVE to a paravertebral vein may be in favor of vascular opacification.


Colombo P.-E.,Montpellier Cancer Institute ICM | Fabbro M.,Montpellier Cancer Institute ICM | Theillet C.,French Institute of Health and Medical Research | Bibeau F.,Montpellier Cancer Institute ICM | And 2 more authors.
Critical Reviews in Oncology/Hematology | Year: 2014

Ovarian carcinoma is the most lethal gynaecologic malignancy. Despite wide initial sensibility to chemotherapy especially to platinum-based regimens, the vast majority of patients with advanced stages of the disease develop recurrences and subsequent resistance to treatments. Ovarian cancer is actually considered as a heterogeneous disease at the clinical, histological and molecular level. In this review, the mechanisms of intrinsic sensitivity or resistance to treatment, especially to platinum-based chemotherapy are considered with particular reference to the significance of tumour heterogeneity. The molecular features involved in acquired resistance are reviewed and the current hypotheses are discussed. In particular, potential disruptions of the DNA reparation pathways are highlighted. © 2013 Elsevier Ireland Ltd.


Lacombe J.,French Institute of Health and Medical Research | Mange A.,Montpellier University Hospital Center | Mange A.,Montpellier University | Mange A.,Montpellier Cancer Institute ICM | And 3 more authors.
Journal of Immunology Research | Year: 2014

The widespread use of screening mammography has resulted in increased detection of early-stage breast disease, particularly for in situ carcinoma and early-stage breast cancer. However, the majority of women with abnormalities noted on screening mammograms are not diagnosed with cancer because of several factors, including radiologist assessment, patient age, breast density, malpractice concerns, and quality control procedures. Although magnetic resonance imaging is a highly sensitive detection tool that has become standard for women at very high risk of developing breast cancer, it lacks sufficient specificity and costeffectiveness for use as a general screening tool. Therefore, there is an important need to improve screening and diagnosis of early-invasive and noninvasive tumors, that is, in situ carcinoma. The great potential for molecular tools to improve breast cancer outcomes based on early diagnosis has driven the search for diagnostic biomarkers. Identification of tumor-specific markers capable of eliciting an immune response in the early stages of tumor development seems to provide an effective approach for early diagnosis. The aim of this review is to describe several autoantibodies identified during breast cancer diagnosis. We will focus on these molecules highlighted in the past two years and discuss the potential future use of autoantibodies as biomarkers of early-stage breast cancer. © 2014 Jérôme Lacombe et al.


Colombo P.E.,Montpellier Cancer Institute ICM | Labaki M.,Montpellier Cancer Institute ICM | Fabbro M.,Montpellier Cancer Institute ICM | Bertrand M.,Montpellier Cancer Institute ICM | And 6 more authors.
Gynecologic Oncology | Year: 2014

Objectives Complete surgery with no macroscopic residual disease (RD) at primary (PDS) or interval debulking surgery (IDS) is the main objective of surgery in advanced epithelial ovarian cancer (EOC). The aim of this work was to evaluate the impact on survival of the number of neoadjuvant chemotherapy (NAC) cycles before IDS in EOC patients.Methods Data from EOC patients (stages IIIC-IV), operated on between 1995 and 2010 were consecutively recorded. NAC/IDS patients were analyzed according to the number of preoperative cycles (< 4 = group B1; > 4 = group B2) and compared with patients receiving PDS (group A). Patients with complete resection were specifically analyzed.Results 367 patients were analyzed, 220 received PDS and 147 had IDS/NAC. In group B, 37 patients received more than 4 NAC cycles (group B2). Group B2 patients presented more frequently stage IV disease at diagnosis (p < 0.01) compared to groups A and B1. The rate of complete cytoreduction was higher in group B (p < 0.001). Patients with no RD after IDS and who had received more than 4 NAC cycles had poor survival (p < 0.001) despite complete removal of their tumor (relative risk of death after multivariate analysis of 3 (p < 0.001)) with an independent impact from disease stage and WHO performance status.Conclusions Patients with advanced EOC receiving complete IDS after more than 4 cycles of NAC have poor prognosis. Despite worse prognostic factors observed in this group of patients, our study reinforces the concept of early and complete removal of all macroscopic tumors in the therapeutic sequence of EOC. © 2014 Elsevier Inc. All rights reserved.


Colombo P.-E.,Montpellier Cancer Institute ICM | Lefevre M.,Montpellier Cancer Institute ICM | Delmond L.,Montpellier Cancer Institute ICM | Traore D.,Montpellier Cancer Institute ICM | And 5 more authors.
Annals of Surgical Oncology | Year: 2015

Background: Oncoplastic surgery for breast cancer (BC) may result in postoperative morbidity that can delay adjuvant treatment(s). The McKissock procedure is a reliable mammaplasty technique used in plastic surgery. The authors present their experiences in using a derived technique for the oncoplastic resection of extended malignancies located in the lower-inner (LIQ) or lower-outer (LOQ) breast quadrants. Methods: Between 2011 and 2014, operative data of 25 patients receiving an oncoplastic resection for invasive BC or ductal carcinoma in situ (DCIS), using the modified McKissock procedure, were recorded. This technique conserved a bipedicle dermoglandular flap to improve the nipple–areola complex blood supply. Oncological and cosmetic results, as well as aesthetic outcomes and patients’ satisfaction, were analyzed. Results: Invasive BCs (n = 21) and DCIS (n = 4) were located in the LIQ (n = 18) or LOQ (n = 7). The median age of patients was 62 years (range 34–85), the mean resection weight was 134 g (range 43–314), and the global morbidity rate was 12 %. No nipple necrosis occurred in these patients. Free margins were obtained in 22 cases (88 %) and the secondary mastectomy rate was 8 %. Contralateral symmetrization was performed, or was required, in the majority of cases (17/23). Cosmetic results were classified as excellent or good in 93 % of patients, and the median satisfaction rate on a visual analog scale was 9.6. Conclusion: The modified McKissock procedure allows wide resection of cancers located in the LOQ or LIQ, and produced favorable postoperative outcomes and cosmetic results despite important resection weights. © 2015, Society of Surgical Oncology.

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