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Marquez-Rodas I.,Servicio de Oncologia Medica | Solis R.M.,Servicio de Oncologia Medica | Cobo S.L.-T.,Servicio de Oncologia Medica | MartIn M.,Servicio de Oncologia Medica | MartIn M.,Spanish Breast Cancer Research Group GEICAM
European journal of Clinical and Medical Oncology | Year: 2012

Genetic background is an important determinant of the etiology of breast cancer and varies between subtle changes in risk caused by common genetic variants and high-risk susceptibility genes such as BRCA1 and BRCA2. We present an updated overview of the most important molecular and clinical features of the genes involved in breast cancer. We focus on the well-known BRCA1 and BRCA2 genes and on the management of patients in terms of risk assessment, screening, prevention, and emerging therapies based on BRCA molecular pathology. We also address other recently discovered susceptibility genes (eg, CHEK2, RAD51C, PALB2, and BRIP1) and other hereditary syndromes in which breast cancer frequently appears such as Li-Fraumeni Syndrome, Cowden Syndrome, Peutz Jeghers Syndrome, hereditary diffuse gastric cancer, and Lynch Syndrome. Finally, we briefly analyze the new concept of high-prevalence-low-penetrance genetic variants, which has arisen from genome-wide associated studies.

Ocana A.,University of Toronto | Ocana A.,Hospital Universitario Of Albacete | Amir E.,University of Toronto | Seruga B.,Institute of Oncology Ljubljana | And 3 more authors.
Cancer Treatment Reviews | Year: 2013

Dysfunction of protein kinases has been associated with the development of the various molecular subtypes of breast cancer. The best example is the known role of HER2 in the tumorigenesis of a proportion of breast tumors. In this article, we review the state of the art knowledge on protein kinases involved in breast cancer. Special attention is given to those that are potentially druggable and those for which targeted agents are currently under clinical evaluation. Options for targeted drug combinations will be discussed, as well as the optimal way to integrate new kinase inhibitors in the clinical armamentarium to fight breast cancer. We will review recent results from clinical studies with agents targeting different kinases involved in the pathophysiology of breast cancer. In addition, we will evaluate the clinical development of kinase inhibitors to identify areas of knowledge that could be explored in future preclinical and clinical studies. © 2012 Elsevier Ltd.

Martin M.,University Complutente Of Madrid | Brase J.C.,Sividon Diagnostics | Ruiz A.,Valencian Institute of Oncology IVO | Prat A.,Vall dHebron Institute of Oncology VHIO | And 14 more authors.
Breast Cancer Research and Treatment | Year: 2016

There are several prognostic multigene-based tests for managing breast cancer (BC), but limited data comparing them in the same cohort. We compared the prognostic performance of the EndoPredict (EP) test (standardized for pathology laboratory) with the research-based PAM50 non-standardized qRT-PCR assay in node-positive estrogen receptor-positive (ER+) and HER2-negative (HER2−) BC patients receiving adjuvant chemotherapy followed by endocrine therapy (ET) in the GEICAM/9906 trial. EP and PAM50 risk of recurrence (ROR) scores [based on subtype (ROR-S) and on subtype and proliferation (ROR-P)] were compared in 536 ER+/HER2− patients. Scores combined with clinical information were evaluated: ROR-T (ROR-S, tumor size), ROR-PT (ROR-P, tumor size), and EPclin (EP, tumor size, nodal status). Patients were assigned to risk-categories according to prespecified cutoffs. Distant metastasis-free survival (MFS) was analyzed by Kaplan–Meier. ROR-S, ROR-P, and EP scores identified a low-risk group with a relative better outcome (10-year MFS: ROR-S 87 %; ROR-P 89 %; EP 93 %). There was no significant difference between tests. Predictors including clinical information showed superior prognostic performance compared to molecular scores alone (10-year MFS, low-risk group: ROR-T 88 %; ROR-PT 92 %; EPclin 100 %). The EPclin-based risk stratification achieved a significantly improved prediction of MFS compared to ROR-T, but not ROR-PT. All signatures added prognostic information to common clinical parameters. EPclin provided independent prognostic information beyond ROR-T and ROR-PT. ROR and EP can reliably predict risk of distant metastasis in node-positive ER+/HER2− BC patients treated with chemotherapy and ET. Addition of clinical parameters into risk scores improves their prognostic ability. © 2016 The Author(s)

