Biomarqueurs tumoraux circulants

Publications

Année de publication : 2010

Lucas Caussa, Youlia M Kirova, Nathalie Gault, Jean-Yves Pierga, Alexia Savignoni, François Campana, Rémi Dendale, Alain Fourquet, Marc A Bollet (2010 Sep 17)

The acute skin and heart toxicity of a concurrent association of trastuzumab and locoregional breast radiotherapy including internal mammary chain: a single-institution study.

European journal of cancer (Oxford, England : 1990) : 65-73 : DOI : 10.1016/j.ejca.2010.08.013 En savoir plus
Résumé

To evaluate the skin and heart toxicity of a concurrent adjuvant trastuzumab-radiotherapy for breast cancer (BC), especially in the case of internal mammary chain (IMC) irradiation.

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Jean-Yves Pierga, Suzette Delaloge, Marc Espié, Etienne Brain, Brigitte Sigal-Zafrani, Marie-Christine Mathieu, Philippe Bertheau, Jean Marc Guinebretière, Marc Spielmann, Alexia Savignoni, Michel Marty (2010 May 19)

A multicenter randomized phase II study of sequential epirubicin/cyclophosphamide followed by docetaxel with or without celecoxib or trastuzumab according to HER2 status, as primary chemotherapy for localized invasive breast cancer patients.

Breast cancer research and treatment : 429-37 : DOI : 10.1007/s10549-010-0939-3 En savoir plus
Résumé

To assess anti-tumor activity of sequential epirubicin/cyclophosphamide followed by docetaxel with the randomized addition of celecoxib in HER2 negative patients or trastuzumab in HER2 positive patients. From May 2004 till October 2007, 340 patients with stage II and III breast adenocarcinoma, ineligible for breast conserving surgery, received eight sequential three weekly cycles of EC-D [epirubicin (75 mg/m(2))-cyclophosphamide (750 mg/m(2)) for four cycles followed by docetaxel (100 mg/m(2)) for four cycles]. HER2-negative patients (N = 220) were randomized to receive concomitantly with docetaxel celecoxib 800 mg/day during cycles 5-8 or no additional treatment, while HER2-positive patients confirmed by FISH (N = 120) were randomized to trastuzumab concomitant to docetaxel (8 mg/kg then 6 mg/kg IV every 3 weeks) or no additional preoperative treatment. In the HER2 negative group, pCR (grade 1 and 2 of Chevallier’s classification) was observed in 11.5 and 13% of patients treated without and with neoadjuvant Celecoxib, respectively. In the HER2 positive group, pCR rate reached 26% in those who received neoadjuvant trastuzumab versus 19% in the others. There was no unexpected toxicity, no cardiac toxicity, and no toxic death. Triple negative breast cancers experience the highest pCR rate of 30%. Celecoxib is not likely to improve pCR rates in addition to EC-D in patients with HER2-negative tumor. In HER2-positive tumor patients, trastuzumab added to ECD leads to increased pCR rates. It was the only combination to deserve further study according to the two-stage Fleming’s design used in this trial.

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Année de publication : 2009

Anne Vincent-Salomon, Martial Caly, Yann De Rycke, Paul Fréneaux, Jerzy Klijanienko, Marick Laé, Frédérique Viard, Claude Nos, François-Clément Bidard, Séverine Alran, Rémy Salmon, Youlia Kirova, Jean-Yves Pierga, Brigitte Sigal-Zafrani, Xavier Sastre-Garau (2009 Apr 21)

Lobular phenotype related to occult-metastatic spread in axillary sentinel node and/or bone marrow in breast carcinoma.

