PubMed | Center Francois Baclesse, Hopital Rene Huguenin Institute Curie, University of Lyon, CLCC Oscar Lambret and 6 more.
Type: Clinical Trial | Journal: PloS one | Year: 2015
Breast Cancer is a complex multifactorial disease for which high-penetrance mutations have been identified. Approaches used to date have identified genomic features explaining about 50% of breast cancer heritability. A number of low- to medium penetrance alleles (per-allele odds ratio < 1.5 and 4.0, respectively) have been identified, suggesting that the remaining heritability is likely to be explained by the cumulative effect of such alleles and/or by rare high-penetrance alleles. Relatively few studies have specifically explored the mitochondrial genome for variants potentially implicated in breast cancer risk. For these reasons, we propose an exploration of the variability of the mitochondrial genome in individuals diagnosed with breast cancer, having a positive breast cancer family history but testing negative for BRCA1/2 pathogenic mutations. We sequenced the mitochondrial genome of 436 index breast cancer cases from the GENESIS study. As expected, no pathogenic genomic pattern common to the 436 women included in our study was observed. The mitochondrial genes MT-ATP6 and MT-CYB were observed to carry the highest number of variants in the study. The proteins encoded by these genes are involved in the structure of the mitochondrial respiration chain, and variants in these genes may impact reactive oxygen species production contributing to carcinogenesis. More functional and epidemiological studies are needed to further investigate to what extent variants identified may influence familial breast cancer risk.
PubMed | University of Cologne, University of Turin, Vilnius University, Erasmus Medical Center and 133 more.
Type: Journal Article | Journal: JAMA | Year: 2015
Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists.To identify mutation-specific cancer risks for carriers of BRCA1/2.Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk.Mutations of BRCA1 or BRCA2.Breast and ovarian cancer risks.Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR=1.46; 95% CI, 1.22-1.74; P=210(-6)), c.4328 to c.4945 (BCCR2; RHR=1.34; 95% CI, 1.01-1.78; P=.04), and c. 5261 to c.5563 (BCCR2, RHR=1.38; 95% CI, 1.22-1.55; P=610(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR=0.62 (95% CI, 0.56-0.70; P=910(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR=1.71; 95% CI, 1.06-2.78; P=.03), c.772 to c.1806 (BCCR1; RHR=1.63; 95% CI, 1.10-2.40; P=.01), and c.7394 to c.8904 (BCCR2; RHR=2.31; 95% CI, 1.69-3.16; P=.00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR=0.51; 95% CI, 0.44-0.60; P=610(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR=0.57; 95% CI, 0.41-0.80; P=.001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers.Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.
Ricard D.,Service de Neurologie |
Ricard D.,University Pierre and Marie Curie |
Soussain C.,University Pierre and Marie Curie |
Soussain C.,Hopital Rene Huguenin Institute Curie |
Psimaras D.,Groupe Hospitalier Pitie Salpetriere
Revue Neurologique | Year: 2011
Treatment-induced CNS toxicity remains a major cause of morbidity in patients with cancer. Real advances in the design of safer radiation procedures have been counterbalanced by a wider use of combined radiotherapy (RT)-chemotherapy regimens, the development of radiosurgery, and the increasing number of long-term survivors. While classic radionecrosis or chemonecrosis have become less common, more subtle changes such as progressive cognitive dysfunction are increasingly reported after RT (radiation-induced leukoencephalopathy) or chemotherapy (administered alone or in combination). The most important and controversial complications of RT, chemotherapy and combined treatments in the CNS are reviewed here, including new diagnostic tools, practical management and prevention that will influence the future management of cancer patients. © 2011 Elsevier Masson SAS. All rights reserved.
PubMed | Hopital Rene Huguenin Institute Curie, Fundacion Arturo Lopez Perez, Medical University of Lódz, Przychodnia Lekarska NZOZ KOMED and 7 more.
