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IntroductionPolyphenols have shown capacity to improve appetite sensation, leading to enhanced control of body weight. However, despite being related with hunger-related hormones, metabolic and mechanism are not well known.MethodsThe effectiveness of a nutraceutical composed of extract toLippia citriodoraandHibiscus sabdarrifa(Lc-Hs) for controlling satiety and hunger was analyzed in a cross-over, placebo-controlled (Pla) clinical intervention. The study was divided in two 60-day periods separated by 30-day length wash-out period. At the end of each period, overweight and obese subjects (n = 33; age = 33.76 ± 12.23; BMI = 28.20 kg/m2 ± 2.47; fat mass 30.65 ± 8.39%; both sexes were proposed to eat an ad-libitum meal. Meanwhile, appetite sensation was determined by visual analog scales at different times. Moreover, blood extraction was performed to determine biochemical parameters (lipid and glucidic profile and safety parameters) and to evaluate hunger-related hormones (insulin, leptin, ghrelin, adiponectin, GLP-1 and peptide YY).ResultsA decrease in appetite sensation was observed in Lc-Hs treatment, showing higher satiety quotient (Pla = 3.36 ± 2.33%mm/kcal; Lc-Hs = 5.53 ± 2.91%mm/kcal;p xmin−1; Lc-Hs 8279.73 ± 2745.71%xmin−1;p p p p ConclusionThe supplementation with the Lc-Hs extract decreases appetite sensation in overweight and obese population, reducing calorie intake after an ad-libitum meal. Due to variation on hunger-related hormones and the relationship between satiety feeling, it would be interesting to develop future research focused on the variation of the hormones themselves.

There is scientific evidence of the positive effect of polyphenols from plant foods on inflammation and oxidative status. The aim of the present study was to investigate whether treatment with a high-polyphenolic nutraceutical reduces the plasmatic concentration of certain oxidative and inflammatory biomarkers in a healthy population. One hundred and eight subjects were selected and stratified by sex in the intervention group (n = 53) and the placebo group (n = 55). Ninety-two subjects completed the study after two 16-week treatment periods separated by a four-week washout period. The results revealed statistically significant differences in subjects treated with the polyphenolic extract compared to the placebo: A decrease in homocysteine, oxidized low-density lipoprotein (OxLDL), TNF-α, sTNFR1, and C-reactive protein (CRP). The most significant decrease was observed for OxLDL (from 78.98 ± 24.48 to 69.52 ± 15.64, p &lt, 0.05) and CRP (from 1.50 ± 0.33 to 1.39 ± 0.37, 0.05), both showing significant differences compared to the placebo (p &lt, 0.001). Moreover, catecholamines increased after the administration of the product under investigation, especially in the case of dopamine (from 15.43 ± 2.66 to 19.61 ± 5.73, 0.05). Therefore, the consumption of a nutraceutical based on fruit and vegetables with a high polyphenol content seems to improve the parameters related to health benefits (oxidative and inflammatory biomarkers), including remarkable changes in the expression of catecholamines.

Background Copy Number Alterations (CNAs) represent changes in the copy number of genomic segments of somatic cells due to chromosomal instability. CNAs include gene amplifications or deletions and can be involved in tumorigenesis. We analyzed CNAs data in pre- and post-treatment (ttm) tumors from patients (pts) with early breast cancer (BC) in the neoadjuvant trials GEICAM/2006-03 and GEICAM/2006-14, with the aim to identify CNAs in particular genomic regions (genetic entropy) associated with treatment response. Methods GEICAM/2006-03 (NCT00432172) HER2-negative pts were selectively treated according to clinical subtypes: triple negative (TN) pts were treated with standard anthracycline/taxane -based chemotherapy (AT-CT) +/- carboplatin, while luminal patients were randomized to AT-CT vs. hormonotherapy; GEICAM/2006-14 (NCT00841828) HER2+ pts received AT-CT plus anti-HER2 therapy.Shallow-whole genome Illumina sequencing DNA data from 204 paraffin-embedded tumors (100 pre- and 104 post-ttm) were segmented to obtain CNAs and recurrent altered genomic regions were defined. We used Wilcoxon test to analyze the frequency of altered regions and logistic regression analyses to explore their association with tumor response, in terms of pathological complete response (pCR) in breast and axilla. Validation of altered genes associated with therapy response was performed in the microarray gene expression-based Hatzis dataset (GSE25066) from pts receiving neoadjuvant AT-CT (1). Results A total of 672 regions covering the whole genome were identified upon analysis of CNAs data. Regions were categorized according to their alteration status as amplified, normal and lost. Comparative analysis of alterations revealed 11 regions significantly different (p Conclusions According to our results, neoadjuvant therapy can modulate genomic aberrations landscape in BC. Our data suggest that amplification of specific genes in the genomic locus (21q22.12) is involved in the neoadjuvant therapy response in early BC. (1): Hatzis et al., JAMA 2011, 305(18) 1873-81 Citation Format: Alba E, Rueda OM, Lluch A, Albanell J, Chin S-F, Chacón JI, Calvo L, De la Haba-Rodriguez J, Bermejo B, Ribelles N, Sánchez-Rovira P, Plazaola A, Barnadas A, Cirauqul B, Ramos M, Arcusa A, Carrasco E, Herranz J, Chiesa M, Caballero R, Santonja A, Rojo F, Caldas C. Genome copy number entropy as predictor of response for neoadjuvant therapy in early breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-12-03.

