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Prostate cancer (PCa) is the second most common cancer of men and is typically slow-growing and asymptomatic. The use of blood PSA as a screening method has greatly improved PCa diagnosis, but high levels of false positives has raised much interest in alternative biomarkers. We used next-generation sequencing (NGS) to elucidate the urinary transcriptome of whole urine collected from high-stage and low-stage PCa patients as well as from patients with the confounding diagnosis of benign hyperplasia (BPH). We identified and validated five differentially expressed protein-coding genes (FTH1 BRPF1, OSBP, PHC3, and UACA) in an independent validation cohort of small-volume (1 mL) centrifuged urine (n = 94) and non-centrifuged urine (n = 84) by droplet digital (dd)PCR. These biomarkers were able to discriminate between BPH and PCa patients and healthy controls using either centrifuged or non-centrifuged whole urine samples, suggesting that the urinary transcriptome is a valuable source of non-invasive biomarkers for PCa that warrants further investigation.

Background Interstitial lung disease (ILD) associated with Rheumatoid Arthritis (RA) has a poor prognosis. Treatments such as anti-TNF, have been implicated in the exacerbation of an ILD. Objectives Our objective is to evaluate and compare the evolution of ILD in patients with RA treated with Abatacept (ABA), Rituximab (RTX) and Tocilizumab (TCZ) after 1 year of treatment. Methods Retrospective multicentre study of patients with ILD and AR treated with ABA, RTX and TCZ at standard doses. The ILD was diagnosed by CT. The efficacy was evaluated whith the following measures: i) Dyspnea by modified scale of the Medical Research Council (mMRC); considering variations of 1 point. ii) Respiratory function tests; considering variations in FVC and DLCO ≥10%. iii) Imaging test (CT). Results We included 118 (72 women/46 men) patients, mean age of 62.27±10.55 years. The ILD had a median evolution of 12 12–37 months. The RA was ACPA+in 102 cases (86.4%). At diagnosis, the mean DLCO onset of biological treatment was 65.63±19.38. Table 1 shows the characteristics by subgroups. The Figure expresses the evolution in the cases available at 12 months. There is an improvement in CT in 36.4% of patients with ABA, 28.6% of patients with RTX and only 8.3% of patients with TCZ. Conclusions There seems to be a trend towards a better radiological response in patients treated with RTX and ABA. It would be necessary prospective studies. Disclosure of Interest None declared

The fatty acid (FA) composition of red blood cell (RBC) membrane phospholipids of cancer patients can reflect tumor status, dietary intakes, and cancer type or therapy. However, the characteristic membrane profiles have so far not yet defined as a potential biomarker to monitor disease evolution. The present work provides the first evidence of cancer metabolic signatures affecting cell membranes that are independent of nutritional habits. From the Oncology Outpatient Unit of the Onkologikoa hospital, two groups of cancer patients (n = 54) and healthy controls (n = 37) were recruited, and mature RBCs membrane phospholipids were analyzed for FA profiling (GC-MS). Dietary habits were evaluated using a validated food frequency questionnaire. The adjusted Analysis of Covariance Test (ANCOVA) model revealed cancer patients to have a lower relative percentage of saturated fatty acids (SFA) (C16:0 (5.7%), C18:0 (15.9%)), and higher monounsaturated fatty acids (MUFA) (9c-C18:1 (12.9%) and 11c-C18:1 (54.5%)), compared to controls. In line with this, we observe that the desaturase enzymatic index (delta-9 desaturase (&Delta, 9D), +28.3%) and the membrane saturation index (SI = SFA/MUFA, &minus, 27.3%) were similarly modulated. Polyunsaturated fatty acids (PUFA) families showed an increase of n-6 C18:2 and C20:3 (15.7% and 22.2% respectively), with no differences in n-6 C20:4 and n-3 PUFA (docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)). Importantly, these changes were found independent of foods and fat intakes from the diet. The membrane lipid profile in RBC was useful to ascertain the presence of two main metabolic signatures of increased desaturation activity and omega-6 in cancer patients, statistically independent from dietary habits.

Taste and smell changes are common side effects in cancer patients undergoing chemotherapy treatments (CT). This can lead to a reduced food enjoyment and an inadequate nutrient intake with a high impact on nutritional status and quality of life. The aim of this study was to evaluate the self-reported chemosensory alterations of patients undergoing chemotherapy according to CT type. An observational study was conducted with 151 patients undergoing CT at Oncology Outpatient Unit from Onkologikoa Foundation. An interviewer-assisted questionnaire was designed to investigate chemosensory changes in patients undergoing CT. Seventy-six percent patients reported taste disorders and 45% smell changes. Xerostomia is the most frequent symptom reported by patients receiving chemotherapy in our study (63.6%), and it is strongly associated to bad taste in mouth (OR = 5.96; CI = 2.37–14.94; p value = 0.000) and taste loss (OR = 5.96; CI = 2.37–14.94; p value = 0.000). Anthracyclines, paclitaxel, carboplatin, and docetaxel were the CT agents producing the highest taste disturbance rates. Cisplatin and 5-Fluorouracil are the CT resulting in the lowest complaints. Logistic regression revealed statistically significant associations between taste loss and carboplatin and docetaxel (OR = 3.50; CI = 1.12–10.90; p value = 0.031) and cold hypersensitivity and oxaliplatin (OR = 12.14; CI = 4.18–35.25; p value = 0.000). Not only platin-based CT such as carboplatin produced dysgeusia, but also anthracyclines and paclitaxel treatments. The better knowledge of taste and smell alterations according to CT type may provide valuable information for the design of new strategies to tackle CT side effects. It is important to take into account taste and smell dysfunctions and other alterations such as xerostomia together.

Guideline-based clinical decision support systems (CDSSs) are expected to improve the quality of care by providing best evidence-based recommendations. However, because clinical practice guidelines (CPGs) may be incomplete and often lag behind the publication time of very last scientific results, CDSSs may not provide up-to-date treatments. It happens that clinical decisions made for specific patients do not comply with CDSS recommendations, whereas they comply with the state of the art. They may also be non-compliant because they rely on some implicit knowledge not covered by CPGs. We propose to capitalize the clinical know-how built from such non-compliant decisions and allow physicians to use it in future similar cases by the development of a decisional event structure that allows the modelling, storage, processing, and reuse of all the information related to a decision-making process. This structure allows the analysis of non-compliant decisions, which generates new experience-based rules. These new rules augment the knowledge embedded in CPGs supporting clinician decision for specific patients poorly covered by CPGs. This work is applied to the management of breast cancer within the EU Horizon 2020 project DESIREE.

BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings. METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants. FINDINGS: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings.METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants.FINDINGS: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [INTERPRETATION: At the 5-year follow-up, 1 year of extended adjuvant therapy with neratinib, administered after chemotherapy and trastuzumab, significantly reduced the proportion of clinically relevant breast cancer relapses-ie, those that might lead to death, such as distant and locoregional relapses outside the preserved breast-without increasing the risk of long-term toxicity. An analysis of overall survival is planned after 248 events.FUNDING: Wyeth, Pfizer, and Puma Biotechnology.

// Alberto Ocana 1 , Marta Gil-Martin 2 , Miguel Martin 3 , Federico Rojo 4 , Silvia Antolin 5 , Angel Guerrero 6 , Jose Manuel Trigo 7 , Montse Munoz 8 , Atanasio Pandiella 9 , Nuria Gonzalo Diego 10 , Susana Bezares 11 , Rosalia Caballero 12 , Eva Carrasco 11 and Ander Urruticoechea 13 1 Department of Medical Oncology, Complejo Hospitalario Universitario de Albacete, Albacete, Spain 2 Department of Medical Oncology, Institut Catala d’Oncologia-IDIBELL, L’Hospitalet, Barcelona, Spain 3 Department of Medical Oncology, Instituto de Investigacion Sanitaria Gregorio Maranon, Universidad Complutense, Madrid, Spain 4 Fundacion Jimenez Diaz, Madrid, Spain 5 Department of Medical Oncology, Complejo Hospitalario Universitario A Coruna, La Coruna, Spain 6 Department of Medical Oncology, Instituto Valenciano de Oncologia, Valencia, Spain 7 Department of Medical Oncology, Hospital Clinico Universitario Virgen de la Victoria, Malaga, Spain 8 Department of Medical Oncology, Hospital Clinic i Provincial de Barcelona, Barcelona, Spain 9 Centro de Investigacion del Cancer and CIBERONC, CSIC-Universidad de Salamanca, Salamanca, Spain 10 Pharmacokinetics Laboratory, Farmacia ICO Metropolitana, IDIBELL, Instituto Catalan de Oncologia, Hospital Duran i Reynals, Barcelona, Spain 11 Scientific Department, GEICAM Spanish Breast Cancer Group, Spain 12 Translational Department, GEICAM Spanish Breast Cancer Group, Spain 13 Department of Medical Oncology, Fundacion Onkologikoa, Donostia, Gipuzkoa, Spain Correspondence to: Alberto Ocana, email: // Keywords : HER2 positive breast cancer, dasatinib, SRC kinase, trastuzumab resistance, metastatic breast cancer Received : March 04, 2017 Accepted : April 04, 2017 Published : April 14, 2017 Abstract The anti-HER2 antibody trastuzumab have shown clinical activity in combination with chemotherapy in different breast cancer settings. However, most of patients treated with this antibody progress after a period of treatment. Activation of the kinase SRC has been linked with resistance to trastuzumab in several preclinical studies. We designed a phase I clinical study to explore the activity of weekly trastuzumab (2 mg/kg) plus paclitaxel (80 mg/m 2 ) in combination with the anti-SRC kinase inhibitor Dasatinib in the first line treatment of HER2 metastatic breast cancer. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D); secondary objectives included efficacy, objective response rate (ORR), pharmacokinetics and pharmacodynamics. A “3+3” design guided dose escalation with two oral dose levels of dasatinib: 100mg (DL1) and 140 mg (DL2). 10 patients were included in the phase I part. Dasatinib 100 mg q.d. was established as the recommended RP2D. The median number of administered cycles was 12 (range, 1 to 18). Grade 3 treatment-related AEs at DL1 were diarrhea ( n = 2), hyponatremia ( n = 1), fatigue ( n = 1), and AST/ALT elevation ( n = 1). A significant reduction in p-SRC expression on epidermal keratinocytes on sequential skin biopsies was observed. In conclusion, we describe the feasibility of the combination of dasatinib, trastuzumab and paclitaxel, and its effect on proteins involved in trastuzumab resistance. The phase II part of this study is currently evaluating efficacy.