European journal of cancer (Oxford, England : 1990) : 1979-86 : DOI : 10.1016/j.ejca.2009.03.015 En savoir plus
Résumé

To determine whether any histological trait was associated with regional and/or systemic spread of occult tumour cells (OTCs) in small size invasive breast cancer, we compared tumour characteristics, axillary sentinel lymph node (SN) and bone marrow (BM) status in a series of 287 pT1T2 cases. Surgery was the first step of treatment, associated with SN procedure and with BM aspiration for the detection of OTC. SN was histologically classified as negative, metastatic (>2mm), micro-metastatic (>0.2mm and 2mm) or involved by OTC detected by immunohistochemistry (Ni+, 0.2mm). BM specimens were analysed after immunocytochemistry and classified as negative or positive with atypical cytokeratin-positive OTC. Metastasis and micro-metastasis in the SN were correlated with size, grade and vascular invasion. In contrast, presence of OTC in both SN and BM was independent of these parameters but positively associated with lobular type. This correlation was also observed for BM status, which was similarly independent of the tumour characteristics. No association was found between SN status and BM status. Our data indicate that, in the course of breast cancer, OTC spreading is frequent and could be an early event, related to lobular histological type but independent of classical histoprognostic parameters, and that the loco-regional metastatic spread of OTC is not a prerequisite for systemic involvement.

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Année de publication : 2008

François-Clément Bidard, Anne Vincent-Salomon, Brigitte Sigal-Zafrani, Manuel Rodrigues, Véronique Diéras, Laurent Mignot, Xavier Sastre-Garau, Marie-France Poupon, Jean-Yves Pierga (2008 Nov 8)

Time to metastatic relapse and breast cancer cells dissemination in bone marrow at metastatic relapse.

Clinical & experimental metastasis : 871-5 : DOI : 10.1007/s10585-008-9203-1 En savoir plus
Résumé

Breast cancer dissemination can be monitored in patients by detecting circulating and/or disseminated tumor cells. However, bone marrow disseminated tumor cells (BM DTC) may undergo a dormancy during several years before growing (or not) into clinically detectable metastases. We therefore hypothesized that breast cancers which have formed BM DTC in the course of their metastatic growth might exhibit a longer interval before metastatic relapse. We examined the association of DTC detection (cytokeratin 8, 18 or 19 positive epithelial cells with cancerous morphological features), at metastatic relapse, with the metastasis-free interval in breast cancer patients. In the 110 metastatic patients studied, 42% (n = 64/110) were classified as BM DTC-negative. These patients had a significantly shorter metastasis-free interval than BM DTC-positive patients (P = 0.02). In multivariate logistic regression analysis, the metastasis-free interval was an independent predictor of DTC detection (P = 0.02), together with bone metastasis (P = 0.0003) and low tumor grade (grade I or II, P = 0.05). We finally suggest that a faster metastatic process might skip in some patients the BM DTC-associated dormancy step. Dissemination of DTC in other host organ and/or epithelial-mesenchymal transition from cytokeratin-positive to cytokeratin-negative DTC may explain this observation.

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Jean-Yves Pierga, François-Clément Bidard, Claire Mathiot, Etienne Brain, Suzette Delaloge, Sylvie Giachetti, Patricia de Cremoux, Rémy Salmon, Anne Vincent-Salomon, Michel Marty (2008 Nov 5)

Circulating tumor cell detection predicts early metastatic relapse after neoadjuvant chemotherapy in large operable and locally advanced breast cancer in a phase II randomized trial.

Clinical cancer research : an official journal of the American Association for Cancer Research : 7004-10 : DOI : 10.1158/1078-0432.CCR-08-0030 En savoir plus
Résumé

Circulating tumor cells in blood from metastatic breast cancer patients have been reported as a surrogate marker for tumor response and shorter survival. The aim of this study was to determine whether circulating tumor cells are present in the blood of patients with large operable or locally advanced breast cancer before neoadjuvant chemotherapy and after neoadjuvant chemotherapy before surgery.

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Véronique Girre, Marie-Christine Falcou, Mathilde Gisselbrecht, Geneviève Gridel, Véronique Mosseri, Carole Bouleuc, Rollon Poinsot, Lionel Vedrine, Liliane Ollivier, Valérie Garabige, Jean-Yves Pierga, Véronique Diéras, Laurent Mignot (2008 Aug 12)

Does a geriatric oncology consultation modify the cancer treatment plan for elderly patients?

The journals of gerontology. Series A, Biological sciences and medical sciences : 724-30 En savoir plus
Résumé

This study was performed to describe the treatment plan modifications after a geriatric oncology clinic. Assessment of health and functional status and cancer assessment was performed in older cancer patients referred to a cancer center.

