Publications

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Adjuvant chemotherapy for localised breast cancer aims at reducing the risk of relapse and at increasing overall survival. Decision criteria include tumour burden and biological profile. It appears currently difficult to evaluate the benefit/risk ratio in certain borderline cases, which are more and more frequent. We have evaluated through an anonymous web survey conducted as part of the 2013 Annual Saint-Paul-de-Vence breast conference, the chemotherapy decisions, use of guidelines and level of certainty with decisions in this type of situation through four clinical cases. The survey was proposed to 1,190 French physicians who are directly in charge of breast cancer care, whatever their specialty. Three hundred and fifty-three of them replied, of whom 67 % were oncologists and 15 % surgeons. A significantly heterogeneous decision was observed for two out of four cases, in which 52 and 69 % of the physicians opted for adjuvant chemotherapy, versus 48 and 21 % for abstention respectively. Eighty seven percent of responding physicians used guidelines to guide their decision. These guidelines were regional for 63 %, national for 36 %, local in 21 % and international in 16 % of the cases. The level of certainty varied with clinical cases but not with the physician’s specialty, nor type of decision.

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We present a low cost microfluidic chip integrating 3D micro-chambers for the capture and the analysis of cells. This device has a simple design and a small footprint. It allows the implementation of standard biological protocols in a chip format with low volume consumption. The manufacturing process relies on hot-embossing of cyclo olefin copolymer, allowing the development of a low cost and robust device. A 3D design of microchannels was used to induce high flow velocity contrasts in the device and provide a selective immobilization. In narrow distribution channels, the liquid velocity induces a shear stress that overcomes adhesion forces and prevents cell immobilization or clogging. In large 3D chambers, the liquid velocity drops down below the threshold for cell attachment. The devices can be operated in a large range of input pressures and can even be handled manually using simple syringe or micropipette. Even at high flow injection rates, the 3D structures protect the captured cell from shear stress. To validate the performances of our device, we implemented immuno-fluorescence labeling and Fluorescence in Situ Hybridization (FISH) analysis on cancer cell lines and on a patient pleural effusion sample. FISH is a Food and Drug Administration approved cancer diagnostic technique that provides quantitative information about gene and chromosome aberration at the single cell level. It is usually considered as a long and fastidious test in medical diagnosis. This process can be easily implanted in our platform, and high resolution fluorescence imaging can be performed with reduced time and computer intensiveness. These results demonstrate the potential of this chip as a low cost, robust, and versatile tool adapted to complex and demanding protocols for medical diagnosis.

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Circulating tumor DNA (ctDNA) is a new circulating tumor biomarker which might be used as a prognostic biomarker in a way similar to circulating tumor cells (CTCs). Here, we used the high prevalence of TP53 mutations in triple negative breast cancer (TNBC) to compare ctDNA and CTC detection rates and prognostic value in metastatic TNBC patients. Forty patients were enrolled before starting a new line of treatment. TP53 mutations were characterized in archived tumor tissues and in plasma DNA using two next generation sequencing (NGS) platforms in parallel. Archived tumor tissue was sequenced successfully for 31/40 patients. TP53 mutations were found in 26/31 (84%) of tumor samples. The same mutation was detected in the matched plasma of 21/26 (81%) patients with an additional mutation found only in the plasma for one patient. Mutated allele fractions ranged from 2 to 70% (median 5%). The observed correlation between the two NGS approaches (R(2) = 0.903) suggested that ctDNA levels data were quantitative. Among the 27 patients with TP53 mutations, CTC count was ≥1 in 19 patients (70%) and ≥5 in 14 patients (52%). ctDNA levels had no prognostic impact on time to progression (TTP) or overall survival (OS), whereas CTC numbers were correlated with OS (p = 0.04) and marginally with TTP (p = 0.06). Performance status and elevated LDH also had significant prognostic impact. Here, absence of prognostic impact of baseline ctDNA level suggests that mechanisms of ctDNA release in metastatic TNBC may involve, beyond tumor burden, biological features that do not dramatically affect patient outcome.

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The international phase IIIb study, ATHENA assessed the combination of bevacizumab/taxane-based chemotherapy in the first-line treatment of HER2 negative metastatic breast cancer (mBC) in real-life setting. Among the 365 patients included in France, median overall survival (OS) is 28.4 months (CI95% 24.8-33.0), with a median time from treatment start to end of study of 36,5 months (25,1-45,4). Exploratory analyses in three sub-groups show that the median OS in long responder patients (not progressing for at least one year; n = 116) is not reached. In responder patients (n = 308), median OS is 33.0 months (CI95% 28.6-37.4) and 12.4 months (CI95% 11.2-17.4) in non-responders (n = 41). In patients with mBC expressing hormone receptors (HR+), treated with first-line hormone therapy before inclusion (n = 87) median OS in is 23.2 months (CI95% 19.6-28.6), and 35.3 months (CI95% 32.2-not reached); P = 0.004 in patients treated first with chemotherapy + bevacizumab (n = 179). The safety analysis in the various sub-groups of grade 3-5 adverse events of particular interest to bevacizumab of this study was comparable to the safety data of randomized phase III studies.

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Longer duration of first-line chemotherapy for patients with metastatic breast cancer is associated with prolonged overall survival and improved progression-free survival. We investigated capecitabine added to maintenance bevacizumab after initial treatment with bevacizumab and docetaxel in this setting.