Introduction: Previous small-molecule antiangiogenics have compromised chemotherapy dose intensity in breast cancer. We present a phase I trial of a novel selective agent, nintedanib, plus standard chemotherapy in early breast cancer. Methods: Her-2-negative breast cancer patients with tumours larger than 2 cm were eligible for dose-escalation trial (classic 3+3 method). Results: The recommended phase II dose (RP2D) was 150 mg BID of nintedanib combined with standard dose of weekly paclitaxel followed by adriamycin plus cyclophosphamide. The dose-limiting toxicity was transaminase elevation. At the RP2D, the dose intensity was ∼100%. The pathologic complete response was 50%. Conclusions: The combination allows the delivery of full-dose intensity, while efficacy seems promising.

Resumen Objetivos La importancia de obtener margenes libres en la cirugia conservadora de mama es conocida. Sin embargo, no existe uniformidad a la hora de plantear una reescision, por ello desde el Grupo de Estudios Senologicos decidimos conocer la realidad de nuestro pais mediante una encuesta Material y metodo Se elaboro una encuesta en linea que constaba de 28 items distribuidos en 4 apartados: generalidades, informacion y decision peroperatoria, informacion y decision postoperatoria, y otros. Se envio a 87 centros de los que contestaron 55 (63,2%). Resultados En el 60% de los casos los margenes se examinan de forma intraoperatoria siempre y en el 22% de forma ocasional. El 58% entiende por margen proximo el margen inferior a 1 mm. Cuando la informacion de margen afecto, focalmente afecto o proximo a tumor es intraoperatoria, en la mayoria de los centros se opta por la ampliacion quirurgica. Si la informacion es postoperatoria, en caso de margen afecto o focalmente afecto se realiza una reescision en una amplio porcentaje de pacientes (70-100%) y si son proximos solo en el 18-29%. En caso de afectacion de margenes y no reescision quirurgica en el 50% de los casos se aumenta la dosis de radiacion. Conclusion Actualmente en nuestro medio, ante la afectacion de los margenes quirurgicos la decision mayoritaria es la reescision. Sin embargo, existe una variabilidad no despreciable en esta decision cuando la informacion es de proximidad del margen quirurgico.

BACKGROUND: The combination of a CDK4/6 inhibitor (palbociclib, abemaciclib, or ribociclib) with an aromatase inhibitor (AI) significantly reduces Ki67 compared to single-agent AI in the neoadjuvant setting, but the rates of pathological complete response (pCR) or residual cancer burden (RCB) 0-I remain modest. Despite this inadequate pathological downstaging, to date, there is no data about the efficacy of this treatment in terms of molecular downstaging detected by a more refined genomic signature than Ki67, such as the Oncotype DX Breast Recurrence Score® (RS) test. The aim of this trial is to validate the ability of neoadjuvant palbociclib plus letrozole to modify two initial intermediate or high RS tumor cohorts. TRIAL DESIGN: This is an international, multicenter, open-label, non-comparative, phase II trial. Main selection criteria include: (1) Pre- or post-menopausal women with treatment-naïve, centrally assessed, HR-positive/HER2-negative, Ki67 ≥ 20%, and stage II-IIIB breast cancer; (2) Pre-treatment RS result ≥ 18; (3) Patients agree to collect tissue samples at screening, at Cycle 1 Day 14 of treatment, and at surgery. Patients will be allocated, according to the pre-treatment RS result, either to Cohort A (RS 18-25) or Cohort B (RS 26-100) and will receive treatment with palbociclib (125 mg QD, 3/1 schedule) in combination with letrozole (2.5 mg QD, every 28-day cycle), ± LHRH analogs if pre-menopausal status, for 24 weeks. Definitive breast surgery will be performed within 7 days after completion of 6 treatment cycles. The primary objective of the study is to explore the ability of palbociclib in combination with letrozole to induce global molecular changes, measured by either the post-treatment RS result at surgery, or pCR. Secondary objectives include: (1) Concordance rate among post-treatment RS result and RCB, Ki67, and preoperative endocrine prognostic index (PEPI) score; (2) Overall response rate; (3) Safety-related outcome as per Common Terminology Criteria for Adverse Events v. 5.0. Patients will be accrued in a Simon’s two-stage design trial: optimal design in Cohort A and minimax design in Cohort B. With a unilateral type one error (alpha) set at 0.025 and a 0.8 power (type two error beta = 0.2), the required number of evaluable patients are 28. Considering a drop-out rate no lower than 10%, a sample size of 33 patients in each cohort will be needed. First Patient First Visit: Expected on April 2019. Citation Format: Antonio Llombart Cussac, José Pérez-García, Ángel Guerrero, Begoña Bermejo, Miguel Gil, Vicente Carañana, Serafín Morales, Juan de la Haba, María Fernández, Emilio Alba, Ander Urruticoechea, Lourdes Calvo, Mireia Margeli, Antonio Antón, Manuel Ruíz Borrego, Joan Albanell, Pedro Sánchez Rovira, Meritxell Bellet, Sofia Braga, Passos Coelho, Miguel Abreu, Javier Cortés. Neoadjuvant letrozole and palbociclib in stage II-IIIB HR[+]/HER2[-] breast cancer with Oncotype DX Recurrence Score® (RS) 18-25 or 26-100. Analysis of RS changes at surgery (DxCARTES trial) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT219.

Background: The PI3K/Akt/mTOR pathway is the most frequently activated signaling pathway in breast cancer (BC). Activation of this pathway promotes tumor growth and progression, and resistance to anticancer therapies, including paclitaxel (PTX). BEZ235 is an oral, ATP-competitive inhibitor that targets class l PI3K and downstream effectors mTORC1/2. BEZ235 has shown antiproliferative, proapoptotic, and antiangiogenic activity in multiple preclinical cancer models. In a Ph I study, single-agent BEZ235 given twice daily (BID) showed preliminary signs of clinical activity. Methods: This was a multicenter, open-label Ph Ib/II study of daily, oral BEZ235 given BID in combination with weekly (QW) intravenous PTX in women with HER2-, metastatic or locally advanced BC (NCT01495247). For the Ph Ib part, the primary objective was to determine the maximum tolerated dose (MTD)/recommended Ph II dose (RP2D) of BEZ235 in combination with PTX based on dose-limiting toxicities (DLTs) using a 5-parameter adaptive Bayesian logistic regression model with overdose control. MTD was defined as the highest dose not causing medically unacceptable DLTs in >35% of pts during Cycle 1 (28 days). Secondary objectives included safety, preliminary activity, and PK. Safety was monitored by physical exams, vital signs, laboratory tests, weight, and cardiac health. AEs were assessed continuously by CTCAE v4.03. Tumor evaluations were performed at screening and every 8 wks after starting treatment, and assessed locally by RECIST v1.1. Results: As of April 12, 2013, 18 pts (mean age: 50 yr; 67% ≥4 prior lines of antineoplastic therapy) had been enrolled into Ph Ib. 13 pts received BEZ235 200 mg BID + PTX 80 mg/m2 QW. The dose level was then reduced to BEZ235 100 mg BID + PTX 80 mg/m2 QW (n = 5). Of 17 evaluable pts (12 at the 200-mg BID dose; 5 at the 100-mg BID dose), 6 (35%) developed ≥1 DLTs (5 [42%] at the 200-mg BID dose; 1 [20%] at the 100-mg BID dose): neutropenia (n = 3 [1 at the 100-mg BID dose]), stomatitis (n = 3), nausea (n = 2), and vomiting (n = 1). Of 18 pts, 12 have discontinued (6 due to disease progression; 4 AEs; 1 physician decision; 1 pt/guardian decision). Median duration of exposure to BEZ235 and PTX was 76 days each. The most common suspected study drug-related AEs included asthenia (78%), nausea (72%), neutropenia (72%), diarrhea (67%), stomatitis (61%), and decreased appetite (56%). Among 13 pts receiving BEZ235 200 mg BID, 2 (15%) achieved a PR, 4 (31%) had SD, and 4 (31%) had PD; all 5 pts receiving BEZ235 100 mg BID had SD. PK results showed large interpatient variability at both dose levels. Analysis of pAKT and p4EBP1 was performed on peripheral blood mononuclear cells collected from pts before treatment and 4 h following treatment (Cmax). PK/PD analysis did not provide evidence of a strong and consistent correlation between BEZ235 plasma concentrations and pAKT inhibition. Conclusions: The MTD/RP2D of BEZ235 in combination with PTX in pts with locally advanced or metastatic HER2- BC was not reached. Based on the observed overall safety profile, efficacy, variable PK, and PD data from the Ph Ib part of this study, further enrollment has stopped. The Ph II part of the study will not be conducted. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-22.

The aqueous solubility of lapatinib declines significantly at pH >4, suggesting that its bioavailability might be lowered by acid-reducing drugs. A study was therefore conducted to assess the effects of esomeprazole on lapatinib pharmacokinetics (PK). Women with metastatic human epidermal growth factor receptor 2 positive (HER2(+) ) breast cancer were enrolled. Patients received 1,250 mg lapatinib once daily (QD) in the morning on Days 1-7 (Period 1) and Days 8-14 (Period 2) with 40 mg esomeprazole QD at bedtime 3 hours after dinner on Days 8-14. Lapatinib PK sampling occurred during the 24-hour steady-state dosing intervals on Day 7 (lapatinib alone) and Day 14 (lapatinib with esomeprazole). Esomeprazole treatment resulted in decreased lapatinib bioavailability (mean 26%, range 6-49%) that was inversely associated with patient age as a significant covariate.