Purpose We aimed to evaluate the current situation of electronic health records (EHRs) and patient registries in the oncology departments of hospitals in Spain. Methods This was a cross-sectional study conducted from December 2018 to September 2019. The survey was designed ad hoc by the Outcomes Evaluation and Clinical Practice Section of the Spanish Society of Medical Oncology (SEOM) and was distributed to all head of medical oncology department members of SEOM. Results We invited 148 heads of oncology departments, and 81 (54.7%) questionnaires were completed, with representation from all 17 Spanish autonomous communities. Seventy-seven (95%) of the respondents had EHRs implemented at their hospitals; of them, over 80% considered EHRs to have a positive impact on work organization and clinical practice, and 73% considered that EHRs improve the quality of patient care. In contrast, 27 (35.1%) of these respondents felt that EHRs worsened the physician–patient relationship and conveyed an additional workload (n = 29; 37.6%). Several drawbacks in the implementation of EHRs were identified, including the limited inclusion of information on both outpatients and inpatients, information recorded in free text data fields, and the availability of specific informed consent. Forty-six (56.7%) respondents had patient registries where they recorded information from all patients seen in the department. Conclusion Our study indicates that EHRs are almost universally implemented in the hospitals surveyed and are considered to have a positive impact on work organization and clinical practice. However, EHRs currently have several drawbacks that limit their use for investigational purposes. Clinical trial registration Not applicable

Chemotherapy-Related Cognitive Impairment (CRCI) can be an adverse effect in women treated for breast cancer. Some longitudinal studies reported deficits in attention, memory, and executive function following treatment, but other studies did not find cognitive changes. It is known that practice effects (PE) on repeated assessments with cognitive tests contribute to the discrepancies in these results, but its influence on scores has not been systematically explored. The present study examines the impact of PE on retest scores in a group of women with breast cancer treated with chemotherapy and evaluated longitudinally.51 women with breast cancer treated with a combination of 5-fluorouracil, epirubicin, and cyclophosphamide with or without taxanes were assessed after surgery but before chemotherapy (T1), post-chemotherapy (T2), and at one year after T2 (T3). Longitudinal changes on cognitive performance were analyzed twice: when retest scores were not corrected for PE and when correction for PE was applied to T2 and T3 scores.When PE was not corrected, progressive improvement over time in measures of memory and divided attention at T2 and T3 was observed. In contrast, when PE was corrected, worsening was found in measures of memory, fluency, executive function, and attention at T2 and in attention and executive function at T3. Results after correction for PE are in line with previous longitudinal studies that report cognitive impairment after treatment with chemotherapy for breast cancer.Accounting for PE is recommended to identify true change on cognition through treatment with chemotherapy for breast cancer.

The aim of this study is to elucidate the role of taxanes on cognition when they are administered as a part of the treatment with a fluorouracil, epirubicin and cyclophosphamide (FEC) regimen for breast cancer (BC). Two groups of women (n = 51) with a novel diagnostic of BC that were treated with a combination of FEC alone (6 cycles of FEC) or with taxanes (4 cycles of FEC plus 8 cycles of taxanes) were compared at three moments: before chemotherapy, after its completion (short-term evaluation) and at a mean of 74.5 weeks from baseline as a long-term evaluation. Both groups showed worsening in tests of attention and executive functions on the short-term assessment, with the group treated with taxanes showing more number of affected cognitive measures at this time point, including verbal learning and speed measures. At the long-term evaluation, cognitive dysfunction was still found in attention and executive functions in both groups. Our results suggest that chemotherapy for BC with a FEC regimen can have a negative effect on cognition. Acute deficits seem to be larger when taxanes are added, but treatment seems to affect cognition also at long term.

Debulking surgery, followed by taxane/platinum-based chemotherapy has traditionally been the first-line treatment for advanced ovarian cancer. However, most patients will experience recurrence afterwards, and receive subsequent lines of therapy. It has been proposed that extending the treatment-free interval of platinum can improve the response to a subsequent platinum-based chemotherapy, and reduce associated toxicities in women with recurrent, platinum-sensitive ovarian cancer. The aim was to determine the impact, in clinical practice, of trabectedin with pegylated liposomal doxorubicin (trabectedin/PLD) on the subsequent platinum-based therapy in these patients, and to explore the prognosis for breast cancer gene status and the expression of diverse genes. This was a multicenter, retrospective, postauthorization study that involved 79 patients. Germline or somatic mutations of breast cancer gene 1/2 were present in 21.5%. The median time between trabectedin/PLD and the onset of the subsequent treatment was 6.7 months. The overall response rate during the trabectedin/PLD period was 36.7%. In the subsequent first-line platinum-based therapy, the overall response rate was 51.4%. Progression-free survival and overall survival were 11.8 and 25.4 months, respectively, from the onset of trabectedin/PLD treatment. Partially platinum-sensitive (between 6 and 12 months) and platinum-sensitive patients (treatment-free interval of platinum >= 12 months) showed no differences in progression-free survival and overall survival. Grade 3 neutropenia and asthenia were reported in 15.2 and 10.1% of patients, respectively. Most frequent adverse events in more than 10% of patients were neutropenia (45.6%), asthenia (43.0%), nausea (25.3%), and anemia (13.9%). The intercalation with a nonplatinum regimen may improve the response to a subsequent platinum-based therapy in women with recurrent, platinum-sensitive ovarian cancer.