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Francois-Clément Bidard, Anne Vincent-Salomon, Stéphanie Gomme, Claude Nos, Yann de Rycke, Jean Paul Thiery, Brigitte Sigal-Zafrani, Laurent Mignot, Xavier Sastre-Garau, Jean-Yves Pierga, (2008 Jun 4)

Disseminated tumor cells of breast cancer patients: a strong prognostic factor for distant and local relapse.

Clinical cancer research : an official journal of the American Association for Cancer Research : 3306-11 : DOI : 10.1158/1078-0432.CCR-07-4749 En savoir plus
Résumé

Clinical significance of disseminated tumor cells (DTC) in bone marrow of early breast cancer patients has been reported, but improvements in detection methods are needed.

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Année de publication : 2007

François-Clément Bidard, Jean-Yves Pierga, Anne Vincent-Salomon, Marie-France Poupon (2007 Dec 11)

A « class action » against the microenvironment: do cancer cells cooperate in metastasis?

Cancer metastasis reviews : 5-10 En savoir plus
Résumé

The authors review how cancer cells may cooperate in metastasis by means of microenvironmental changes. The main mechanisms underlying this cooperation are clustered migration of cancer cells, extracellular matrix degradation, paracrine loops of released signaling factors and/or induction of adhesion molecules on stromal cells. Another critical factor could be temporal cooperation: successive waves of cancer cells may induce progressive conditioning of the microenvironment. The « class action » of cancer cells against the microenvironment involves successive steps of the metastatic process: invasion of the primary tumor microenvironment, collective migration through the extracellular matrix, blood vessel disruption, vascular or lymphatic tumor emboli, establishment of a premetastatic niche by secreted factors and endothelial precursor recruitment, induction of cell adhesion molecule expression in endothelial cells, extravasation, micrometastasis dormancy and establishment of a new growth in distant sites. As a result, after completion of the metastatic process, the series of microenvironmental changes from the primary tumor to the metastatic site may promote colonization of metastases by nonmetastatic cancer cells of the primary tumor.

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Année de publication : 2005

Véronique Diéras, Jacques Bonneterre, Valérie Laurence, Marian Degardin, Jean-Yves Pierga, Marie-Edith Bonneterre, Sandrine Marreaud, Denis Lacombe, Pierre Fumoleau (2005 Sep 8)

Phase I combining a P-glycoprotein inhibitor, MS209, in combination with docetaxel in patients with advanced malignancies.

Clinical cancer research : an official journal of the American Association for Cancer Research : 6256-60 En savoir plus
Résumé

The purpose of this study was to investigate the safety and tolerability of MS209, a potent inhibitor of P-glycoprotein, when given in combination with docetaxel and to determine whether MS209 affects docetaxel pharmacokinetics.

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Valérie Laurence, Jean-Yves Pierga, Sophie Barthier, Antoine Babinet, Claire Alapetite, Thao Palangié, Gonzagues de Pinieux, Philippe Anract, Pierre Pouillart (2005 Jun 1)

Long-term follow up of high-dose chemotherapy with autologous stem cell rescue in adults with Ewing tumor.

American journal of clinical oncology : 301-9 En savoir plus
Résumé

Ewing tumors remain of poor prognosis, with 5-year overall survival of 55% to 65% in localized patients and not exceeding 25% in primarily metastatic disease. Several reports, mainly in children, have reported that some patients with poor-risk Ewing tumors may benefit from high-dose chemotherapy (HDCT) with autologous stem cell rescue. This retrospective study analyzed 46 patients treated in our institution between 1987 and 2000 for localized or primary metastatic Ewing tumors by HDCT followed by stem cell rescue. Median follow up was 7.1 years. Median age was 21 years (range, 15-46 years). Twenty-two percent of patients had metastases at diagnosis. The tumor site was axial in 56% of patients. Median tumor size was 9.5 cm. The treatment regimen consisted of induction chemotherapy, local treatment, maintenance chemotherapy, and consolidation HDCT based on alkylating agents. No toxic death was observed in the intensive therapy phase. Five-year overall survival and progression-free survival were 63 +/- 7.7% and 47 +/- 7.6%, respectively. Pejorative prognostic factors in this population were metastases at diagnosis (5-year overall survival 34% vs.71%, P = 0.017) and poor pathologic response (5-year overall survival 44% vs.77%, P = 0.03). This retrospective study shows a high long-term survival rate with high-dose chemotherapy in adults.