Background: The PI3K/AKT/mTOR pathway is frequently altered in breast cancer (BC). Alterations in PIK3CA or inactivation of PTEN are observed in 10–40% and in up to 50% of breast tumors, respectively. The PI3K/AKT/mTOR pathway can be further activated through various receptor classes or cross-talk with other pathways, making it a rational target for therapeutic intervention in BC. BEZ235 is an oral dual inhibitor of mTOR and PI3K. It has demonstrated anti-proliferative activity, substantial growth inhibition, and induction of apoptosis in preclinical studies. In a Ph I study, single-agent BEZ235 (600 mg BID) was shown to have less toxicity than the equivalent once-daily dosing, and have preliminary evidence of activity in advanced solid tumors (Arkenau, et al. ASCO 2012:#3097). Methods: This is a multicenter, open-label Ph IB/II study of continuous, oral BEZ235 twice daily (BID) in combination with paclitaxel (80 mg/m2; IV weekly [QW]) in women with HER2-negative (HER2–), metastatic or inoperable locally advanced BC (NCT01495247). For the Ph IB part, women with HER2–, metastatic or inoperable locally advanced BC, who are suitable for treatment with paclitaxel, are eligible for enrollment. The primary objective is to determine the maximum tolerated dose (MTD)/recommended Ph II dose (RP2D) of BEZ235 in combination with paclitaxel based on dose-limiting toxicities (DLTs) using an adaptive 5-parameter Bayesian logistic regression model with overdose control. The MTD is defined as the highest drug dosage not causing medically unacceptable DLTs in more than 35% of the treated patients during Cycle 1 (1 cycle = 28 days). Secondary objectives include safety (CTCAE), preliminary activity (RECIST), and pharmacokinetics (PK). Estimated enrollment is 15–30 patients into the Ph IB part. Results: As of June 2012, 13 pts have been enrolled into the Ph IB part of the trial. The first cohort (n = 7 pts) received BEZ235 200 mg BID + 80 mg/m2 QW paclitaxel. Of these 7 pts, 3 are ongoing, with 2 pts having received treatment for more than 12 weeks so far, and 4 pts have discontinued (2 due to an adverse event [AE]; 1 due to an AE/pt's decision; and 1 due to disease progression). Of the 6 evaluable pts in the first cohort, 2 experienced DLTs: Grade 3 stomatitis (1 pt) and Grade 2/3 neutropenia (1 pt). Most common AEs included stomatitis and GI toxicity (e.g. diarrhea, nausea/vomiting). To date, reported Grade 3 AEs related to study drug were stomatitis (2 pts), neutropenia (1 pt), and skin rash (1 pt). Among the 3 pts with at least one tumor evaluation, 1 pt with a triple-negative metastatic BC, who had previously been treated with paclitaxel, experienced a RECIST partial response which was confirmed on second tumor evaluation. PK analysis is ongoing. Conclusions: Additional patients have been enrolled at BEZ235 200 mg BID/paclitaxel 80 mg/m2 QW to provide further information on the safety and activity profile of this combination. Updated safety and efficacy results will be presented. Upon determination of the MTD/RP2D, the randomized Ph II part will begin to compare weekly paclitaxel given with or without BEZ235 BID as the first-line treatment of HER2– metastatic BC. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-11-08.

Introduction: Resistance to dual biological blockade of HER2 positive breast cancer arises as a novel therapeutic challenge with high clinical relevance. We have shown that inhibition of fatty acid synthase (FASN) has anticancer activity and enhances the effect of chemotherapy and anti-HER2 drugs in pre-clinical breast cancer models. Furthermore, our group has recently observed that inhibition of FASN can reverse resistance to anti-HER2 therapies. The development of FASN inhibitors has consequently appeared as a novel anti-target modality for treating cancer. However, the clinical use of FASN inhibitors, such as Cerulenin, C75 and Epigallocatechin 3-gallate (EGCG) is limited by anorexia and induced body weight loss or by its low in vivo potency and stability. We synthesized novel EGCG-related inhibitors to improve their use as anti-tumor agents. Within these, G28UCM was selected for its inhibitory effect of FASN activity and selective cytotoxicity in tumor cells. Recently, it has been reported that mTOR blockade acts synergistically with HER2 inhibition to induce cell death and tumor regression in resistant breast cancer models. Materials and Methods: We have developed long term HER2+/ FASN+ breast cancer cell lines (SKBr3) resistant to the HER2-monoclonal antibody Trastuzumab (SKTR), the EGFR/HER2-tyrosine kinase inhibitor Lapatinib (SKLR) or both (SKLTR). Once established, we have characterized these cells by studying a panel of EGF receptors signaling proteins with western blot analysis, changes in adherence to extracellular matrix proteins and invasion capacity with colorimetric assays. Using MTT assay, we have assessed the effect of the mTOR-inhibitor, Temsirolimus, and G28UCM on viability of parental and resistant cells. The isobologram method has been used to estimate the possible synergistic effect between both treatments. Results: Resistant cells maintained downstream HER2 pathway activation by stimulating the expression/activation of alternative EGF family receptors and/or those specific ligands. Moreover, these cells increased adherence to extracellular matrix proteins and invasion capacity. Different combination regiment of Temsirolimus with G28UCM displayed a strong synergistic effect in inducing cell death of both, parental and resistant HER2+ breast cancer cells. Conclusions: The inhibition of mTOR and FASN is a potential novel therapeutic strategy in dual resistant HER2 positive breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-11-02.

Resumen Objetivo En los ultimos anos, ha cambiado la indicacion de la linfadenectomia axilar como gesto integrante del manejo del cancer de mama, sobre todo desde la introduccion de la biopsia del ganglio centinela. El objetivo es conocer la actitud actual en funcion de los hallazgos de enfermedad en este. Pacientes y metodos Se realizo un estudio descriptivo a partir de datos obtenidos de una encuesta, dirigida especificamente a unidades de mama espanolas, sobre las consideraciones que, en el tratamiento quirurgico y adyuvante, supone el hallazgo de metastasis en el ganglio centinela dependiendo de su carga tumoral. Resultados Se recibieron un total de 66 encuestas cumplimentadas de 110 solicitadas (60%). El estudio del ganglio centinela se hace mayoritariamente de forma intraoperatoria (84,8%) y mediante la tecnica de OSNA (69,7%). El hallazgo de celulas tumorales aisladas no conlleva linfadenectomia, aunque hay mas variabilidad ante el hallazgo de macrometastasis y, sobre todo, de micrometastasis (en las que se realiza en un 86,3 y un 33,3%, respectivamente). En este sentido resulta llamativa la falta de uniformidad en los criterios para indicar o no la linfadenectomia y la asociacion de tratamientos adyuvantes. Conclusiones En la actualidad existe una gran variabilidad en la actitud ante el hallazgo de enfermedad ganglionar en el ganglio centinela en el cancer de mama, especialmente en el caso de enfermedad considerada de baja carga tumoral (micrometastasis). Esta variabilidad se refiere tanto a la indicacion de completar la linfadenectomia, como a la indicacion de tratamientos adyuvantes en esos casos concretos.

Paracrine signaling through receptor activator of NF-κB (RANK) pathway mediates the expansion of mammary epithelia that occurs during pregnancy, and activation of RANK pathway promotes mammary tumorigenesis in mice. In this study we extend these previous data to human cells and show that the RANK pathway promotes the development of mammary stem cells and breast cancer. Overexpression of RANK (FL-RANK) in a panel of tumoral and normal human mammary cells induces the expression of breast cancer stem and basal/stem cell markers. High levels of RANK in untransformed MCF10A cells induce changes associated with both stemness and transformation, including mammary gland reconstitution, epithelial–mesenchymal transition (EMT), increased migration, and anchorage-independent growth. In addition, spheroids of RANK overexpressing MCF10A cells display disrupted acinar formation, impair growth arrest and polarization, and luminal filling. RANK overexpression in tumor cells with nonfunctional BRCA1 enhances invasiveness in acinar cultures and increases tumorigenesis and metastasis in immunodeficient mice. High levels of RANK were found in human primary breast adenocarcinomas that lack expression of the hormone receptors, estrogen and progesterone, and in tumors with high pathologic grade and proliferation index; high RANK/RANKL expression was significantly associated with metastatic tumors. Together, our findings show that RANK promotes tumor initiation, progression, and metastasis in human mammary epithelial cells by increasing the population of CD44+CD24− cells, inducing stemness and EMT. These results suggest that RANK expression in primary breast cancer associates with poor prognosis. Cancer Res; 72(11); 2879–88. ©2012 AACR.