To evaluate the effect of boost radiotherapy on ipsilateral breast tumor recurrence (IBTR) for ductal carcinoma in situ (DCIS) after breast-conserving surgery and whole breast radiotherapy (WBRT) with or without boost.Retrospective, multicentre study of 622 patients (624 tumors) diagnosed with pure DCIS from 1993-2011.Most tumors (377/624; 60.4%) received a boost. At a median follow-up of 8.8 years, IBTR occurred in 64 cases (10.3%). A higher percentage of patients with risk factors for IBTR received a boost (p 0.05). Boost was not associated with lower rates of IBTR than WBRT alone (HR 0.75, 95% CI 0.42-1.35). On the univariate analyses, IBTR was significantly associated with tumor size (11-20 mm, HR 2.32, 95% CI 1.27-4.24; and 20 mm, HR 2.10, 95% CI 1.14-3.88), re-excision (HR 1.76, 95% CI 1.04-2.96), and tamoxifen (HR 2.03, 95% CI 1.12-3.70). Boost dose 16 Gy had a protective effect (HR 0.39, 95% CI 0.187-0.824). Multivariate analyses confirmed the independent associations between IBTR and 11-20 mm (p = 0.02) and 20 mm (p = 0.009) tumours, and re-excision (p = 0.006). On the margin-stratified multivariate analysis, tamoxifen was a poor prognostic factor in the close/positive margin subgroup (HR 4.28 95% CI 1.23-14.88), while the highest boost dose ( 16 Gy) had a significant positive effect (HR 0.34, 95% CI 0.13-0.86) in the negative margin subgroup.Radiotherapy boost did not improve the risk of IBTR. Boost radiotherapy was more common in patients with high-risk disease. Tumor size and re-excision were significant independent prognostic factors.

The aim of the study was to analyze how cardiovascular risk factors can be modified using nutritionally improved cooked ham enriched with a pool of antioxidants to influence relevant metabolic targets. Sixty-five untreated subjects (49.2% males, 50.8% females, mean age 40.92 ± 9.03 years) with total cholesterol level ≥180 mg/dL or LDL cholesterol ≥130 mg/dL participated in a 8-weeks randomized, double-blind controlled trial. Participant in the intervention group (51.5% males, 48.5% females, mean age 41.6 ± 9.8 years and mean BMI 25.1 ± 3.6 kg/m2) consumed cooked ham enriched with antioxidants (100 g/d) and controls (49.9% males, 53.1% females, mean age 40.2 ± 8.3 years and mean BMI 26.3 ± 3.2 kg/m2) received placebo. At 8 weeks, oxidized LDL decreased significantly between experimental and placebo groups (p < 0.036). Experimental group differences were also significant (p < 0.05). Similar findings in malondialdehyde, total cholesterol, high-sensitivity C-reactive protein, and interleukin 6 were observed in the intervention group. Significant between-group differences in these variables were also found, except for total cholesterol and interleukin 6. The effects on inflammation and oxidation support the direct action of these antioxidants on the etiopathogenic factors of atheromatous plaque. We also observed an improvement in the lipid profiles among the subjects.

The clinical index of stable febrile neutropenia (CISNE) can contribute to patient safety without increasing the complexity of decision-making. However, febrile neutropenia (FN) is a diverse syndrome. The aim of this analysis is to assess the performance of CISNE according to the type of tumor and infection and to characterize these patients. We prospectively recruited 1383 FN episodes in situations of apparent clinical stability. Bonferroni-adjusted z tests of proportions were used to assess the association between the infections suspected at the time of onset and the type of tumor with the risk of serious complications and mortality. The performance of CISNE was appraised in each category using the Breslow-Day test for homogeneity of odds ratios and Forest Plots. 171 patients had a serious complication (12.3 %, 95 % confidence interval 10.7–14.2 %). The most common initial assumptive diagnoses were: fever without focus (34.5 %), upper respiratory infection (14.9 %), enteritis (12.7 %), stomatitis (11.8 %), and acute bronchitis (10.7 %). Lung and breast were the most common tumors, accounting for approximately 56 % of the series. The distribution of complications, mortality, and bacteremia varies for each of these categories. However, Breslow-Day tests indicate homogeneity of the odds ratio of the dichotomized CISNE score to predict complications in all infection and tumor subtypes. Despite FN’s clinical and microbiological heterogeneity, the CISNE score was seen to be consistent and robust in spite of these variations. Hence, it appears to be a safe tool in seemingly stable FN.

Adiposity and physical activity are modifiable factors that could be important determinants of breast cancer (BC) prognosis through their effects on endogenous reproductive hormones, chronic inflammation and metabolic changes. Therefore, it is necessary to evaluate whether offering lifestyle interventions to BC survivors could affect the levels of certain biomarkers involved in these mechanisms. We designed a pre-post intervention study offering diet and exercise sessions over 12 weeks to 42 overweight/obese BC survivors. Before and after the intervention, we obtained dietary information, anthropometry and cardiorespiratory fitness (CRF) measurements and blood samples to measure metabolic risk, insulin resistance and adipokines biomarkers. Wilcoxon signed-rank tests and Spearman partial correlation coefficients were used to compare pre- and post-measurements and assess the correlations between changes in biomarkers and changes in anthropometry and CRF. Breast cancer survivors showed significant improvements in metabolic risk biomarkers and insulin resistance indicators along with a non-significant leptin decrease and a significant adiponectin decrease. The improvements in metabolic risk biomarkers, insulin resistance indicators and leptin were moderately correlated (0.32 ≤ |r| ≤ 0.55) with the decrease in body mass index and the increase in CRF. Diet and exercise interventions implemented in overweight/obese BC survivors may improve metabolic risk, insulin resistance and leptin biomarkers.