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Patricia de Cremoux, Véronique Diéras, Marie-France Poupon, Henri Magdelénat, Brigitte Sigal-Zafrani, Alain Fourquet, Jean-Yves Pierga (2005 Jan 7)

[Tamoxifen and aromatase inhibitors in the treatment of breast cancer in menopausal women: pharmacological and clinical aspects].

Bulletin du cancer : 917-27 En savoir plus
Résumé

Estrogen is the main hormone involved in the development and growth of hormone-dependent breast cancer. Endocrine adjuvant treatment in recent years focused primarily on the use of SERMs, mainly tamoxifen. Tamoxifen actions are complex. It acts by competitive antagonism of estrogen at its receptor site. It has beneficial agonistic effects in preventing bone demineralization in postmenopausal women, but a detrimental agonistic effect by increasing the risk of uterine cancer and of thrombo-embolism. However, the situation is changing rapidly with the introduction of recent aromatase inhibitors, which display high specificity towards aromatase. They suppress plasma estrogen levels in postmenopausal women by inhibiting or inactivating aromatase, the enzyme responsible of the synthesis of estrogens from androgenic substrates. A complete estrogen deprivation in target tissues may eventually induce osteoporosis. Unlike tamoxifen, aromatase inhibitors have no partial agonistic action. During the last 20 years, adjuvant tamoxifen treatment for 5 years was the « gold standard » endocrine treatment in postmenopausal women with hormone-receptor-positive breast cancers. A 25% reduction risk of deaths was observed. Recently, the results of clinical trials comparing aromatase inhibitors to tamoxifen in post menopausal women with hormone-dependent breast cancer showed a benefit in favor of aromatase inhibitors in reducing the risk of recurrence. These trials were either comparative (for anastrozole) or sequential (for anastrozole, letrozole and exemestane). The issues of long term adverse effects (bone) and hormone treatment sequence remain to be addressed.

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Année de publication : 2004

Jean-Yves Pierga, Charlyne Bonneton, Henri Magdelénat, Anne Vincent-Salomon, Claude Nos, Evelyne Boudou, Pierre Pouillart, Jean-Paul Thiery, Patricia de Cremoux (2004 Nov 16)

Real-time quantitative PCR determination of urokinase-type plasminogen activator receptor (uPAR) expression of isolated micrometastatic cells from bone marrow of breast cancer patients.

International journal of cancer : 291-8 En savoir plus
Résumé

Disseminated tumor cells (DTC) in bone marrow are independently related to poor outcome in patients with breast cancer. Phenotypic characterization of DTC may be useful to improve evaluation of the metastasizing potential of DTC and also to more accurately target aggressive tumor cells. DTC were screened in bone marrow aspirates from breast cancer patients by immunocytochemistry with an anticytokeratin (anti-CK) antibody (A45B/B3). Because the cell permeabilization and fixation required for intracellular CK staining is deleterious for mRNA, we used microaspiration to isolate single tumor cells stained with a monoclonal antibody directed against a membrane epitope, epithelial cell adhesion molecule (EpCAM), in CK-positive cases. Urokinase-type plasminogen activator receptor (uPAR) was quantified by real-time quantitative RT-PCR. The SKBR3 human breast cancer cell line was used to calibrate RT-PCR. A linear relationship was observed between the cycle threshold (Ct) of uPAR and 18S gene expression and SKBR3 cells spiked (1, 3, 7, 10 and 20) in control patient bone marrow. EpCAM-positive cells were aspirated in 21 out of 25 bone marrow specimens from breast cancer patients with CK-positive cells and uPAR mRNA expression was determined in 16 cases. A high level of uPAR mRNA in DTC was detected in 8 out of 16 patients (50%) and was associated with a more aggressive primary tumor phenotype (estrogen receptor [ER]-negative, progesterone receptor [PR]-negative or HER2-positive) (p = 0.01). We demonstrated that real-time quantitative RT-PCR was reliably adapted to phenotype analysis of isolated micrometastatic cells. A larger study would be useful to confirm the importance of uPAR to define higher risk subgroups of breast cancer patients with micrometastatic disease.