Background In preclinical models, oestrogen causes a rapid induction of VEGF in mammary tumours leading to tumour angiogenesis, tumor growth and cell migration whereas aromatase inhibitors (AI) have the opposite effect. Exemestane (E) is an AI, effective in metastatic hormone-dependent breast cancer, as well as in the adjuvant and neoadjuvant settings. Sunitinib (S) is an oral multitargeted tyrosine kinase inhibitor with antiangiogenic activities via inhibition of VEGFR, PDGFR, KIT, RET, CSF-1R and FLT-3, and direct antitumor activity shown in heavily pretreated subjects with advanced breast cancer. The use of antiangiogenic agents at initial stages of the disease, when fewer proangiogenic factors are present, may result in significantly greater efficacy than using these agents at a later stage. Safety profiles of both agents indicate only modest toxicity and do not overlap. We hypothesize that since antiangiogenic and hormonal agents use different mechanisms of action, combination will have additive activity. Regarding (S), continuous dosing (CD) at low doses might result in improved efficacy while maintaining good tolerability. Methods: This is a phase I study to evaluate the safety of (S) in combination with (E) administered for 24 weeks (1cycle=4weeks) as neoadjuvant therapy for post-menopausal women with newly diagnosed hormone-sensitive, Her-2 negative primary breast cancer. We report the results of the first dose escalation part of the study intended to determine a safe dose level of (S) that can be combined with (E) at conventional fixed dose of 25mg/d. Preliminary efficacy data in terms of objective clinical response by WHO criteria will also be reported. Results: 18 postmenopausal women with ER-positive invasive breast cancer, adequate organ function and ECOG 0–1 were enrolled in the study (median age 74, range 57–84) to be treated at two dose levels: 25 mg of (E) with either 25mg or 37.5mg of (S) CD. Two DLTs were identified: grade 3 mucositis at level 25mg of (S) and grade 3 asthenia at level 37.5mg of (S). Main toxicities were asthenia, leucopenia, mucositis, diarrhea and HBP. 78% of patients had grade 2 toxicities; 22% had grade 3. There were no serious adverse events reported. Median time on treatment with the combination was 23 weeks (range 2–24). 16% of patients needed one dose reduction of (S), 16% needed two or more and 28% suspended (S) administration due to toxicity. 50% of patients completed 24 weeks of treatment. None of the patients at 37.5mg (S) level could tolerate full doses for the entire treatment period, therefore in our study the recommended dosage of (S) that can be safely combined with (E) is 25mg. Concerning efficacy, 11 out of 18 patients had partial response (61%), 6 out of 18 had SD (33%) and only one patient had PD (5%) as best response. Conclusion: Safety profile of the combination seems to be manageable in most patients. Toxicities were observed mainly within the two first cycles. Response rates were similar than those previously observed with (E) as monotherapy in the neoadjuvant setting. Biomarkers information will be provided. This study was supported by an Independent Investigator Research grant from Pfizer, Inc. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-16-15.

Fatty acid synthase (FASN) expression and activity has emerged as a common phenotype in most human carcinomas, including breast cancer, and its expression is tightly linked to HER2 signaling pathways. The development of inhibitors of FASN activity has consequently appeared as a novel antitarget modality for treating cancer. However, the clinical use of FASN inhibitors, such as cerulenin, C75, and epigallocatechin 3-gallate (EGCG), is limited by anorexia and induced body weight loss or by its low in vivo potency and stability. Here, we summarize the design and development of G28UCM, the lead-compound of a novel family of synthetic FASN inhibitors, with both in vitro and in vivo activity in a human breast cancer model of FASN(+) and HER2(+) .

Aromatase inhibitors play a key role in the clinical management of hormone receptor–positive breast cancer and have potential utility as chemopreventive agents. Further understanding of the molecular effects of estrogen and its deprivation in normal breast tissue may allow the development of biomarkers of risk of breast cancer and help to predict the value of chemoprevention with aromatase inhibitors. Core biopsies of normal breast tissue were taken before and after letrozole treatment from postmenopausal women in the LITMaS pilot prevention study. RNA was extracted from these samples and used for cDNA microarray analysis. Gene expression changes induced by letrozole treatment were much less extensive than observed in estrogen receptor–positive malignant tissue; however, overall, they correlated to a highly significant degree (ρ = 0.511; P < 10−20). As well as some classically estrogen-associated genes, many genes associated with extracellular matrix remodeling were affected by estrogen deprivation in the normal breast in vivo. These data indicate for the first time that gene expression of normal breast tissue remains dependent on endogenous estrogens after the menopause. The modest degree of gene change suggests that intermediate markers of chemoprevention may be difficult to identify. (Cancer Epidemiol Biomarkers Prev 2008;17(4):855–63)

Introduction Changes in breast cancer cell biology following hormonal treatment have been claimed as promising predictor markers of clinical benefit even outperforming clinical response. From previous work we selected 10 genes showing both a well known regulation by oestrogen and a high level of early transcriptional regulation following therapy with aromatase inhibitors. Here we use an animal breast cancer model to explore the feasibility of the determination of their expression in minimally invasive samples and to further assess the magnitude of their regulation by letrozole. Animal and methods Aromatase inhibitor sensitive breast cancer tumours were grown in athymic mice under supplement with androstenedione. Following initial tumour growth animals were assigned to a control group or to receive letrozole at two different dosages. Fine needle aspirates were obtained at the moment of treatment assignation and one week later. Expression of the following genes at both time points was determined: Ki-67, Cyclin D1, pS2, Trefoil Factor 3, PDZ domain containing 1, Ubiquitin-conjugating enzyme E2C, Stanniocalcin 2, Topoisomerase 2 alfa, MAN1A1 and FAS. Results Fine needles aspirates were found to be a feasible and reproducible technique for RNA extraction. Trefoil Factor 3, pS2, Cyclin D1 and Stanniocalcin 2 were significantly downregulated by letrozole. Among them pS2 appears to be most sensitive to aromatase inhibitor treatment even differentiating sub-optimal from optimal letrozole dosage. Discussion We present pre-clinical evidence to justify the exploration in clinical trials of pS2, Trefoil factor 3, Cyclin D1 and Stanniocalcin as dynamic markers of oestrogen-driven pathway activation.