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Evidence-based definitions of ‘poor-prognosis’ or ‘aggressive’ advanced breast cancer are lacking.

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Patients with luminal breast cancer (LBC) often become endocrine resistant over time. We investigated the molecular changes associated with acquired hormonoresistances in patient-derived xenografts of LBC.

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We aimed to assess the clinical validity of circulating tumour cell (CTC) quantification for prognostication of patients with metastatic breast cancer by undertaking a pooled analysis of individual patient data.

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The detection and molecular characterization of circulating tumor cells (CTCs) are one of the most active areas of translational cancer research, with more than 400 clinical studies having included CTCs as a biomarker. The aims of research on CTCs include: a) estimation of the risk for metastatic relapse or metastatic progression (prognostic information); b) stratification and real-time monitoring of therapies; c) identification of therapeutic targets and resistance mechanisms; and d) understanding metastasis development in cancer patients. This review focuses on the technologies used for the enrichment and detection of CTCs. We outline and discuss the current technologies that are based on exploiting the physical and biological properties of CTCs. A number of innovative technologies to improve methods for CTC detection have recently been developed, including CTC microchips, filtration devices, quantitative reverse-transcription PCR assays, and automated microscopy systems. Molecular characterization studies have indicated, however, that CTCs are very heterogeneous, a finding that underscores the need for multiplex approaches to capture all of the relevant CTC subsets. We therefore emphasize the current challenges of increasing the yield and detection of CTCs that have undergone an epithelial-mesenchymal transition. Increasing assay analytical sensitivity may lead, however, to a decrease in analytical specificity (e.g., through the detection of circulating normal epithelial cells). A considerable number of promising CTC detection techniques have been developed in recent years. The analytical specificity and clinical utility of these methods must be demonstrated in large prospective multicenter studies to reach the high level of evidence required for their introduction into clinical practice.

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Aromatase inhibitors (AIs) are the first-line treatment in women with breast cancer for total estrogen depletion. Half the treated women may develop pain, and this condition may therefore be seen as a clinical model of pain related to estrogen deprivation. In this prospective multicenter study, we classified AI-related pain syndromes and identified their predictors. A 1-year, prospective, multicenter cohort study, with 6 visits, was carried out on 135 women with early-stage breast cancer and no pain at the start of AI treatment. At initial assessment, we investigated clinical (demographic and psychosocial, cancer characteristics and treatment, sleep, quality of life), biological (sex hormones, vitamin D, bone biomarkers, oxidative stress, immunologic and inflammatory markers), environmental, and genetic (polymorphism for pain mechanisms) risk factors for pain. During 1 year of follow-up, 77 women (57%) developed pain, leading to AI discontinuation in 12 cases. Five pain syndromes were identified: joint pain (36%), diffuse pain (22%), tendinitis (22%), neuropathic pain (9%), and mixed pain (11%), which are mostly persistent (57%), with diffuse and joint pains the most intense. Risk factors for the development of pain included higher levels of anxiety and impaired quality of life at the initial assessment, whereas cancer characteristics, genetic background, inflammation, and immunologic and hormonal status at baseline were not significant predictors.

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Molecular analyses of circulating tumor DNA (ctDNA) in plasma from cancer patients have the potential to deliver minimally invasive diagnostic and disease-monitoring biomarkers. Drawing from experience gained through the translation of circulating tumor cell detection to clinical tests, we discuss ctDNA as a source of tumor material for biomarker development.

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We investigated the feasibility of helical tomotherapy (HT) for inoperable large breast tumors, after failing to achieve adequate treatment planning with conformal radiation techniques.

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Decrease of circulating tumor cells (CTC) during treatment is an independent prognostic factor in metastatic breast cancer (MBC). We specifically evaluated the impact of CTC on brain metastasis outcome.

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Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) have been recently investigated in several cancer types, but their respective clinical significance remains to be determined. In our prospective study, we compared the detection rate and the prognostic value of these two circulating biomarkers in patients with metastatic uveal melanoma. GNAQ/GNA11 mutations were characterized in archived tumor tissue. Using a highly sensitive and mutation-specific bidirectional pyrophosphorolysis-activated polymerization (bi-PAP) technique, GNAQ c.626A>T, GNAQ c.626A>C and GNA11 c.626A>T copy numbers were quantified in plasma from 12 mL of blood. CTCs were detected at the same time in 7.5 mL of blood by the CellSearch technique. Patient characteristics and outcome were prospectively collected. CTCs (≥1) were detected in 12 of the 40 included patients (30%, range 1-20). Among the 26 patients with known detectable mutations, ctDNA was detected and quantified in 22 (84%, range 4-11,421 copies/mL). CTC count and ctDNA levels were associated with the presence of miliary hepatic metastasis (p = 0.004 and 0.03, respectively), with metastasis volume (p = 0.005 and 0.004) and with each other (p < 0.0001). CTC count and ctDNA levels were both strongly associated with progression-free survival (p = 0.003 and 0.001) and overall survival (p = 0.0009 and <0.0001). In multivariate analyses, ctDNA appeared to be a better prognostic marker than CTC. In conclusion, ctDNA and CTC are correlated and both have poor prognostic significance. CTC detection can be performed in every patient but, in patients with detectable mutations, ctDNA was more frequently detected than CTC and has possibly more prognostic value.