Purpose: Hormone receptor–positive (HR+) breast cancer is clinically and biologically heterogeneous, and subgroups with different prognostic and treatment sensitivities need to be identified. Experimental Design: Research-based PAM50 subtyping and expression of additional genes was performed on 63 patients with HR+/HER2− disease randomly assigned to neoadjuvant multiagent chemotherapy versus endocrine therapy in a phase II trial. The biology associated with treatment response was used to derive a PAM50-based chemoendocrine score (CES). CES's predictive ability was evaluated in 4 independent neoadjuvant data sets (n = 675) and 4 adjuvant data sets (n = 1,505). The association of CES, intrinsic biology, and PAM50 risk of relapse (ROR) was explored across 6,007 tumors. Results: Most genes associated with endocrine sensitivity were also found associated with chemotherapy resistance. In the chemotherapy test/validation data sets, CES was independently associated with pathologic complete response (pCR), even after adjusting for intrinsic subtype. pCR rates of the CES endocrine–sensitive (CES-E), uncertain (CES-U), and chemotherapy-sensitive (CES-C) groups in both data sets combined were 25%, 11%, and 2%, respectively. In the endocrine test/validation data sets, CES was independently associated with response. Compared with ROR, >90% of ROR-low and ROR-high tumors were identified as CES-E and CES-C, respectively; however, each CES group represented >25% of ROR-intermediate disease. In terms of survival outcome, CES-C was associated with poor relapse-free survival in patients with ROR-intermediate disease treated with either adjuvant endocrine therapy only or no adjuvant systemic therapy, but not in patients treated with (neo)adjuvant chemotherapy. Conclusions: CES is a genomic signature capable of estimating chemoendocrine sensitivity in HR+ breast cancer beyond intrinsic subtype and risk of relapse. Clin Cancer Res; 23(12); 3035–44. ©2016 AACR.

Improved understanding of risk of recurrence (ROR) is needed to reduce cases of recurrence and more effectively treat breast cancer patients. The purpose of this study was to examine how a gene-expression profile (GEP), identified by Prosigna, influences physician adjuvant treatment selection for early breast cancer (EBC) and the effects of this influence on optimizing adjuvant treatment recommendations in clinical practice. A prospective, observational, multicenter study was carried out in 15 hospitals across Spain. Participating medical oncologists completed pre-assessment, post-assessment, and follow-up questionnaires recording their treatment recommendations and confidence in these recommendations, before and after knowing the patient’s ROR. Patients completed questionnaires on decision-making, anxiety, and health status. Between June 2013 and January 2014, 217 patients enrolled and a final 200 were included in the study. Patients were postmenopausal, estrogen receptor positive, human epidermal growth hormone factor negative, and node negative with either stage 1 or stage 2 tumors. After receiving the GEP results, treatment recommendations were changed for 40 patients (20%). The confidence of medical oncologists in their treatment recommendations increased in 41.6% and decreased in 6.5% of total cases. Patients reported lower anxiety after physicians made treatment recommendations based on the GEP results (p Though this study does not include evaluation of the impact of GEP on long-term outcomes, it was found that GEP results influenced the treatment decisions of medical oncologists and their confidence in adjuvant therapy selection. Patients’ anxiety about the selected adjuvant therapy decreased with use of the GEP.

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.

Background: Prosigna™ (PAM50) is a standardized test that measures the expression levels of 50 classifier genes in formalin-fixed paraffin-embedded (FFPE) breast tissue tumor samples. It provides subtype classification based on the fundamental biology of an individual patient’s tumor (referred to as "intrinsic subtyping"), as well as a prognostic score (referred to as "risk of recurrence [ROR] score") that predicts the probability of distant recurrence over 10 years. This decision impact study examines whether the Prosigna™ test influences both physician and patient adjuvant treatment selection, beyond standard immunohistochemistry (IHC) testing. Methods: The analytic sample was comprised of postmenopausal women with node-negative, estrogen-receptor positive (ER+), HER2 negative (HER2-), early-stage breast cancer with tumors Results: A total of 200 patients met eligibility criteria and were enrolled in the study between June 2013 and January 2014. According to Prosigna™ results, intrinsic tumor subtypes of these patients were distributed as follows: 129 Luminal A (64.5%), 66 Luminal B (33.0%), 3 HER2-enriched (1.5%) and 2 basal-like (1.0%). Modifications to the adjuvant treatment recommendations by ROR score can be seen in the following table: Change in physician pre- to post- Prosigna recommendation Low ROR (N=101), N (%)Intermediate ROR (N=66), N (%)High ROR (N=33), N (%)TOTAL (N=200), N (%)HT to CHT0 (0.0)8 (12.1)10 (30.3)18 (9.0)CHT to HT11 (10.9)9 (13.6)0 (0.0)20 (10.0)TOTAL11 (10.9)17 (25.7)10 (30.3)38 (19.0) Treatment decisions changed for 19.0% of all patients: 10.0% and 9.0% of patients went from CHT to HT and HT to CHT, respectively. The percentage of patients who received chemotherapy in the low, intermediate and high risk groups was 5%, 36% and 88%, respectively. Both the central and each local laboratory analyzed the samples using IHC. We found 60% concordance between central IHC and Prosigna™ intrinsic subtypes (Kappa=0.2365). Prosigna™ results were consistent across labs (Kappa = 0.89). Conclusions: The Prosigna™ test can be reliably performed in hospital laboratories to provide useful information beyond standard clinical-pathological variables that oncologists can use to optimize adjuvant treatment decisions in clinical practice. Subtype determined using IHC is not an interchangeable proxy for subtype determined by Prosigna™. *Two last authors have contributed equally to the study. Citation Format: Miguel Martín, Milagros González-Rivera, Serafín Morales, Juan de la Haba, Lucía González-Cortijo, Luis Manso, Joan Albanell, Antonio González-Martín, Sónia González, Angels Arcusa, Luis de la Cruz-Merino, Federico Rojo, Maria Vidal, Uxue Goicoechea, Patricia Galván, Rosalía Caballero, Eva Carrasco, Steven Michalopoulos, John Hornberger, Aleix Prat. Prospective study of the impact of the Prosigna™ assay on adjuvant clinical decision-making in women with estrogen receptor-positive, HER2-negative, node-negative breast cancer: A GEICAM study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-08-10.