The study was partially funded by the “Accion Transversal del Cancer”, approved on the Spanish Ministry Council on the 11th October 2007, by the Instituto de Salud Carlos III-FEDER (PI08/1770, PI08/0533, PI08/1359, PS09/00773, PS09/01286,PS09/01903, PS09/02078, PS09/01662, PI11/01403, PI11/01889,PI11/00226, PI11/01810, PI11/02213, PI12/00488, PI12/00265,PI12/01270, PI12/00715, PI12/00150), Castaño-Vinyals, G., Aragonés, N., Pérez-Gómez, B., Martín, V., Llorca, J., Moreno, V., Altzibar, J.M., Ardanaz, E., de Sanjosé, S., Jiménez-Moleón, J.J., Tardón, A., Alguacil, J., Peiró, R., Marcos-Gragera, R., Navarro, C., Pollán, M., Kogevinas, M., Alonso, M.T., Amiano, P., Arias, C., Azpiri, M., Benavente, Y., Boldo, E., Bueno, A., Bustamante, M., Caballero, F.J., Campo, E., Cantón, R., Capelo, R., Carmona, C., Casabonne, D., Chirlaque, M.D., Cirac, J., Clofent, J., Colado, E., Costas, L., Crous, M., Del Campo, R., Santos, M.D., Dierssen-Sotos, T., Ederra, M., Espinosa, A., Cabrera, M.F., Somoano, A.F., Villa, T.F., García-Esquinas, E.G., Martín, P.G., Gómez-Acebo, I., Puga, C.G., Gràcia, E., Eslava, M.G., Guinó, E., Huerta, J.M., Lope, V., López-Abente, G., Lopez-Otín, C., Argüelles, B.M., Salas, S.M., Pozo, B.M., de la Torre, A.J., Moreno, E., Iribas, C.M., Olea, N., Gelis, G.O., Paré, L., Porta, M., Puig, M., Del Fresno, M.R., Robles, C., Suarez, M.M., Romero, B., Castillo, A.I., Serra, M.S., Trejo, D.S., Santaballa, A., Santibáñez, M., Sierra, Á., Souto, A., Villanueva, C.M., Carrasco, E., Sabaté, Y., Persavento, C., García, M., Carrasco, G., Expósito, A., Andreu, M., Bessa, X., Piracés, M., Lorente, J.A., Tusquets, I., Collet, I., Bory, F., Pera, M., Abella, E., Garcia, F., Salar, A., Piñol, M., Fernandez-Llamazares, J., Martín, M.V., Garsot, E., Servio, L.I., Arzoz-Fabregas, M., Suarez, L., Ruiz, J.M., Castells, A., Serradesanferm, A., Bosch, A., Muñoz, M., Fontanillas, M., Alcaraz, A., Mengual, L., Duran, E., Izard, C., López, C., Benítez, J.M., Massanes, A.B., Ferrer, O.G., Almeda, J., Sarret, S., Rodriguez, M.A., Valmaseda, A.B., Liceran, M., Petitbó, D., Nolla, J.I., Pérez, S., Martínez, S., Vilaseca, J.M., Sebastián, L., Quesada, P., Sequera, G., Barca, E.G., Domingo-Domenech, E., Oliveira, A., Alonso, E., de la Banda, E., Sabater, Y., Vergara, M., Exposito, A., Alonso, T., Padrol, I., Klaustermeier, J., Florencia, Y., Camon, V., Esteban, A., Aymerich, M., Lopez-Otin, C., Muñoz, A., Torralba, Y., Dot, D., Mercadal, S., Sarra, J., Medina, P., Atienza, C., Biondo, S., de Oca, J., Ferran, L., Rodriguez-Moranta, F., Soriano, A., Guardiola, J., Urruticoechea, A., Galan, M., Banda, J.M., Zumel, Á., Saez, A., Garrido, J.A., Lacasaña, M., Ariza, J.L., García, T., García, M.Á., Hidalgo, M.Á., Asuero, M., Bayo, J., Vázquez, V.C., Franco, F., Gurucelain, J.L., Frías, M.J., Van de Haar, R., Viñas, J., Jiménez, H., Aguayo, M., Pereira, A., Gutiérrez, S.P., Rada, R., Candón, J., Domínguez, J., Ramos, M., Pedraza, G., Braulio, J., Salas, J., Labrero, D., Muñoz, D., Barrero, F., Delgado, S., Galisteo, L., Camacho, A., Elena, H., Caballero, J., Muñoz, M.J., Arredondo, F., Linares, R., Tejada, A., Tinto, H., Alés, J.D., Coronado, M.V., Bernal, M.L., Ortiz, J.L., Ocaña, M.N., Cavanillas, A.B., Miguel, Mejías, E.J., Abril, O.M., Requena, R.O., Morata, J.L., Echezarreta, E.G., López, L.M., Martínez, M.M., Sedano, P.P., de la Pedraja Pavón, A., López-Rojo, C., Mendiola, J., Pellicer, E., Caparrós, J.M., Oltra, E.G., Martínez, J.M., Molina, A., Villanueva, V., Miranda, M.J., Abril, C., Martinez, J., Salas, D., Ruiz, J.L., Ponce, M., Noos, P., Cervera, J., Del Val, A., Segura, A., Jiménez, N., Bellmunt, E., Aznar, I., Ramos, D., Montón, T., Solera, M.C., Mora, E.M., Estañ, N., Camarasa, N., Solanas, J.V., Ripoll, J., Cantero, J., Díaz, C.A., García, A.S., Avellón, S.M., Neumann, M., González, M.J., Suárez, M.M., Fernández, G., Fresno, M.R., Gómez, A., Garín, U., de Gros, A., Tamayo, E., Rua, M., Lasarte, C.S., Jauregi, M., Recio, J., Fernández, M., Múgica, M., Ciria, J.P., Guimón, E., Adúriz, C., Lacasta, A., Francisco, J.S., Alvarez, I., Enriquez-Navascués, J.M., Ruiz, I., Michelena, M., Alberro, J.A., Almansa, A.M., Goñi, L.M., Elizagaray, M.I., Técnico, M.O., Pérez, R.B., De Miguel Medina, M.C., Repáraz Romero, M., de Azúa Ciria, A.Y., Díaz, M.M., Lizárraga, M.S., Jiménez, Y.L., López, C.E., Legaz, S.O., Lezaun, R.A., Hurtado, H.O., De Miguel Velasco, M., Rubio, P.A., Cunchillos, F.D., de Liaño Arguelles, Á.D., Peñuela, J.M., Dorronsoro, M.L., Celaya, F.B., García, D.R., de la Higuera Carnicer, B.G., Tricas, J.M., Rivera, E.M., García, F.V., Noain, J.J., Erdozain, E.A., Ulibarrena, C.I., Lopeandía, J.G., Caden, M.A., Moraza, F.A., Domench, J.J., Arteaga, A.A., Navarro, K.A., Del Burgo Tajadura, M.A., Irastorza, F.C., Urrisarri, M.J., Zubicoa, B.F., Lorente, P.G., Sevilla, P.H., Echamendi, M.L., Díaz, Á.M., Salaverri, J.M., Gorricho, F.J., Del Valle, M.P., de Prado Marcilla, J., Garcésducar, M., Herce, P.A., Barasoain, J.E., Campos, I.A., Vergara, E.A., Beraza, B.C., Blasco, L.F., Díaz, L.G., Larrañeta, J.G., Ruiz, N.G., García, J.G., Orduna, M.S., Larena, D.I., Fernández, M.P., de Ciriza Pejenaute, F.J., Escuin, R., Puertas, I.R., Samper, I.A., Sesma, M.E., López, M.J., Apestegui, C.Z., Linares, C., Cervantes, M., Ferreras, E., García-Pérez, J., Fernández-Navarro, P., Pastor, R., Ramis, R., González, Á., Ruiz, T., Muñoz, V., Delgado, R., Lanza, M., Marín, M., Posada, M., Cosmen, J., Villanueva, A., Castaño, A., Jiménez, J.A., Rin, A., Díaz, G., Herreros, M., Pedraza, V., López, P., de la Fuente, M., de Castro, M.F., Sobrino, J., Calvo, R., Carrascal, I., Bernal, R., Mateo, A., García-Olmo, D., Zarazaga, A., Gombau, M.Á., Díaz, J., Gómez, T., Sánchez, T., de la Quintana, P., Ordás, J., Cuevas, P., Sánchez-Pastor, M., de la Peña, J.J., Tabernero, Á., Cámara, N., Hardisson, D., Suárez, A., Burgos, E., Alves, J., Miguel, M., Feliú, J., Belda, C., Zamora, P., Sánchez, A., Hernández, A., Beato, T., Arroba, A., Ballesteros, A., Canora, S., García, C., Romero, M., José, T.S., Espinel, M., Mañas, A., Sánchez, M., Ramón, H., Morillo, J.L., Cuchí, M., García, M.J., Ramos, J.M., Rojo, R., Sanjuanbenito, A., Villanueva, A.G., Gras, M., Cabañas, J.L., Collado, V., Arano, I., Capela, I., Mojarrieta, C., Peñas, B., Rodríguez, M., Ramos, A., Sancho, S., Hervás, A., Moreno, P., Sánchez, C., DoloresRubio, Montoya, L., Sancho, P., Rodríguez, L., Durán, E., Morel, S., Burgos, J., García, R., Del Cañizo, C.G., Díaz, A., González, F., Cristóbal, E., Barahona, C., Vázquez, S., Esteban, V., Pedrera, M., Martínez, J., Carrato, A., Ponce, C.G., Santos-Olmo, A., Barrientos, R.R., López, G., Fernández, A., García, A.B., Noriega, A., Campo, M., Varona, E., López, F., Montero, M., Gómez, M.T., Bartibas, P., Sanz, R., Montes, T., Salinero, M.Á., Herrero, M., Igea, M., Calvo, C., Pérez-Pellón, C., Maestre, M., Agora, M.A., Martín, M.G., Velázquez, D., Fernández, B., Castro, M., Ayuso, E., Masa, R., 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J.G., Carbajo, M.J., Esteras, T.R., Baz, B.V., Baticón, C.H., Baza, E.Á., Urdiales, A.U., Gil, J.I., López, M.A., Ule, E.C., Diez, C.B., Marín, A.I., Bernabeu, M.Á., de Abajo Olea, S., Rojo, C.V., Fernández, M.Á., González, F.G., Martínez, L.G., Del Huertotrancón Moratiel, M., Ramos, N.C., Fidalgo, S.P., Coque, P.R., González, Á.G., Díez, A.B.

This phase II study assessed the clinical efficacy and tolerability of a combination of mitomycin C, vinblastine and cisplatin in patients with metastatic breast cancer (MBC) previously treated with chemotherapy. A total of 87 patients with MBC, most of whom had been exposed to anthracyclines (92%) and/or taxanes (29%) in the adjuvant and/or metastatic setting, were treated with mitomycin C (8 mg m(-2) day 1 cycles 1, 2, 4 and 6), vinblastine (6 mg m(-2) day 1) and cisplatin (50 mg m(-2) day 1) repeated each 21 days for a maximum of six cycles. The overall response rate (ORR) was 32% (95% CI: 22-42%) with 31% partial response (PR) and one complete response (CR). Stable disease (SD) rate was 21% (95% CI: 12-29%). There was no statistically significant difference in the ORR when MVP was given as the first-line treatment for MBC vs second or subsequent line (38 vs 30%, P=0.6), or between patients with an early (6 months) vs late (6 months) relapse post-anthracyclines (30 vs 52%, P=0.3). Toxicity profile was mild. This platinum-based chemotherapy is an effective, well-tolerated and low-cost regimen for patients with MBC, including those pretreated with anthracyclines.

Background: The outcome for oestrogen receptor positive (ER+) breast cancer patients has improved greatly in recent years largely due to targeted therapy. However, the presence of involved multiple synchronous lymph nodes remains associated with a poor outcome. Consequently, these patients would benefit from the identification of new prognostic biomarkers and therapeutic targets. The expression of G-protein-coupled receptor kinase-interacting protein 1 (GIT1) has recently been shown to be an indicator of advanced stage breast cancer. Therefore, we investigated its expression and prognostic value of GIT1 in a cohort of 140 ER+ breast cancer with synchronous lymph node involvement.Methods: Immunohistochemistry was employed to assess GIT1 expression in a tissue microarray (TMA) containing duplicate non-adjacent cores with matched primary tumour and lymph node tissue (n=140). GIT1 expression in tumour cells was scored and statistical correlation analyses were carried out.Results: The results revealed a sub-group of patients that displayed discordant expression of GIT1 between the primary tumour and the lymph nodes (i.e. spatial intratumoural heterogeneity). We observed that loss of GIT1 expression in the tumour cells of the metastasis was associated with a shorter time to recurrence, poorer overall survival, and a shorter median survival time. Moreover, multivariate analysis demonstrated that GIT1 expression was an independent prognostic indicator.Conclusions: GIT1 expression enabled the identification of a sub-class of ER+ patients with lymph node metastasis that have a particularly poor prognostic outcome. We propose that this biomarker could be used to further stratify ER+ breast cancer patients with synchronous lymph node involvement and therefore facilitate adjuvant therapy decision making.

2554 Background: 2OHOA is an orally bioavailable, first-in-class synthetic hydroxylated fatty acid, that activates SGMS1 and modulates the lipid content of cancer cell membranes. This regulates the localization of key signaling proteins, including Ras and PKC at the plasma membrane, leading to inactivation of Ras/MAPK, PI3K/Akt and PKC/cyclin/CDK signaling pathways. A dose escalation (DE) and partial expansion cohorts (EC) results of the phase 1 study have previously been reported. We now present the final results of the study. Methods: 2OHOA was evaluated in a 3+3 DE design (7 cohorts from 500mg/d to 16000mg/d) and 2 EC at 4000mg TID in 21 days cycles. PK profiles were determined after single dose (fasted [D-7] or fed [D1]) and multiple doses (fed [D21]) during DE phase and only on D1 throughout EC.Safety assessments were based on CTCAEv4.Tumor response was measured by RECIST and RANO every 6 weeks. Results: Overall 54 pt (DE: 32 pt; 21AST/11rHGG; EC: 22 pt; 12 AST/10 rHGG) were treated (median age 60, range 19-78 years). During the EC the most common treatment related G1-G2 toxicities were diarrhea (n = 13;11pt),nausea (n = 7;6pt), ALT increase (n = 6;4pt), pruritus in throat (4pt), fatigue (4pt) and vomiting (3pt). No G3-G4 toxicities or DLTs were reported confirming the MTD from the DE at 4g TID. Food intake did not alter oral 2OHOA bioavailability. Steady state was already achieved at D8. Power model showed dose proportionality in terms of AUC and Cmax, after single and multiple BID dosing. Average t1/2 ranged from1-2h to 8-12h with delayed Tmax and longer half-lives at higher doses. One glioblastoma (GBM) pt had sustained partial response ( > 2,5 years) and 4rHGG pt (3 GBM) achieved stable disease for at least 6 months. They had previously received 2 lines of treatment without bevacizumab. Tumor markers were measured and will be presented. Conclusions: 2OHOA is well tolerated at the P2RD of 4000mg TID PO daily. The preliminary antitumor activity including a sustained PR in heavy pretreated rHGG pt warrants further investigation in a Ph2 study Clinical trial information: NCT01792310.