Type: Clinical Trial, Phase II | Journal: Breast (Edinburgh, Scotland) | Year: 2015
Lapatinib plus capecitabine (lap+cap) is approved as treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC), who have progressed on prior trastuzumab in the metastatic setting. We previously reported progression-free survival (PFS), overall survival (OS) and safety results from this open-label, multicentre, phase II study (VITAL; NCT01013740) conducted in women with HER2 positive MBC, to evaluate the efficacy and safety of lap plus vinorelbine (lap+vin), an important chemotherapy option for MBC, compared with lap+cap. In total, 112 patients were randomised 2:1 to treatment with lap+vin (N = 75) or lap+cap (N = 37). Results showed that the median PFS (primary endpoint) and OS (secondary endpoint) post-randomisation were comparable between treatment arms, with no new safety signals detected. Here, we assessed the final OS in this study at 40 months post-randomisation. At the time of final analyses, 24 (32%) patients were ongoing in the lap+vin arm, compared with 14 (38%) patients in the lap+cap arm (92% in both arms had discontinued treatment). Median OS in the lap+vin arm was 23.3 months (95% confidence intervals [CI]: 18.5, 31.1), compared with 20.3 months (95% CI: 16.4, 31.8) in the lap+cap arm. The median follow-up in the lap+vin arm was 18.86 months (95% CI: 10.68, 26.02), compared with 19.38 (95% CI: 25.56) months in the lap+cap arm. Similar rates of death (56-57%) were observed in both arms. The final OS was consistent with the previously reported data and suggest that lap+vin offers an effective treatment option for women with HER2-positive MBC.
Cardoso F.,Champalimaud Cancer Center |
Bischoff J.,Otto Von Guericke University of Magdeburg |
Brain E.,Hopital Rene Huguenin Institute Curie |
Brain E.,HopitalReneHuguenin Institute Curie |
And 6 more authors.
Cancer Treatment Reviews | Year: 2013
Endocrine therapy is the corner stone treatment for postmenopausal women with hormone receptor-positive metastatic breast cancer (MBC). Besides tamoxifen and many older agents, recently developed endocrine agents for the treatment of MBC include the third generation aromatase inhibitors (AI) - anastrozole, exemestane, letrozole - and the pure oestrogen receptor antagonist fulvestrant. As treatment of breast cancer evolves, both tamoxifen and the AIs are being increasingly used in the adjuvant setting. As such, a significant proportion of patients with hormone receptor-positive MBC will have previously received tamoxifen, an AI or both, as adjuvant treatment. This has changed the metastatic landscape and has an impact on treatment choices for patients with hormone receptor-positive MBC. In this review, we evaluate the available evidence supporting the use of endocrine therapy for the treatment of hormone receptor-positive MBC. Additionally, we consider the effect of prior adjuvant therapy on treatment choice in the metastatic setting and the optimal treatment sequence. Finally, we discuss endocrine-responsive HER2 positive tumours and the ongoing research initiatives which aim to improve outcomes for patients with MBC. © 2012 Elsevier Ltd.
Intensive chemotherapy with thiotepa, busulfan and cyclophosphamide and hematopoietic stem cell rescue in relapsed or refractory primary central nervous system lymphoma and intraocular lymphoma: A retrospective study of 79 cases
Soussain C.,Institute Curie |
Choquet S.,University Pitie Salpetriere |
Fourme E.,Hopital Rene Huguenin Institute Curie |
Delgadillo D.,Center Hospitalier University Pitie Salpetriere |
And 10 more authors.