BRCA1-associated breast cancers have been associated to a triple-negative phenotype. The prevalence of BRCA1 germline mutations in young onset TNBC based on informativeness of family history has not been reported. From January 2008 to May 2009 were collected blood and tumor samples from patients with TNBC younger than 50 years and without a family history of breast and ovarian cancer in first- and second-degree relatives. Analysis of BRCA1 germline mutations was made. Age at diagnosis and informativeness of family history (presence of female in first- and second-degree relatives alive until age 45) was collected in all cases. Immunohistochemistry of basal-like features was performed centrally in all available tumors. Seven pathogenic mutations were detected in 92 patients (7.6 %), two of them in patients younger than 35 years (28.6 %) (Fisher's exact test, p = 0.631). Three non-classified variants were detected (3.2 %). Family history was informative in two patients with a pathogenic mutation (28.6 %) and not informative in five (71.4 %) (Fisher's exact test, p = 0.121). Of the seven patients with a pathogenic mutation, four had a basal-like phenotype. Patients with apparently sporadic TNBC younger than 50 years and a non-informative family history are candidates for germline genetic testing of BRCA1.

Background Luminal breast cancer is a highly endocrine responsive disease. However, the therapeutic benefit of chemotherapy (CT) in this population is not fully characterized. This study investigates the value of CT and hormone therapy (HT) in luminal breast cancer patients in the neoadjuvant setting. Patients and Methods Patients with operable breast cancer and immunophenotypically defined luminal disease (ER+/PR+/HER2-/cytokeratin 8/18+) were recruited. Patients were randomized to CT (epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 × 4 cycles followed by docetaxel 100 mg/m2 × 4 cycles [EC-T]) or HT (exemestane 25 mg daily × 24 weeks [combined with goserelin in premenopausal patients]). The primary end point was the clinical response measured by magnetic resonance imaging. Results Ninety-five patients were randomized (47 CT, 48 HT). The clinical response rate was 66% for CT and 48% for HT (P = 0.075). We performed an unplanned analysis based on Ki67 levels (cut-off of 10%). Similar clinical response was seen between arms in patients with low Ki67 (CT: 63%, HT: 58%; P = 0.74); patients with high Ki67 had a better response with CT (67 versus 42%; P = 0.075). Grade 3/4 toxicity was more frequent with CT. Conclusions Luminal immunophenotype is not enough to identify patients who do not benefit from neoadjuvant CT. Luminal patients with low proliferation index could potentially avoid CT.

This work was presented, in part, as an oral communication at the ASCO 2012 annual meeting (Abstract #10500). Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; BACKGROUND In this study, we evaluated the ability of gene expression profiles to predict chemotherapy response and survival in triple-negative breast cancer (TNBC). METHODS Gene expression and clinical-pathological data were evaluated in five independent cohorts, including three randomised clinical trials for a total of 1055 patients with TNBC, basal-like disease (BLBC) or both. Previously defined intrinsic molecular subtype and a proliferation signature were determined and tested. Each signature was tested using multivariable logistic regression models (for pCR (pathological complete response)) and Cox models (for survival). Within TNBC, interactions between each signature and the basal-like subtype (vs other subtypes) for predicting either pCR or survival were investigated. RESULTS Within TNBC, all intrinsic subtypes were identified but BLBC predominated (55-81%). Significant associations between genomic signatures and response and survival after chemotherapy were only identified within BLBC and not within TNBC as a whole. In particular, high expression of a previously identified proliferation signature, or low expression of the luminal A signature, was found independently associated with pCR and improved survival following chemotherapy across different cohorts. Significant interaction tests were only obtained between each signature and the BLBC subtype for prediction of chemotherapy response or survival. CONCLUSIONS The proliferation signature predicts response and improved survival after chemotherapy, but only within BLBC. This highlights the clinical implications of TNBC heterogeneity, and suggests that future clinical trials focused on this phenotypic subtype should consider stratifying patients as having BLBC or not. Yes

Background: We sought to develop and externally validate a nomogram and web-based calculator to individually predict the development of serious complications in seemingly stable adult patients with solid tumours and episodes of febrile neutropenia (FN). Patients and methods: The data from the FINITE study (n = 1133) and University of Salamanca Hospital (USH) FN registry (n = 296) were used to develop and validate this tool. The main eligibility criterion was the presence of apparent clinical stability, defined as events without acute organ dysfunction, abnormal vital signs, or major infections. Discriminatory ability was measured as the concordance index and stratification into risk groups. Results: The rate of infection-related complications in the FINITE and USH series was 13.4% and 18.6%, respectively. The nomogram used the following covariates: Eastern Cooperative Group (ECOG) Performance Status >= 2, chronic obstructive pulmonary disease, chronic cardiovascular disease, mucositis of grade >= 2 (National Cancer Institute Common Toxicity Criteria), monocytes 0.1). The concordance index was 0.855 and 0.831 in each series. Risk group stratification revealed a significant distinction in the proportion of complications. With a >= 116-point cutoff, the nomogram yielded the following prognostic indices in the USH registry validation series: 66% sensitivity, 83% specificity, 3.88 positive likelihood ratio, 48% positive predictive value, and 91% negative predictive value. Conclusions: We have developed and externally validated a nomogram and web calculator to predict serious complications that can potentially impact decision-making in patients with seemingly stable FN.