1023 Background: T-DM1 was approved for pts with HER2+ MBC previously treated with trastuzumab (H) and a taxane based on the phase III EMILIA study. P in combination with H + docetaxel (T) later became the first-line standard of care for HER2+ MBC, but there are limited data on T-DM1 efficacy in pts who previously received P. We present exploratory efficacy results from pts treated with T-DM1 any time after P from 2 phase III studies: CLEOPATRA and PHEREXA. Methods: CLEOPATRA (NCT00567190) and PHEREXA (NCT01026142) are randomized, 2-arm trials evaluating P-based regimens for HER2+ MBC. CLEOPATRA studies H + T + P vs HT + placebo in pts with no prior anti-HER2 treatment (tx) or chemotherapy for MBC, while PHEREXA studies H + capecitabine (C) +/− P in pts who progressed during/after previous H tx for MBC. We assessed overall survival (OS) in an exploratory analysis of pts who either received or did not receive T-DM1 at any time after discontinuing study-assigned tx in CLEOPATRA or PHEREXA. Results: Of 408 pts who received HTP in CLEOPATRA and 228 pts who received HCP in PHEREXA, 32 and 43 pts received subsequent T-DM1, respectively (Table). Median duration of T-DM1 tx was 7.1 mo (range 0−44) and 4.2 mo (range 0−22), respectively, and median time from discontinuation of P to start of T-DM1 was 3.5 mo (range 1−47) and 10.6 mo (range 1−28). Conclusions: Although data are limited in these exploratory analyses, our results provide additional evidence of T-DM1 clinical activity in pts with HER2+ MBC who progressed on prior P + H, a finding with real-world implications. Clinical trial information: NCT00567190, NCT01026142. [Table: see text]

Purpose: Phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway activation in patients with HER2-positive (HER2+) breast cancer has been implicated in de novo and acquired trastuzumab resistance. The purpose of this study was to determine the clinical activity of the PI3K inhibitor buparlisib (BKM120) in patients with HER2+ advanced/metastatic breast cancer resistant to trastuzumab-based therapy. Experimental Design: In the dose-escalation portion of this phase I/II study, patients with trastuzumab-resistant locally advanced or metastatic HER2+ breast cancer were treated with daily oral doses of buparlisib and weekly intravenous trastuzumab (2 mg/kg). Dose escalation was guided by a Bayesian logistic regression model with overdose control. Results: Of 18 enrolled patients, 17 received buparlisib. One dose-limiting toxicity of grade 3 general weakness was reported at the 100-mg/day dose level (the single-agent maximum tolerated dose) and this dose level was declared the recommended phase II dose (RP2D) of buparlisib in combination with trastuzumab. Common (>25%) adverse events included rash (39%), hyperglycemia (33%), and diarrhea (28%). The pharmacokinetic profile of buparlisib was not affected by its combination with trastuzumab. At the RP2D, there were two (17%) partial responses, 7 (58%) patients had stable disease (≥6 weeks), and the disease control rate was 75%. Pharmacodynamic studies showed inhibition of the PI3K/AKT/mTOR and RAS/MEK/ERK pathways. Conclusions: In this patient population, the combination of buparlisib and trastuzumab was well tolerated, and preliminary signs of clinical activity were observed. The phase II portion of this study will further explore the safety and efficacy of this combination at the RP2D. Clin Cancer Res; 20(7); 1935–45. ©2014 AACR.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License.-- et al., [Introduction]: Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor α (ERα) are among the most effective systemic treatments for ERα-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through mechanisms that involve ERα transcriptional regulatory plasticity. Herein we identify VAV3 as a critical component in this process. [Methods]: A cell-based chemical compound screen was carried out to identify therapeutic strategies against resistance to endocrine therapy. Binding to ERα was evaluated by molecular docking analyses, an agonist fluoligand assay and short hairpin (sh)RNA-mediated protein depletion. Microarray analyses were performed to identify altered gene expression. Western blot analysis of signaling and proliferation markers, and shRNA-mediated protein depletion in viability and clonogenic assays, were performed to delineate the role of VAV3. Genetic variation in VAV3 was assessed for association with the response to tamoxifen. Immunohistochemical analyses of VAV3 were carried out to determine its association with therapeutic response and different tumor markers. An analysis of gene expression association with drug sensitivity was carried out to identify a potential therapeutic approach based on differential VAV3 expression. [Results]: The compound YC-1 was found to comparatively reduce the viability of cell models of acquired resistance. This effect was probably not due to activation of its canonical target (soluble guanylyl cyclase), but instead was likely a result of binding to ERα. VAV3 was selectively reduced upon exposure to YC-1 or ERα depletion, and, accordingly, VAV3 depletion comparatively reduced the viability of cell models of acquired resistance. In the clinical scenario, germline variation in VAV3 was associated with the response to tamoxifen in Japanese breast cancer patients (rs10494071 combined P value = 8.4 × 10-4). The allele association combined with gene expression analyses indicated that low VAV3 expression predicts better clinical outcome. Conversely, high nuclear VAV3 expression in tumor cells was associated with poorer endocrine therapy response. Based on VAV3 expression levels and the response to erlotinib in cancer cell lines, targeting EGFR signaling may be a promising therapeutic strategy. [Conclusions]: This study proposes VAV3 as a biomarker and a rationale for its use as a signaling target to prevent and/or overcome resistance to endocrine therapy in breast cancer., This work was supported by grants from the Eugenio Rodríguez Pascual Foundation (2012, to MAP), the Government of Catalonia (2009-SGR283, to AV and MAP), the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (R01 DK015556, to JAK), the Red Cooperative Research Thematic Network on Cancer (RTICC) (12/0036/0002 to XRB and 12/0036/0008 to XRB and MAP) and the Spanish Ministry of Health, Fund for Health Research–Institute of Health Carlos III (11/00951 to AU and 12/01528 to MAP).

Energy restriction from a low-calorie diet and increased energy expenditure induced by physical activity (PA) could promote weight loss/maintenance and be important determinants of breast cancer (BC) prognosis. The aim of this study was to assess participation and adherence of overweight and obese BC survivors to a lifestyle intervention and to demonstrate the capacity of this intervention to induce weight loss and nutritional changes. This single-arm pre-post study, which involved one-hourly weekly diet sessions delivered by a dietician and 75-min bi-weekly PA sessions of moderate-to-high intensity led by PA monitors, was offered to overweight and obese BC survivors shortly after treatment. Before and after the intervention, anthropometry, dietary information, quality of life (QoL) and cardiorespiratory fitness (CRF) were collected. A total of 112 BC survivors were invited to participate: 42 of them started the intervention and 37 completed it. Participants attended more than 90 % of the sessions offered and showed a significant weight loss of 5.6 ± 2.0 kg, as well as significant decreases in body mass index, fat mass and waist circumference. Significant decreases in total energy (-25 %), fat (-35 %), saturated fat (-37 %) and carbohydrate (-21 %) intakes were observed while QoL and CRF showed significant increases. This feasibility study demonstrated the success of a short-term diet and PA intervention to induce weight loss and promote healthful changes in BC survivors. Assessing the long-term effects of these changes, and in particular their possible impact of BC prognosis, and designing interventions reaching a wider number of BC survivors are still issues to be addressed.

High rates of inherent primary resistance to the humanized monoclonal antibody trastuzumab (Herceptin) are frequent among HER2 gene-amplified breast carcinomas in both metastatic and adjuvant settings. The clinical efficacy of trastuzumab is highly correlated with its ability to specifically and efficiently target HER2-driven populations of breast cancer stem cells (CSCs). Intriguingly, many of the possible mechanisms by which cancer cells escape trastuzumab involve many of the same biomarkers that have been implicated in the biology of CS-like tumor-initiating cells. In the traditional, one-way hierarchy of CSCs in which all cancer cells descend from special self-renewing CSCs, HER2-positive CSCs can occur solely by self-renewal. Therefore, by targeting CSC self-renewal and resistance, trastuzumab is expected to induce tumor shrinkage and further reduce breast cancer recurrence rates when used alongside traditional therapies. In a new, alternate model, more differentiated non-stem cancer cells can revert to trastuzumab-refractory, CS-like cells via the activation of intrinsic or microenvironmental paths-to-stemness, such as the epithelial-to-mesenchymal transition (EMT). Alternatively, stochastic transitions of trastuzumab-responsive CSCs might also give rise to non-CSC cellular states that lack major attributes of CSCs and, therefore, can remain "hidden" from trastuzumab activity. Here, we hypothesize that a better understanding of the CSC/non-CSC social structure within HER2-overexpressing breast carcinomas is critical for trastuzumab-based treatment decisions in the clinic. First, we decipher the biological significance of CSC features and the EMT on the molecular effects and efficacy of trastuzumab in HER2-positive breast cancer cells. Second, we reinterpret the genetic heterogeneity that differentiates trastuzumab-responders from non-responders in terms of CSC cellular states. Finally, we propose that novel predictive approaches aimed at better forecasting early tumor responses to trastuzumab should identify biological determinants that causally underlie the intrinsic flexibility of HER2-positive CSCs to "enter" into or "exit" from trastuzumab-sensitive states. An accurate integration of CSC cellular states and EMT-related biomarkers with the currently available breast cancer molecular taxonomy may significantly improve our ability to make a priori decisions about whether patients belonging to HER2 subtypes differentially enriched with a "mesenchymal transition signature" (e.g., luminal/HER2 vs. basal/HER2) would distinctly benefit from trastuzumab-based therapy ab initio.

e14086Background: 2-OHOA, is a first-in-class, synthetic hydroxylated lipid that activates SGSM1 and modulates the lipid content of cancer cell membranes. 2-OHOA reduces tumor growth in numerous xe...

