[Show abstract][Hide abstract] ABSTRACT: Microarray studies identified a subgroup of molecular apocrine tumors (estrogen receptor [ER] negative/androgen receptor [AR] positive) that express luminal genes including FOXA1. FOXA1 may direct AR to sites normally occupied by ER in luminal tumors, inducing an estrogen-like gene program that stimulated proliferation.
Expression of AR and FOXA1 was evaluated by immunohistochemistry in 592 patients with nonmetastatic triple-negative breast cancer (TNBC).
Coexpression of AR and FOXA1 was found in 15.2% of patients. These tumors were more frequently lobular, found in older patients and exhibited a lower nuclear grade and a greater degree of node involvement. They less often exhibited lymphocytic infiltrate, pushing margins, syncytial architecture, central fibrosis or necrosis.
TNBC with coexpression of AR and FOXA1 seems to behave like luminal tumors with a morphological profile distinct from other TNBC. These biomarkers could be useful to identify a subgroup of TNBC and could have future therapeutic implications.
[Show abstract][Hide abstract] ABSTRACT: Metastatic breast cancer (MBC) is an incurable disease and represents a complex therapeutic challenge for oncologists. Despite the possibility of prescribing new agents such as tailored therapy, cytotoxic chemotherapy and hormone therapy remain the major treatments for MBC. Several lines of chemotherapy can be proposed for these patients, but beyond the second-line, evidence of effectiveness is lacking and such treatment has important associated toxicity affecting quality of life (QoL). Prospective data on third-line chemotherapy is very poor. There is no recent retrospective data and it mainly includes single-centre experiences. Moreover, prognostic parameters considered in these retrospective studies are limited to clinico-pathological factors. Previous reports don't evaluate prognostic impact of circulating tumour cells (CTC) and baseline QoL. METAL3 METAstatic Line 3 is a prospective, multicentric trial designed to prospectively construct a prognostic score (including selected clinico-pathological factors, CTC and baseline QoL) to identify patients who benefit from third-line chemotherapy for MBC in terms of overall survival (training cohort). Score will then be validated with another cohort (validation cohort). The aim of this paper is to review literature data on third-line chemotherapy for MBC and to describe in detail our prospective study. We hope that this prognostic score could be used by physicians to develop new therapeutic strategies when there will be limited benefit of third-line chemotherapy; this score will also help to improve patient information on their outcome.
[Show abstract][Hide abstract] ABSTRACT: IntroductionTriple Negative Breast Cancers (TNBC) represent about 12% to 20% of all breast cancers (BC) and have a worse outcome compared to other BC subtypes. TNBC often show a deficiency in DNA double-strand break repair mechanisms. This is generally related to the inactivation of a repair enzymatic complex involving BRCA1 caused either by genetic mutations, epigenetic modifications or by post-transcriptional regulations.The identification of new molecular biomarkers that would allow the rapid identification of BC presenting a BRCA1 deficiency could be useful to select patients who could benefit from PARP inhibitors, alkylating agents or platinum-based chemotherapy.Methods
Genomic DNA from 131 formalin-fixed paraffin-embedded (FFPE) tumors (luminal A and B, HER2+ and triple negative BC) with known BRCA1 mutation status or unscreened for BRCA1 mutation were analysed by array Comparative Genomic Hybridization (array CGH). One highly significant and recurrent gain in the 17q25.3 genomic region was analysed by fluorescent in situ hybridization (FISH). Expression of the genes of the 17q25.3 amplicon was studied using customized Taqman low density arrays and single Taqman assays (Applied Biosystems).ResultsWe identified by array CGH and confirmed by FISH a gain in the 17q25.3 genomic region in 90% of the BRCA1 mutated tumors. This chromosomal gain was present in only 28.6% of the BRCA1 non-mutated TNBC, 26.7% of the unscreened TNBC, 13.6% of the luminal B, 19.0% of the HER2+ and 0% of the luminal A breast cancers. The 17q25.3 gain was also detected in 50% of the TNBC with BRCA1 promoter methylation. Interestingly, BRCA1 promoter methylation was never detected in BRCA1 mutated BC. Gene expression analyses of the 17q25.3 sub-region showed a significant over-expression of 17 genes in BRCA1 mutated TNBC (n¿=¿15) as compared to the BRCA1 non mutated TNBC (n¿=¿13).Conclusions
In this study, we have identified by array CGH and confirmed by FISH a recurrent gain in 17q25.3 significantly associated to BRCA1 mutated TNBC. Up-regulated genes in the 17q25.3 amplicon might represent potential therapeutic targets and warrant further investigation.