579Background: Integrative Clustering (IntClust) is a breast cancer (BC) classification of 10 different subgroups with distinctive molecular profiles and clinical outcomes (Curtis et al., Nature 20...

Background: Germline mutation screening of BRCA1 and BRCA2 genes is performed in suspected familial breast cancer cases, but a causative mutation is found in only 30% of patients. The development of additional methods to identify good candidates for BRCA1 and BRCA2 analysis would therefore increase the efficacy of diagnostic mutation screening. With this in mind, we developed a study to determine molecular signatures of BRCA1—or BRCA2—mutated breast cancers. Materials and Methods: Array-cgh (comparative genomic hybridization) and transcriptomic analysis were performed on a series of 103 familial breast cancers. The series included 7 breast cancers with a BRCA1 mutation and 5 breast cancers with a BRCA2 mutation. The remaining 91 cases were obtained from 73 families selected on the basis of at least 3 affected first-degree relatives or at least 2 affected first-degree relatives with breast cancer at an average age of 45 years. Array-cgh analyses were performed on a 4407 BAC-array (CIT-V8) manufactured by IntegraGen. Transcriptomic analyses were performed using an Affymetrix Human Genome U133 Plus 2.0 chip. Results: Using supervised clustering analyses we identified two transcriptomic signatures: one for BRCA1-mutated breast cancers consisting of 600 probe sets and another for BRCA2-mutated breast cancers also consisting of 600 probes sets. We also defined cgh-array signatures, based on the presence of specific genomic rearrangements, one for BRCA1-mutated breast cancers and one for BRCA2-mutated breast cancers. Conclusions: This study identified molecular signatures of breast cancers with BRCA1 or BRCA2 germline mutations. Genes present in these signatures could be exploited to find new markers for such breast cancers. We also identified specific genomic rearrangements in these breast cancers, which could be screened for in a diagnostic setting using fluorescence in situ hybridization, thus improving patient selection for BRCA1 and BRCA2 molecular genetic analysis.

Objectives Gemcitabine has well-recognized activity in the treatment of ovarian cancer. Fixed-dose rate (FDR) delivery has been proposed as a more rationale way to administer gemcitabine, to avoid saturation of the enzyme that catalyzes its intracellular transformation into the active metabolites, difluorodeoxycitidine biphosphate, and triphosphate. Our aim was to assess clinical activity of gemcitabine delivered by FDR infusion in patients with platinum resistant ovarian cancer. Materials and methods Patients with platinum-resistant ovarian cancer received gemcitabine 1000 mg/m(2) over 120 minutes on days 1 and 8 of each cycle. Cycles were repeated every 3 weeks, and up to 6 cycles were delivered. Results Forty-eight patients were included in the study. Among 41 patients evaluable for response, 9 clinical responses (1 complete response and 8 partial responses) were observed, achieving a global response rate of 22%. Grade 3 to 4 hematological toxicity consisted of anemia (15% of patients), neutropenia (24%), and thrombopenia (10%). One patient died due to septic shock. The main grade 3 to 4 nonhematological toxicity was asthenia (7 patients, 17%). Conclusion Activity of gemcitabine administered by FDR infusion in patients with platinum-resistant ovarian cancer seems similar to that achieved using 30-minute infusions, with higher toxicity.

Purpose To validate a prognostic score predicting major complications in patients with solid tumors and seemingly stable episodes of febrile neutropenia (FN). The definition of clinical stability implies the absence of organ dysfunction, abnormalities in vital signs, and major infections. Patients and Methods We developed the Clinical Index of Stable Febrile Neutropenia (CISNE), with six explanatory variables associated with serious complications: Eastern Cooperative Oncology Group performance status ≥ 2 (2 points), chronic obstructive pulmonary disease (1 point), chronic cardiovascular disease (1 point), mucositis of grade ≥ 2 (National Cancer Institute Common Toxicity Criteria; 1 point), monocytes < 200 per μL (1 point), and stress-induced hyperglycemia (2 points). We integrated these factors into a score ranging from 0 to 8, which classifies patients into three prognostic classes: low (0 points), intermediate (1 to 2 points), and high risk (≥ 3 points). We present a multicenter validation of CISNE. Results We prospectively recruited 1,133 patients with seemingly stable FN from 25 hospitals. Complication rates in the training and validation subsets, respectively, were 1.1% and 1.1% in low-, 6.1% and 6.2% in intermediate-, and 32.5% and 36% in high-risk patients; mortality rates within each class were 0% in low-, 1.6% and 0% in intermediate-, and 4.3% and 3.1% in high-risk patients. Areas under the receiver operating characteristic curves in the validation subset were 0.652 (95% CI, 0.598 to 0.703) for Talcott, 0.721 (95% CI, 0.669 to 0.768) for Multinational Association for Supportive Care in Cancer (MASCC), and 0.868 (95% CI, 0.827 to 0.903) for CISNE (P = .002 for comparison between CISNE and MASCC). Conclusion CISNE is a valid model for accurately classifying patients with cancer with seemingly stable FN episodes.