Amadori D.,Romagnolo Scientific Institute for the Study and Treatment of Cancer I.R.S.T. S.r.l. | Carrasco E.,Spanish Breast Cancer Research Group GEICAM | Roesel S.,Gutersloh Oncology Practice | Labianca R.,Riuniti Hospital | And 6 more authors.
International Journal of Oncology | Year: 2013

Pemetrexed-carboplatin and gemcitabine vinorelbine combination therapies were efficacious in phase II and phase III studies as first-line breast cancer treatment. Thus, Arm A and Arm B combinations were investigated in patients pretreated with anthracycline and taxanes. Women with advanced breast cancer, with ≥1 measurable lesion per RECIST, were stratified by line of treatment (1st, 2nd), visceral disease (yes/no), ECOG PS (0-1 vs. 2) and randomized 1:1 to Arm A (pemetrexed 600 mg/m2, D1 i.v. q21; carboplatin, AUC 5, D1 i.v. q21) or Arm B (gemcitabine 1,200 mg/m2 D1, D8 i.v. q21; vinorelbine 30 mg/m2 D1, D8 i.v. q21). Treatment continued until progression. The primary endpoint was objective response rate (RR). Secondary endpoints were duration of response (DoR), time-to-response (TTR), time-to-progressive disease (TTPD), time-to-treatment failure (TTTF) and safety. A two-stage design was employed independently for each arm. Of 135 randomized patients, 125 (Arm A, n=64; Arm B, n=61) qualified for tumor-response analysis. The mean (standard deviation) number of cycles administered was 6.3 (4.13) in Arm A and 6.2 (4.39) in Arm B. Efficacy in Arm A and Arm B were: RR (95% CI), 26.6 (16.3-39.1) and 29.5 (18.5-42.6); time-to-events (months), DoR 7.7 and 7.5; TTPD, 5.1 and 5.6; TTR, 1.8 and 1.8; TTTF, 4.8 and 5.1; respectively. Most common grade 3/4 adverse events possibly related to study-drug were neutropenia, thrombocytopenia, anemia and leucopenia in Arm A and neutropenia, leucopenia and fatigue in Arm B. In this study, both combinations showed moderate activity as predefined RR was not reached and were well tolerated.

Llombart-Cussac A.,Hospital Universitario Arnau Of Vilanova | Ruiz A.,Polytechnic University of Valencia | Anton A.,University of Zaragoza | Barnadas A.,Medical Oncology Service | And 10 more authors.
Cancer | Year: 2012

BACKGROUND: Several aromatase inhibitor studies have reported variations in the inhibitory potency of these agents that could lead to differences in clinical outcomes. In the current study, the authors formally evaluated the activity of anastrozole and exemestane in postmenopausal women with hormone-responsive, advanced breast cancer. METHODS: Postmenopausal women who had measurable disease according to Response Evaluation Criteria in Solid Tumors and had not received previous endocrine therapy for advanced breast cancer were randomized to receive either oral exemestane 25 mg daily or oral anastrozole 1 mg daily until they had disease progression. The primary endpoint was the objective response rate (ORR), and secondary endpoints included the clinical benefit rate (CBR), time to progression (TTP), overall survival, and safety. Crossover to the other aromatase inhibitor was permitted at the time of disease progression; ORR, CBR, and TTP after second-line treatment also were explored. RESULTS: In total, 103 patients were enrolled. The median patient age was 71.6 years, 52.4% of patients had visceral disease, and 75.8% of patients had ≥2 disease sites. Half of the patients had received previous tamoxifen, and 60% had received previous chemotherapy. The efficacy observed in the exemestane and anastrozole groups was an ORR of 36.2% and 46%, respectively; a CBR of 59.6% and 68%, respectively, and a TTP of 6.1 months and 12.1 months, respectively. At progression, 28 patients crossed over to the other aromatase inhibitor, including 16 patients who switched to exemestane (CBR, 43.7%; TTP, 4.4 months) and 12 patients who switched to anastrozole (CBR, 8.3%; TTP, 2 months). Both drugs were generally well tolerated, and no study drug-related serious adverse events were reported. CONCLUSIONS: In this phase 2 randomized trial, no significant differences in clinical activity were observed in favor of exemestane to justify a superiority phase 3 trial design in the first-line setting. Copyright © 2011 American Cancer Society.

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