Breast Cancer Group

Villejuif, France

Breast Cancer Group

Villejuif, France
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Esteve-Puig R.,Hospital Universitari Vall dHebron | Esteve-Puig R.,University of California at San Francisco | Gil R.,Hospital Universitari Vall dHebron | Gonzalez-Sanchez E.,Hospital Universitari Vall dHebron | And 15 more authors.
PLoS Genetics | Year: 2014

Exposure to ultraviolet (UV) radiation from sunlight accounts for 90% of the symptoms of premature skin aging and skin cancer. The tumor suppressor serine-threonine kinase LKB1 is mutated in Peutz-Jeghers syndrome and in a spectrum of epithelial cancers whose etiology suggests a cooperation with environmental insults. Here we analyzed the role of LKB1 in a UV-dependent mouse skin cancer model and show that LKB1 haploinsufficiency is enough to impede UVB-induced DNA damage repair, contributing to tumor development driven by aberrant growth factor signaling. We demonstrate that LKB1 and its downstream kinase NUAK1 bind to CDKN1A. In response to UVB irradiation, LKB1 together with NUAK1 phosphorylates CDKN1A regulating the DNA damage response. Upon UVB treatment, LKB1 or NUAK1 deficiency results in CDKN1A accumulation, impaired DNA repair and resistance to apoptosis. Importantly, analysis of human tumor samples suggests that LKB1 mutational status could be a prognostic risk factor for UV-induced skin cancer. Altogether, our results identify LKB1 as a DNA damage sensor protein regulating skin UV-induced DNA damage response. © 2014 Esteve-Puig et al.


PubMed | Complutense University of Madrid, Institute Of Cancerologie Of Louest, Petrov Research Institute of Oncology, Centro Oncologico Of Galicia and 12 more.
Type: | Journal: Annals of oncology : official journal of the European Society for Medical Oncology | Year: 2016

Phosphatidylinositol 3-kinase (PI3K) pathway activation in preclinical models of breast cancer is associated with tumor growth and resistance to anticancer therapies, including paclitaxel. Effects of the pan-Class I PI3K inhibitor buparlisib (BKM120) appear synergistic with paclitaxel in preclinical and clinical models.BELLE-4 was a 1:1 randomized, double-blind, placebo-controlled, adaptive phase II/III study investigating the combination of buparlisib or placebo with paclitaxel in women with human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer with no prior chemotherapy for advanced disease. Patients were stratified by PI3K pathway activation and hormone receptor status. The primary endpoint was progression-free survival (PFS) in the full and PI3K pathway-activated populations. An adaptive interim analysis was planned following the phase II part of the study, after 125 PFS events had occurred in the full population, to decide whether the study would enter phase III (in the full or PI3K pathway-activated population) or be stopped for futility.As of August 2014, 416 patients were randomized to receive buparlisib (207) or placebo (209) with paclitaxel. At adaptive interim analysis, there was no improvement in PFS with buparlisib versus placebo in the full (median PFS 8.0 vs 9.2 months, hazard ratio [HR] 1.18), or PI3K pathway-activated population (median PFS 9.1 vs 9.2 months, HR 1.17). The study met protocol-specified criteria for futility in both populations, and phase III was not initiated. Median duration of study treatment exposure was 3.5 months in the buparlisib arm versus 4.6 months in the placebo arm. The most frequent adverse events with buparlisib plus paclitaxel (40% of patients) were diarrhea, alopecia, rash, nausea, and hyperglycemia.Addition of buparlisib to paclitaxel did not improve PFS in the full or PI3K pathway-activated study population. Consequently, the trial was stopped for futility at the end of phase II.


News Article | September 22, 2016
Site: www.techtimes.com

Ticked Off! Here's What You Need To Know About Lyme Disease A survey carried out by the UK Breast Cancer Group (UKBCG) has revealed that just a quarter of breast cancer oncologists in the UK are able to prescribe bisphosphonates to women with the condition due to lack of guidance from the National Health Service (NHS). If at least 35,700 women are diagnosed with primary breast cancer every year, and just a quarter of the eligible patients are receiving the drug, that leaves out almost 27,000 women from being provided with affordable yet effective breast cancer treatment. Bisphosphonates were originally prescribed to strengthen the bones of those who have osteoporosis and those who have cancers that have spread to the bone. But the drug was shown by meta-analyses in July 2015 to be also effective at reducing the likelihood of breast cancer spreading in the body, where it becomes harder to treat. Taken by post-menopausal women with primary breast cancer, the cancer treatment can lead not only to a reduced risk in the cancer spreading, from 21.2 percent down to 17.9 percent, but also reduced risks of death from the disease, from 18 percent to 14.7 percent within a 10-year period. Additionally, if bisphosphonates are administered routinely to all women eligible in the UK, an additional 1,180 breast cancer deaths could be prevented each year. That's one in every 10 deaths attributed to the cancer! At what cost? On average, just 43p ($0.56) a day, including consultations and what it would cost to monitor a patient for potential side effects. Unfortunately, without clear guidance on who will be funding the prescriptions, breast cancer oncologists have not been able to prescribe bisphosphonates to their patients, no matter how effective the drug is as a treatment. "While bisphosphonates are not routinely available to all eligible breast cancer patients, women's lives are needlessly being put to at risk," said Baroness Delyth Morgan, Breast Cancer Now chief executive. Breast Cancer Now got in touch with NHS England back in March seeking funding clarifications but has not yet been provided with a response. Armed with results from the UKBCG, however, the charity is renewing its call on NHS England to make a decision on who should be tasked with funding bisphosphonates for UK women with breast cancer. It is estimated that it would cost the NHS nearly £17 million ($22 million) to administer the affordable cancer drug annually to eligible patients. However, these costs could be offset by short- and long-term savings, allowing the agency to pocket almost £5 million ($6.5 million) over 10 years for every year breast cancer patients are treated. © 2017 Tech Times, All rights reserved. Do not reproduce without permission.