Background: The aim of the study was to analyse the toxicity and health related quality of life (HRQoL) of breast cancer patients treated with FAC (5-fluorouracil, doxorubicin, cyclophosphamide) and TAC (docetaxel, doxorubicin, cyclophosphamide) with and without primary prophylactic G-CSF (PPG). Patients and methods: This was a phase III study to compare FAC and TAC as adjuvant treatment of high-risk node-negative breast cancer patients. After the entry of the first 237 patients, the protocol was amended to include PPG in the TAC arm due to the high incidence of febrile neutropenia. A total of 1047 evaluable patients from 49 centres in Spain, two in Poland and four in Germany were included in the trial. Side-effects and the scores of the EORTC QLQ-C30 and QLQ BR-23 questionnaires were compared in the three groups (FAC, TAC pre-amendment and TAC post-amendment). Results: The addition of PPG to TAC significantly reduced the incidence of neutropenic fever, grade 2–4 anaemia, asthenia, anorexia, nail disorders, stomatitis, myalgia and dysgeusia. Patient QoL decreased during chemotherapy, more with TAC than FAC, but returned to baseline values afterwards. The addition of PPG to TAC significantly reduced the percentage of patients with clinically relevant Global Health Status deterioration (10 or more points over baseline value) at the end of chemotherapy (64% versus 46%, P < 0.03). Conclusions: The addition of PPG significantly reduces the incidence of neutropenic fever associated with TAC chemotherapy as well as that of some TAC-induced haematological and extrahaematological side-effects. The HRQoL of patients treated with TAC is worse than that of those treated with FAC but improves with the addition of PPG, particularly in the final part of chemotherapy treatment.

Background The purpose of this study was to assess the toxicity and efficacy of the combination of docetaxel and gemcitabine every 2 weeks as first-line therapy in metastatic breast cancer. Patients and Methods We selected patients between the ages of 18 years and 70 years with a Karnofsky performance status of ≥ 60 to receive docetaxel 65 mg/m 2 followed by gemcitabine 2500 mg/m 2 on day 1 every 14 days for 10 cycles. Patients could receive more cycles at the discretion of investigator. Results Of the 52 patients entered, 48 were evaluable for efficacy and toxicity. The overall response rate was 75% (95% confidence interval, 60%–86%), with 8 patients (17%) exhibiting a complete response. The median time to progression was 10.7 months, and the median survival was 32.2 months. The predominant grade 3/4 hematologic toxicity was neutropenia (44% of patients), and the predominant grade 3/4 nonhematologic toxicity was asthenia (15% of patients). Other grade 3/4 toxicities, such as anemia, nausea/vomiting, and diarrhea, were present but infrequent (≤ 10% of patients). The relative dose intensities of both drugs were > 88%. Conclusion The combination of docetaxel/gemcitabine once every 2 weeks is active and well tolerated in patients with untreated advanced breast carcinoma. This chemotherapy regimen might be useful in advanced breast cancer when anthracycline combinations are not preferred, such as cases previously treated with adjuvant anthracycline chemotherapy.

Our objective was to assess the antitumoral activity and toxicity of irinotecan (CPT-11) 60-min i.v. infusion every 2 weeks as second-line monotherapy of advanced colorectal cancer. Two doses were studied (250 and 200 mg/m 2 ) according to the risk of developing toxicity. Two groups of patients were studied: high-risk group (HR, 200 mg/m 2 , n=45; Karnofsky score 60-80% and/or the record of prior pelvic irradiation) and low-risk-group (LR, 250 mg/m 2 , n=51; Karnofsky score >80% and without prior pelvic irradiation). The mean number of cycles per patient was 7: 6.6 (HR group) and 8.3 (LR group). Median RDI was 0.96. The overall response rate was 8.9% [95% confidence interval (Cl) 2.5-21.2%; HR group] and 15.7% (95% Cl 7.0-28.5%; LR group), respectively. The LR group showed two complete responses and a higher percentage of stable disease (56.9 versus 33.3% in HR group). The median survival was 7.1 months (95% Cl 5.2-8.9 months, HR group) and 11.7 months (95% Cl 8.4-15.1 months, LR group). The median time to disease progression was 3.2 months (95% Cl 1.0-5.4 months, HR group) and 5.3 months (95% Cl 3.8-6.7 months, LR group). Both CPT-11 treatments were well tolerated. Grade 3/4 toxicity incidence was low, e.g. granulocytopenia (7% of patients in HR group and 9% in LR group) and delayed diarrhea (18% of patients in HR group and 14% in LR group). We conclude that the treatment of patients with the adjusted dose of CPT-11 according to prognostic factors for toxicity resulted in the improved toxicity profile, but showed poorer efficacy outcome. Therefore, the dose reduction in patients with low performance and treated with radiotherapy needs further investigation to provide some new insights on the benefit:risk ratio of such treatment.

Background A prospective randomized clinical trial was implemented to assess whether the concomitant or the sequential addition of tamoxifen to chemotherapy provides improved clinical benefit in the adjuvant treatment of breast cancer in postmenopausal patients. Patients and methods Four-hundred and eighty-five patients with node-positive operable disease were randomized to receive tamoxifen (20 mg/day) concomitantly (CON) or sequentially (SEQ) to EC chemotherapy (epirubicin 75 mg/m2 + cyclophosphamide 600 mg/m2 on day 1, every 21 days for four cycles). Results In the 474 fully evaluable patients there were 96 events; eight being second neoplasms and 88 being related to the breast cancer. Of these, 48 of 88 occurred in the CON arm and 40 of 88 in the SEQ arm. The Kaplan–Meier estimation of disease-free survival (DFS) at 5 years was 70% in the CON and 75% in the SEQ group (log-rank test, P = 0.43). Adjusted hazard ratio for treatment was 1.11 (95% confidence interval 0.71–1.73; P = 0.64). Conclusion This study fails to show an advantage of one treatment arm over the other, but a trend, albeitnon-significant, appears to favor the sequential addition of tamoxifen to epirubicin + cyclophosphamide and, as such, warrants further investigation.