504Background: P provides a progression-free and overall survival (PFS, OS) benefit in HER2-positive MBC, and is standard of care in the 1st line. Continuing H post-progression on 1st-line H improves response and time to progression. H + X is well tolerated and more effective than X in these pts, and dual P + H anti-HER2 therapy has activity in this population. However, efficacy and safety of P + H + X is unknown. We report the primary analysis of a multicenter, open-label randomized study of H + X vs P + H + X (NCT01026142). Methods: Pts who received a prior taxane and progressed during/after 1st-line H-based therapy for HER2-positive MBC were randomized to intravenous (IV) H 8 mg/kg then 6 mg/kg q3w + oral X 1250 mg/m2 twice daily (2 weeks on, 1 week off q3w; Arm A) or IV P 840 mg then 420 mg q3w + IV H per Arm A + oral X per Arm A but at 1000 mg/m2 (Arm B). The primary endpoint was independent review facility-assessed PFS (IRF PFS). The secondary endpoints of OS and safety are also reported. Hierarchic...

The aqueous solubility of lapatinib declines significantly at pH4, suggesting that its bioavailability might be lowered by acid-reducing drugs. A study was therefore conducted to assess the effects of esomeprazole on lapatinib pharmacokinetics (PK). Women with metastatic human epidermal growth factor receptor 2 positive (HER2(+) ) breast cancer were enrolled. Patients received 1,250 mg lapatinib once daily (QD) in the morning on Days 1-7 (Period 1) and Days 8-14 (Period 2) with 40 mg esomeprazole QD at bedtime 3 hours after dinner on Days 8-14. Lapatinib PK sampling occurred during the 24-hour steady-state dosing intervals on Day 7 (lapatinib alone) and Day 14 (lapatinib with esomeprazole). Esomeprazole treatment resulted in decreased lapatinib bioavailability (mean 26%, range 6-49%) that was inversely associated with patient age as a significant covariate.

One of the most efficacious primary therapies in HER2-positive breast cancer was published by the M.D. Anderson group in 2005. This randomized trial evaluated the addition of trastuzumab to a taxane-anthracycline based chemotherapy. Despite largely significant differences in pathological complete response (pCR) in the trastuzumab group (65 vs. 26 %) this regimen did not become a common standard due to toxicity concerns and its premature closure with a small sample size. In order to evaluate the efficacy and safety of this regimen in an off-trial setting we conducted a prospectively monitorized series of consecutive patients with early or locally advanced Her-2 positive breast cancer following the same treatment strategy. Stage II-IIIC HER2-positive breast cancer patients, including inflammatory disease, were treated with weekly-trastuzumab for 24 weeks administered concurrently with all primary chemotherapy containing paclitaxel (80 mg/m(2)) for 12 weeks and 4 cycles of FEC-75 (fluorouracil 500 mg/m(2), epirubicine 75 mg/m(2), and cyclophosphamide 500 mg/m(2)) followed by surgery. The objectives were efficacy, in terms of pCR in both the breast and lymph nodes, and safety, with close cardiac monitoring during and after treatment. From August 2004 to February 2009, 83 patients were included. Most patients (73.5 %) had node involvement and 13.2 % had inflammatory disease. Fifty-one patients (61.4 %) achieved a pCR in breast and axilla (95 % CI 50-72 %). HR-negative tumors were associated with higher pCR rate than HR-positive tumors (77 vs. 48 %, P = 0.006). At a median follow-up of 50.2 months no patient developed symptomatic cardiac failure, and 9 patients (10.8 %) presented a transient asymptomatic decrease in left ventricular ejection fraction. Primary therapy with concurrent trastuzumab plus paclitaxel-FEC for HER2-positive breast cancer in everyday practice is highly effective and safe confirming the results observed in a randomized trial stopped prematurely.

Introduction. Inhibiting the enzyme Fatty Acid Synthase (FASN) leads to apoptosis of breast carcinoma cells, and this is linked to human epidermal growth factor receptor 2 (HER2) signaling pathways in models of simultaneous expression of FASN and HER2. Methods. In a xenograft model of breast carcinoma cells that are FASN+ and HER2+, we have characterized the anticancer activity and the toxicity profile of G28UCM, the lead compound of a novel family of synthetic FASN inhibitors. In vitro, we have analyzed the cellular and molecular interactions of combining G28UCM with anti-HER drugs. Finally, we have tested the cytotoxic ability of G28UCM on breast cancer cells resistant to trastuzumab or lapatinib, that we developed in our laboratory. Results. In vivo, G28UCM reduced the size of 5/14 established xenografts. In the responding tumours, we observed inhibition of FASN activity, cleavage of poly- ADPribose polymerase (PARP) and decrease of p-HER2, p- protein kinase B (AKT) and p-ERK1/2, which were not observed in the nonresponding tumours. In the G28UCM-treated animals, no significant toxicities occurred, and weight loss was not observed. In vitro, G28UCM showed marked synergistic interactions with trastuzumab, lapatinib, erlotinib or gefitinib (but not with cetuximab), which correlated with increases in apoptosis and with decreases in the activation of HER2, extracellular signal-regulated kinase (ERK)1/2 and AKT. In trastuzumab-resistant and in lapatinib-resistant breast cancer cells, in which trastuzumab and lapatinib were not effective, G28UCM retained the anticancer activity observed in the parental cells. Conclusions. G28UCM inhibits fatty acid synthase (FASN) activity and the growth of breast carcinoma xenografts in vivo, and is active in cells with acquire resistance to anti-HER2 drugs, which make it a candidate for further pre-clinical development

Intracellular signaling mediated by the receptor activator of nuclear factor-κB [Rank, encoded by the tumor necrosis factor receptor superfamily, member 11a (Tnfrsf11a) gene] is fundamental for mammary gland development in mice, regulating the expansion of stem and progenitor cell compartments. Conversely, Rank overexpression in mice promotes abnormal proliferation and impairs differentiation, leading to an increased incidence of tumorigenesis. Here, we show that a common genetic variant near the 5′-end of TNFRSF11A, rs7226991, is associated with breast cancer risk in the general population and among carriers of mutations in the breast cancer 2, early onset (BRCA2) gene. Akin to the results of the Cancer and Genetics Markers of Susceptibility initiative, combined analysis of rs7226991 in two Spanish case–control studies (1,365 controls and 1,323 cases in total) revealed a significant association with risk: odds ratio (OR) = 0.88, 95% confidence interval (CI) 0.78–0.98, P trend = 0.025. Subsequent examination of BRCA1 (n = 1,017) and BRCA2 (n = 885) mutation carriers revealed a consistent association in the latter group: weighted hazard ratio (wHR) = 0.70; 95% CI 0.55–0.88; and P trend = 0.003; compared to BRCA1 mutation carriers, wHR = 0.91; 95% CI 0.76–1.10; and P trend = 0.33. The results of this study need to be replicated in other populations and with larger numbers of BRCA1/2 mutation carriers.

Endocrine therapies targeting the proliferative effect of 17β-estradiol through estrogen receptor α (ERα) are the most effective systemic treatment of ERα-positive breast cancer. However, most breast tumors initially responsive to these therapies develop resistance through molecular mechanisms that are not yet fully understood. The long-term estrogen-deprived (LTED) MCF7 cell model has been proposed to recapitulate acquired resistance to aromatase inhibitors in postmenopausal women. To elucidate this resistance, genomic, transcriptomic and molecular data were integrated into the time course of MCF7-LTED adaptation. Dynamic and widespread genomic changes were observed, including amplification of the ESR1 locus consequently linked to an increase in ERα. Dynamic transcriptomic profiles were also observed that correlated significantly with genomic changes and were predicted to be influenced by transcription factors known to be involved in acquired resistance or cell proliferation (for example, interferon regulatory transcription factor 1 and E2F1, respectively) but, notably, not by canonical ERα transcriptional function. Consistently, at the molecular level, activation of growth factor signaling pathways by EGFR/ERBB/AKT and a switch from phospho-Ser118 (pS118)- to pS167-ERα were observed during MCF7-LTED adaptation. Evaluation of relevant clinical settings identified significant associations between MCF7-LTED and breast tumor transcriptome profiles that characterize ERα-negative status, early response to letrozole and tamoxifen, and recurrence after tamoxifen treatment. In accordance with these profiles, MCF7-LTED cells showed increased sensitivity to inhibition of FGFR-mediated signaling with PD173074. This study provides mechanistic insight into acquired resistance to endocrine therapies of breast cancer and highlights a potential therapeutic strategy.

The landscape of cancer treatment has dramatically changed over the last four decades. The age when surgery and radiotherapy were the only effective way to fight tumour growth has ended. A complex scenario where the molecular features of tumours seem to be the cornerstone of any therapy is now emerging. Here we provide an overview on the different approaches to cancer treatment. This review will help the reader to acknowledge the pivotal role of some classic cancer therapies, including surgery, radiation, chemotherapy and endocrine therapy, now better understood in the mechanims underpinning their efficacy. Following, we focus on the understanding of the value of systemic treatment and on an up-date on the novel, up-coming therapies of the current targeted therapy age, including new antibodies, small molecules, antiangiogenics and viral therapy. We briefly elaborate, finally, on new biomarkers development and how it should rule and determine the future of therapeutic research in cancer.