Haematologica | Year: 2012
Background Relapsing primary central nervous system lymphoma carries a poor prognosis when treated with conventional chemotherapy with a one-year overall survival of 25-40%. Encouraging results have been shown with intensive chemotherapy followed by autologous hematopoietic stem cell rescue. We report the results of a large multicenter retrospective analysis of intensive chemotherapy followed by hematopoietic stem cell rescue in immunocompetent adult patients with primary central nervous system lymphoma or intraocular lymphoma after the failure of high-dose methotrexate-based treatment. Design and Methods Patients were included if they received intensive chemotherapy with a combination of thiotepa, busulfan and cyclophosphamide. Seventy-nine patients (median age 52.4 years, range 23-67 years) were identified. All of the patients except 5 received a salvage treatment after the failure of high-dose methotrexate. After salvage treatment and just before intensive chemotherapy followed by hematopoietic stem cell rescue, 32 patients were in complete response, 26 patients were in partial response, 2 patients had stable disease and 19 patients had progressive disease. Results With a median follow up of 56 months, the 5-year overall survival probability was 51% in the whole population and 62% among patients who were chemosensitive to the salvage treatment. The 5-year event-free survival probability was 37.8% in the whole population and 43.7% in the chemosensitive subpopulation. Neurocognitive assessments in a subset of patients suggest no evidence of intensive chemotherapy-induced neurocognitive decline. Conclusions Thiotepa, busulfan and cyclophosphamide-based intensive chemotherapy is an effective treatment for refractory and recurrent primary central nervous system lymphoma in chemosensitive patients up to 65 years of age. The role of intensive chemotherapy followed by hematopoietic stem cell rescue in chemorefractory patients needs to be more accurately defined. ©2012 Ferrata Storti Foundation.
PubMed | Hopital Rene Huguenin Institute Curie, Kantar Health, Center Leon Berard, Clinique de LUnion and 2 more.
Type: Journal Article | Journal: Bulletin du cancer | Year: 2015
Three thousand eight hundred and twelve patients participated in the TemporELLES survey; these patients were treated for breast cancer with intravenous chemotherapy in 105 different outpatient clinics in France. The survey shows that patients spend on average 3hours in the outpatient clinic per chemotherapy session, which includes on average 50minutes of waiting time. Forty percent of patients would like to reduce this waiting time. Availability of new dosage forms and ready to use medications will address the need for reduced waiting time while freeing up time for providing support to the patients.
Weiswald L.-B.,University of Paris Descartes |
Guinebretiere J.-M.,Institute Curie |
Richon S.,University of Paris Descartes |
Bellet D.,University of Paris Descartes |
And 3 more authors.
BMC Cancer | Year: 2010
Background: Multicellular tumour sphere models have been shown to closely mimic phenotype characteristics of in vivo solid tumours, or to allow in vitro propagation of cancer stem cells (CSCs). CSCs are usually characterized by the expression of specific membrane markers using flow cytometry (FC) after enzymatic dissociation. Consequently, the spatial location of positive cells within spheres is not documented. Confocal microscopy is the best technique for the imaging of thick biological specimens after multi-labelling but suffers from poor antibody penetration. Thus, we describe here a new protocol for in situ confocal imaging of protein expression in intact spheroids.Methods: Protein expression in whole spheroids (150 μm in diameter) from two human colon cancer cell lines, HT29 and CT320X6, has been investigated with confocal immunostaining, then compared with profiles obtained through paraffin immunohistochemistry (pIHC) and FC. Target antigens, relevant for colon cancer and with different expression patterns, have been studied.Results: We first demonstrate that our procedure overcomes the well-known problem of antibody penetration in compact structures by performing immunostaining of EpCAM, a membrane protein expressed by all cells within our spheroids. EpCAM expression is detected in all cells, even the deepest ones. Likewise, antibody access is confirmed with CK20 and CD44 immunostaining. Confocal imaging shows that 100% of cells express β-catenin, mainly present in the plasma membrane with also cytoplasmic and nuclear staining, in agreement with FC and pIHC data. pIHC and confocal imaging show similar CA 19-9 cytoplasmic and membranar expression profile in a cell subpopulation. CA 19-9+cell count confirms confocal imaging as a highly sensitive method (75%, 62% and 51%, for FC, confocal imaging and pIHC, respectively). Finally, confocal imaging reveals that the weak expression of CD133, a putative colon CSC marker, is restricted to the luminal cell surface of colorectal cancer acini, with CD133+cellular debris into glandular lumina.Conclusion: The present protocol enables in situ visualization of protein expression in compact three-dimensional models by whole mount confocal imaging, allowing the accurate localization and quantification of cells expressing specific markers. It should prove useful to study rare events like CSCs within tumour spheres. © 2010 Weiswald et al; licensee BioMed Central Ltd.