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Valérie Choesmel, Jean-Yves Pierga, Claude Nos, Anne Vincent-Salomon, Brigitte Sigal-Zafrani, Jean-Paul Thiery, Nathalie Blin (2004 Aug 21)

Enrichment methods to detect bone marrow micrometastases in breast carcinoma patients: clinical relevance.

Breast cancer research : BCR : R556-70 En savoir plus
Résumé

Improving technologies for the detection and purification of bone marrow (BM) micrometastatic cells in breast cancer patients should lead to earlier prognosis of the risk of relapse and should make it possible to design more appropriate therapies. The technique used has to overcome the challenges resulting from the small number of target cells (one per million hematopoietic cells) and the heterogeneous expression of micrometastatic cell markers. In the present study, we have assessed the clinical relevance of current methods aimed at detecting rare disseminated carcinoma cells.

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Régis Peffault de Latour, Gaëtan Des Guetz, Valérie Laurence, Thao Palangié, Jean-Yves Pierga, Véronique Diéras, Michel Jouve, Jean-Marc Extra, Pierre Pouillart, Didier Decaudin (2004 Aug 4)

Breast cancer associated with idiopathic thrombocytopenic purpura: a single center series of 10 cases.

American journal of clinical oncology : 333-6 En savoir plus
Résumé

The aim of this study was to define the characteristics of patients with idiopathic thrombocytopenic purpura (ITP) and breast cancer and discuss the relationship between these two diseases. Ten patients treated for breast cancer and presenting with ITP were screened for this study. The diagnosis of breast cancer was confirmed by biopsy or surgical sample. The diagnosis of ITP was defined by 1) platelet count less than 140.10(9)/l with normal or increased number of megakaryocytes on bone marrow aspirate, 2) after exclusion of thrombocytopenia-induced medication or disorders, and 3) absence of splenomegaly. ITP was diagnosed before breast cancer in three cases, concomitantly in three, and after the diagnosis of breast cancer in four cases. Platelet count and breast cancer showed an independent course in seven cases, and appeared to be correlated in the other three patients. No correlation was found between the development of ITP and tumor characteristics. In contrast, the median platelet count was 15.10(9)/l (range 3-26) for the 3 patients with a correlation between the course of ITP and breast cancer evolution and 70.10(9)/l (range 20-90) for the other cases (p = 0.05, Mann-Whitney U test). Breast cancers are associated with ITP, with a parallel course of the two diseases in one third of cases. This may suggest tumor-induced immunologic thrombocytopenia.

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Véronique Diéras, Véronique Girre, Jean-Yves Pierga, Valérie Laurence, Sophie Piperno-Neumann, Pierre Pouillart (2004 Jul 30)

[Update on docetaxel and breast cancer].

Bulletin du cancer : 409-17 En savoir plus
Résumé

Docetaxel (Taxotère) has been developed in breast cancer during the last decade. First its activity in monotherapy was proven in metastatic setting after failure of anthracycline therapy. Then the association with anthracycline demonstrated substantial activity leading to its development in early stages of breast cancer and its incorporation in adjuvant and neoadjuvant settings. Recently the first adjuvant trial comparing the association TAC versus FAC was presented. In the TAC arm, the disease free survival was better comparing with FAC (p = 0.0011) and survival was better in the subgroup with less than four positive lymph nodes. In the neoadjuvant setting, the incorporation of docetaxel after an anthracycline-based regimen (protocols Aberdeen and NSABP-B27) led to better clinical response, subsequently to better breast conservation and more important the increase of the pathological response rate. Improvement of survival has been reported in the Aderbeen study but a longer follow-up of the NSABP B27 study is required to confirm the impact of Taxotère in the outcome of breast cancer. The next step will be the development of the combination of the most active chemotherapeutic regimen with targeted therapies according to molecular characteristics of the tumor. The integration of trastuzumab with taxane-based chemotherapy has already demonstrated high activity in metastatic breast cancer with overexpression of HER2 and adjuvant trials are ongoing.

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