The need for axillary lymph node dissection (ALND) in breast cancer patients with sentinel lymph node (SLN) micrometastases remains controversial. The aims of the study were to evaluate the locoregional failure and outcome of breast cancer patients with sentinel node micrometastases who did not undergo completion ALND.Between November 2000 and December 2006, SLN biopsy was successfully performed in 1178 patients with invasive breast carcinoma. Only patients with macrometastasis (2 mm) underwent ALND, while patients with negative SLN or micrometastases did not undergo further treatment of the axilla, by either surgery or radiotherapy. Regarding adjuvant therapy decision, patients with SLN-micrometastases (pN1(mi)) were considered as node-positive patients.Of 1,178 patients, 59 (5%) had micrometastases. Of those with micrometastases, 14 (24%) underwent ALND because the intraoperative study of the SLN yielded a positive result. With a median follow-up of 60 (range, 8-94) months, none of the patients with SLN micrometastases in whom ALND was omitted developed an axillary recurrence, while one patient in whom ALND was performed developed infraclavicular lymph node recurrence. One patient, who declined postoperative breast irradiation, developed breast recurrence and distant metastasis.Breast cancer patients with SLN micrometastases in whom ALND was omitted had a very low locoregional failure rate. This study supports the theory that ALND might be avoided in these patients, providing that adjuvant systemic treatment equal to treatment provided to treat node-positive disease is administered. However, longer follow-up and results of additional prospective studies are needed.

Purpose: Fatty acid synthase (FASN) is overexpressed in human breast carcinoma. The natural polyphenol (−)-epigallocatechin-3-gallate blocks in vitro FASN activity and leads to apoptosis in breast cancer cells without any effects on carnitine palmitoyltransferase-1 (CPT-1) activity, and in vivo, does not decrease body weight. We synthesized a panel of new polyphenolic compounds and tested their effects on breast cancer models. Experimental Design: We evaluated the in vitro effects of the compounds on breast cancer cell growth (SK-Br3, MCF-7, and MDA-MB-231), apoptosis [as assessed by cleavage of poly(ADP-ribose) polymerase], cell signaling (HER2, ERK1/2, and AKT), and fatty acid metabolism enzymes (FASN and CPT-1). In vivo, we have evaluated their antitumor activity and their effect on body weight in a mice model of BT474 breast cancer cells. Results: Two compounds potently inhibited FASN activity and showed high cytotoxicity. Moreover, the compounds induced apoptosis and caused a marked decrease in the active forms of HER2, AKT, and ERK1/2 proteins. Interestingly, the compounds did not stimulate CPT-1 activity in vitro. We show evidence that one of the FASN inhibitors blocked the growth of BT474 breast cancer xenografts and did not induce weight loss in vivo. Conclusions: The synthesized polyphenolic compounds represent a novel class of FASN inhibitors, with in vitro and in vivo anticancer activity, that do not exhibit cross-activation of β-oxidation and do not induce weight loss in animals. One of the compounds blocked the growth of breast cancer xenografts. These FASN inhibitors may represent new agents for breast cancer treatment. (Clin Cancer Res 2009;15(24):7608–15)

Objective The aim of the study was to determine the evolution of patients with internal mammary chain (IMC) drainage whether the IMC-sentinel lymph node (IMC-SLN) was biopsied or not, as well as to determine the clinical implications of the biopsy of the IMC-SLN (IMC-SLNB) in patients with breast cancer and IMC drainage in the lymphoscintigraphy. Methods Eighty-two out of 914 patients included in a prospective database of sentinel node (9%) showed IMC drainage and were included in the study. Two groups were established depending on the IMC-SLN removal: group A (IMC-SLN were removed): 44 patients, mean age 48.8 years, mean follow-up, 35.8 months. Group B (IMC-SLN were not removed): 38 patients, mean age 54.5 years, mean follow-up, 33.5 months. Kaplan-Meier plots were used to determine the overall survival rates. Results Group A: four patients showed only IMC drainage, six patients presented positive IMC-SLN, nodal staging changed in five patients, treatment changed in two patients and tumour node metastasis stage grouping changed in three patients. All patients are currently disease-free. Group B: two patients showed only IMC drainage, axillary-SLN were positive in 12 patients, one patient presented nodal axillary and breast recurrence as well as distant disease and one patient presented multiorganic disease. This last patient died. The overall survival rates were very similar in both the groups. Conclusion IMC-SLNB improves nodal staging in breast cancer but has little impact on adjuvant treatment. However, it should be performed to obtain results, which will determine in the future whether it improves survival rates or not.

Gene expression profiling has identified cancer prognostic and predictive signatures with superior performance to conventional histopathological or clinical parameters. Consequently, signatures are being incorporated into clinical practice and will soon influence everyday decisions in oncology. However, the slight overlap in the gene identity between signatures for the same cancer type or condition raises questions about their biological and clinical implications. To clarify these issues, better understanding of the molecular properties and possible interactions underlying apparently dissimilar signatures is needed. Here, we evaluated whether the signatures of 24 independent studies are related at the genome, transcriptome or proteome levels. Significant associations were consistently observed across these molecular layers, which suggest the existence of a common cancer cell phenotype. Convergence on cell proliferation and death supports the pivotal involvement of these processes in prognosis, metastasis and treatment response. In addition, functional and molecular associations were identified with the immune response in different cancer types and conditions that complement the contribution of cell proliferation and death. Examination of additional, independent, cancer datasets corroborated our observations. This study proposes a comprehensive strategy for interpreting cancer signatures that reveals common design principles and systems-level properties.

It is increasingly clear that complex networks of relationships between genes and/or proteins govern neoplastic processes. Our understanding of these networks is expanded by the use of functional genomic and proteomic approaches in addition to computational modeling. Concurrently, whole-genome association scans and mutational screens of cancer genomes identify novel cancer genes. Together, these analyses have vastly increased our knowledge of cancer, in terms of both "part lists" and their functional associations. However, genetic interactions have hitherto only been studied in depth in model organisms and remain largely unknown for human systems. Here, we discuss the importance and potential benefits of identifying genetic interactions at the human genome level for creating a better understanding of cancer susceptibility and progression and developing novel effective anticancer therapies. We examine gene expression profiles in the presence and absence of co-amplification of the 8q24 and 20q13 chromosomal regions in breast tumors to illustrate the molecular consequences and complexity of genetic interactions and their role in tumorigenesis. Finally, we highlight current strategies for targeting tumor dependencies and outline potential matrix screening designs for uncovering molecular vulnerabilities in cancer cells.

Purpose: Ovarian failure and infertility following adjuvant chemotherapy for early breast cancer are major concerns for some young women. Techniques for oocyte harvesting are associated with delay in starting treatment, potentially undesirable estrogen stimulation and a relatively low success rate. We report an audit of our experience with the luteinising hormone-releasing hormone agonist, goserelin, to achieve transient ovarian suppression during chemotherapy as a means of preserving ovarian function. Patient and methods: Pre-menopausal women were offered goserelin 3.6 mg by subcutaneous injection every 28 days during chemotherapy, starting 0–14 days prior to treatment. The primary end-point was recovery of menstruation. Serum luteinising hormone, follicle stimulating hormone and oestradiol were measured at recovery of menstruation or at first year follow-up if amenorrhoea persisted. Subsequent pregnancies were recorded. Results: Fifty-one evaluable women were audited. Amenorrhoea occurred in all but one. All received combination anthracycline-containing chemotherapy regimens with a mean cumulative cyclophosphamide dose of 3.9 g/m2. Forty-five (90%) recovered menstruation during the first year of follow-up; mean time to recovery 5 months. Eight pregnancies in 10 women attempting this so far. Conclusion: Using goserelin concurrently with chemotherapy is associated with a high rate of ovarian function preservation.

Background The consecutive acquisition of genetic alterations characterizes neoplastic processes. As a consequence of these alterations, molecular interactions are reprogrammed in the context of highly connected and regulated cellular networks. The recent identification of the collection of somatically mutated genes in breast tumors (breast cancer somatic "mutome") allows the comprehensive study of its function and organization in complex networks. Results We analyzed functional genomic data (loss of heterozygosity, copy number variation and gene expression in breast tumors) and protein binary interactions from public repositories to identify potential novel components of neoplastic processes, the functional relationships between them, and to examine their coordinated function in breast cancer pathogenesis. This analysis identified candidate tumor suppressors and oncogenes, and new genes whose expression level predicts survival rate in breast cancer patients. Mutome network modeling using different types of pathological and healthy functional relationships unveils functional modules significantly enriched in genes or proteins (genes/proteins) with related biological process Gene Ontology terms and containing known breast cancer-related genes/proteins. Conclusion This study presents a comprehensive analysis of the breast somatic mutome, highlighting those genes with a higher probability of playing a determinant role in tumorigenesis and better defining molecular interactions related to the neoplastic process.

Molecular markers have been extensively investigated with a view to providing early and accurate information on long-term outcome and prediction of response to treatment of early breast cancer. Proliferation is a key feature of the progression of tumors and is now widely estimated by the immunohistochemical assessment of the nuclear antigen Ki-67. The expression of Ki-67 correlates with other measurements of proliferation, including S-phase and bromodeoxyuridine uptake. High Ki-67 is a sign of poor prognosis associated with a good chance of clinical response to chemotherapy, but its independent significance is modest and does not merit measurements in most routine clinical scenarios. However, its application as a pharmacodynamic intermediate marker of the effectiveness of medical therapy holds great promise for rapid evaluation of new drugs.

Background: Superior vena cava syndrome (SVCS) is a frequent presentation of malignancies involving the mediastinum and can seriously compromise treatment options and prognosis. Stenting of superior vena cava is a well-known but not so commonly used technique to alleviate this syndrome. Patients and methods: Between August 1993 and December 2000 we performed 52 stenting procedures in patients affected by non-small cell lung cancer (NSCLC). Results: Phlebographic resolution of the obstruction was achieved in 100% of cases with symptomatic and subjective improvement in more than 80%. One major complication was observed due to bleeding during anticoagulation. Re-obstruction of the stent occurred in only 17% of the cases, the majority due to disease progression. Improvement of the syndrome allowed hydration necessary for full dose platinum treatment when indicated in patients affected by lung cancer. Conclusions: Stenting of the superior vena cava syndrome is a safe and effective procedure achieving a rapid alleviation of symptoms in almost all patients, and allowing for full dose treatment in lung cancer patients. This procedure could change the traditional poorer prognosis attributed to non-small cell lung cancer patients presenting with this syndrome.