Breast cancer research: BCR 11/2014; 16(6):466. DOI:10.1186/s13058-014-0466-y · 5.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A selective and accurate analytical method is needed to quantify tamoxifen and its phase I metabolites in a prospective clinical protocol, for evaluation of pharmacokinetic parameters of tamoxifen and its metabolites in adjuvant treatment of breast cancer. The selectivity of the analytical method is a fundamental criteria to allow the quantification of the main active metabolites (Z)-isomers from (Z)'-isomers. An UPLC-MS/MS method was developed and validated for the quantification of (Z)-tamoxifen, (Z)-endoxifen, (E)-endoxifen, Z'-endoxifen, (Z)'-endoxifen, (Z)-4-hydroxytamoxifen, (Z)-4'-hydroxytamoxifen, N-desmethyl tamoxifen, and tamoxifen-N-oxide. The validation range was set between 0.5ng/mL and 125ng/mL for 4-hydroxytamoxifen and endoxifen isomers, and between 12.5ng/mL and 300ng/mL for tamoxifen, tamoxifen N-desmethyl and tamoxifen-N-oxide. The application to patient plasma samples was performed.
Journal of Pharmaceutical and Biomedical Analysis 08/2014; 100C:254-261. DOI:10.1016/j.jpba.2014.07.033 · 2.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Despite high initial sensitivity to chemotherapy, triple-negative breast cancer (TNBC) is associated with a poor prognosis, highlighting the need for novel therapeutic strategies. The aim of this multicenter, randomized, open-label phase II trial was to assess the efficacy of ixabepilone as monotherapy, and the combination of ixabepilone plus cetuximab, as first-line treatment in patients with TN locally advanced non-resectable and/or metastatic breast cancer.
Patients and Methods
Women were randomly assigned to receive either ixabepilone (40 mg/m2) every 21 days (n = 40), or ixabepilone (40 mg/m2) every 21 days plus cetuximab (400 mg/m2 loading dose, followed by 250 mg/m2) once weekly (n = 39). The primary endpoint of the trial was to estimate the response rates of ixabepilone monotherapy and ixabepilone plus cetuximab combination therapy.
Of 79 randomized patients, 77 were treated. Based on an intent-to-treat analysis, an objective response rate of 30% (95% confidence interval [CI], 16.6, 46.5) was observed in the monotherapy arm, and 35.9% (95% CI, 21.2, 52.8) in the combination arm. Median progression-free survival was 4.1 months in both treatment groups. Safety findings were consistent with the known individual toxicity profiles of ixabepilone and cetuximab. Skin and subcutaneous tissue disorders were more common with combination therapy, as were discontinuations due to adverse events.
Ixabepilone monotherapy and the ixabepilone and cetuximab combination demonstrated similar levels of clinical activity in first-line treatment of advanced TNBC, with a predictable safety profile. Further investigation of novel therapies for TNBC is required in order to improve patient outcomes.
Clinical Breast Cancer 08/2014; 15(1). DOI:10.1016/j.clbc.2014.07.007 · 2.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Treatment of HER2-positive metastatic breast cancer with ado-trastuzumab emtansine (T-DM1), a novel antibody-drug conjugate, has resulted in both improved progression-free and overall survival. Recognition and treatment of diverse adverse events related to T-DM1 is critical for safety and tolerability. The most frequent adverse events with T-DM1 include fatigue, diarrhea, anemia, elevated transaminases, and mild-to-moderate hemorrhagic events, which are thought to be related to induced thrombocytopenia. Here, we present five case series of cutaneous and mucosal telangiectasias, definitely related to T-DM1. The development of telangiectasias represents a newly recognized adverse effect of T-DM1. We provide description and timing of the telangiectasias and review the mechanisms that may explain the formation of these vascular lesions in association with T-DM1. Further, we describe associated bleeding events and propose that induced telangiectasias could represent an additional cause of T-DM1-associated hemorrhage.
Breast Cancer Research and Treatment 06/2014; 146(2). DOI:10.1007/s10549-014-3001-z · 4.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To examine the association between baseline body mass index (BMI), and disease-free survival (DFS) and overall survival (OS) in a large French early-stage breast cancer population included in the UNICANCER Programme d'Action Concerté Sein-01 (PACS01) and PACS04 phase III randomised trials.
After a median follow-up of 5.9years, this report analyses 4996 patients with node-positive breast cancer, and randomly assigned to adjuvant anthracycline-based chemotherapy combined or not with taxanes. Univariate analyses were used to study the effects of well known prognostic factors and BMI on DFS and OS. BMI was obtained at baseline, before chemotherapy initiation, and obesity was defined as a BMI⩾30kg/m(2). Cox proportional hazards regression models were secondly used to assess the influence of BMI after adjusting for other factors. Exhaustive analysis of the dose intensity delivered was also studied for comparison between obese and non-obese patients.
Obese patients initially present with more advanced disease at diagnosis compared to non-obese patients. By univariate analysis, obesity was moderately associated with poorer DFS (hazard ratio (HR)=1.18 [1.01-1.39] P=0.04), but mostly with poorer OS (HR=1.38 [1.13-1.69] P=0.002). Delivered dose intensity of anthracyclines and taxanes was not significantly different between obese and non-obese patients. After adjustment for disease characteristics, BMI had no influence either on DFS or OS.
This report suggests that in a French population, obesity has no impact on breast cancer prognosis when modern adjuvant chemotherapy, at the appropriate dose intensity, is delivered.
European journal of cancer (Oxford, England: 1990) 12/2013; 50(3). DOI:10.1016/j.ejca.2013.11.013 · 4.82 Impact Factor