Raphael J.,Breast Cancer Group | Mazouni C.,Breast Cancer Group | Caron O.,Breast Cancer Group | Ferchiou M.,Breast Cancer Group | Delaloge S.,Breast Cancer Group
Medical Oncology | Year: 2014

BRCA2 mutation carriers typically develop luminal B breast cancers. Data on the effectiveness of neoadjuvant chemotherapy in these patients are limited because of small patient numbers and lack of prospective studies. We used our 15-year genetic clinic database to compare retrospectively the pathological complete response rates (pCR) and rates of post-chemotherapy nodal involvement among BRCA2 carriers and BRCA1/2-negative (WT) patients with luminal B tumours, all treated with neoadjuvant anthracyclines ± taxanes-based chemotherapy. Twenty-nine BRCA2 carriers and 67 WT patients fulfilled the inclusion criteria and were analysed. Patients and treatment characteristics were represented. A pCR occurred in 3 (10 %) BRCA2 patients and 13 (19 %) WT patients (p = 0.43). Twenty (69 %) BRCA2 carriers and 34 (51 %) WT patients remained node-positive at surgery (p = 0.17). BRCA2 germline mutations are associated with a low probability of pCR and a high risk of axillary invasion. Alternative treatments are highly expected, and clinical trials are needed to set the best treatment regimen in this population. © 2014 Springer Science+Business Media New York.


Communal L.,University of Paris Descartes | Vilasco M.,University of Paris Descartes | Hugon-Rodin J.,University of Paris Descartes | Courtin A.,University of Paris Descartes | And 11 more authors.
Oncotarget | Year: 2016

Women with inherited BRCA1 mutations have an elevated risk (40-80%) for developing breast and ovarian cancers. Reproductive history has been reported to alter this risk, suggesting a relationship between ovarian hormone signaling and BRCA1-related tumor development. BRCA1 interactions with estrogen receptor (ER) and progesterone receptor (PR) signaling were previously described in human breast cancer cell lines and mouse models. However, few studies have examined the effect of ovarian hormone regulation in normal human breast tissues bearing a heterozygous BRCA1 mutation. This study compares the proliferation level (Ki67) and the expression of ER, PR, and of the PR target gene, fatty acid synthase (FASN), in histologically normal breast tissues from women with BRCA1 mutations (BRCA1+/mut, n=23) or without BRCA1 mutations (BRCA1+/+, n=28). BRCA1+/mut tissues showed an increased proliferation and impaired hormone receptor expression with a marked loss of the PR isoform, PR-B. Responses to estradiol and progesterone treatments in BRCA1+/mut and BRCA1+/+ breast tissues were studied in a mouse xenograft model, and showed that PR and FASN expression were deregulated in BRCA1+/mut breast tissues. Progesterone added to estradiol treatment increased the proliferation in a subset of BRCA1+/mut breast tissues. The PR inhibitor, ulipristal acetate (UPA), was able to reverse this aberrant progesterone-induced proliferation. This study suggests that a subset of women with BRCA1 mutations could be candidates for a UPA treatment as a preventive breast cancer strategy.


PubMed | Montpellier University, CNRS Gustave Roussy Institute, Center Oscar Lambret, Breast Cancer Group and 4 more.
Type: Journal Article | Journal: Oncotarget | Year: 2016

Women with inherited BRCA1 mutations have an elevated risk (40-80%) for developing breast and ovarian cancers. Reproductive history has been reported to alter this risk, suggesting a relationship between ovarian hormone signaling and BRCA1-related tumor development. BRCA1 interactions with estrogen receptor (ER) and progesterone receptor (PR) signaling were previously described in human breast cancer cell lines and mouse models. However, few studies have examined the effect of ovarian hormone regulation in normal human breast tissues bearing a heterozygous BRCA1 mutation. This study compares the proliferation level (Ki67) and the expression of ER, PR, and of the PR target gene, fatty acid synthase (FASN), in histologically normal breast tissues from women with BRCA1 mutations (BRCA1+/mut, n=23) or without BRCA1 mutations (BRCA1+/+, n=28). BRCA1+/mut tissues showed an increased proliferation and impaired hormone receptor expression with a marked loss of the PR isoform, PR-B. Responses to estradiol and progesterone treatments in BRCA1+/mut and BRCA1+/+ breast tissues were studied in a mouse xenograft model, and showed that PR and FASN expression were deregulated in BRCA1+/mut breast tissues. Progesterone added to estradiol treatment increased the proliferation in a subset of BRCA1+/mut breast tissues. The PR inhibitor, ulipristal acetate (UPA), was able to reverse this aberrant progesterone-induced proliferation. This study suggests that a subset of women with BRCA1 mutations could be candidates for a UPA treatment as a preventive breast cancer strategy.

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