This phase II study evaluated the activity of gemcitabine (Gemzar) plus cisplatin (Platinol) as first-line treatment of advanced epithelial ovarian cancer. Forty-two chemonaive patients with advanced (stage III and IV) epithelial ovarian cancer received gemcitabine 1,250 mg/m(2) on days 1 and 8 and cisplatin 100 mg/m(2) on day 1, every 3 weeks, up to eight cycles. The median number of cycles completed was 5 (range 2-8). Of the 41 patients evaluable for tumor response, 20 had a partial response and nine had a complete response, for an overall clinical and pathologic response rate of 70.7% (95% CI 56.8-84.6%). Median overall survival for all 42 patients was 23.4 months (95% CI 15.9-29.9 months) and the median progression-free survival time was 10.4 months (95% CI 9.4-13.5 months). The combination was generally manageable. Hematologic toxicity (grade 3/4 neutropenia: 31.0/21.4%; grade 3/4 thrombocytopenia: 9.5/4.8%; grade 3/4 anemia: 11.9/0%) and nausea and vomiting (grade 3/4: 35.7/31.0%) were the most common toxicities. There was one toxic death (septic shock due to hematologic toxicity-induced infection). We conclude that gemcitabine plus cisplatin is active and feasible as first-line treatment of advanced epithelial ovarian cancer. Further clinical trials with the addition of gemcitabine to first-line treatment appear warranted.

The purpose of this study was to evaluate the antitumor activity of vinorelbine and oral estramustine phosphate in patients with metastatic, hormone-refractory prostate cancer. We evaluated the activity of this association using the following schedule: estramustine phosphate 600 mg/m2/day orally days 1-42 and vinorelbine 25 mg/m1 days 1, 8, 22, 29 cycles repeated every 56 days. Twenty-five patients were included in the study, 24 being evaluable for response and 25 for toxicity. Out of 5 patients with measurable disease, none had an objective response. Of the 24 assessable patients with bone metastases, 9 patients had a > or = 65% decline in pretreatment prostate-specific antigen (PSA) level, stable disease was observed in 10 and 5 patients progressed. Toxicities were minimal. Anemia was observed in 5 patients, alopecia in 4 and nausea and vomiting was observed in 6 patients. Anorexia and weight loss of more than 10% were observed in 2 patients. This combination is active and well tolerated in hormone-resistant prostate cancer. These results support the therapeutic strategy of combining agents that impair microtubule function.

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.

Dihydropyrimidine dehydrogenase (DPD) deficiency is a pharmacogenetic syndrome associated with life-threatening toxicity following exposure to the fluoropyrimidine drugs 5-fluorouracil (5-FU) and capecitabine (CAP), widely used for the treatment of colorectal cancer and other solid tumors. The most prominent loss-of-function allele of the DPYD gene is the splice-site mutation c.1905+1G>A. In this study we report the case of a 73-year old woman with metastatic colorectal cancer who died from drug-induced toxicity after the first cycle of 5-FU-containing chemotherapy. Her symptoms included severe neutropenia, thrombocytopenia, mucositis and diarrhea; and she died 16 days later despite intensive care measures. Post-mortem genetic analysis revealed that the patient was homozygous for the c.1905+1G>A deleterious allele and several family members consented to being screened for this mutation. This is the first report in Spain of a case of 5-FU-induced lethal toxicity associated with a genetic defect that results in the complete loss of the DPD enzyme. Although the frequency of c.1905+1G>A carriers in the white population ranges between 1-2%, the few data available for the Spanish population and the severity of this case prompted us to design a genotyping procedure to prevent future toxic effects of 5-FU/CAP. Since our group had previously developed a high-resolution melting (HRM) assay for the simultaneous detection of KRAS, BRAF and/or EGFR somatic mutations in colorectal and lung cancer patients considered for EGFR-targeted therapies, we included the DPYD c.1905+1G>A mutation in the screening test that we describe herein. HRM provides a rapid, sensitive and inexpensive method that can be easily implemented in diagnostic settings for the routine pre-therapeutic testing of a gene mutation panel with implications in the pharmacologic treatment.

BACKGROUND: Aromatase inhibitors are more effective than is tamoxifen in prevention of breast-cancer recurrence, but at the expense of increased musculoskeletal side-effects, such as carpal tunnel syndrome. The aim of this study was to assess risk factors and the prognostic value of musculoskeletal symptoms during treatment with the steroidal aromatase inhibitor exemestane or with tamoxifen after 2-3 years of tamoxifen. METHODS: In the Intergroup Exemestane Study, postmenopausal women treated for early invasive breast cancer who remained disease free and on treatment after 2-3 years of tamoxifen were randomised to switch to exemestane or to continue tamoxifen for the remainder of the 5-year period of endocrine treatment. The primary endpoint for this retrospective analysis was occurrence of carpal tunnel syndrome and any musculoskeletal events, analysed in the safety population, which consisted of all patients who had received any trial treatment. As well as case-report forms, questionnaires were distributed retrospectively to gain more details of cases of carpal tunnel syndrome. The relation between musculoskeletal symptoms reported by 6 months from randomisation and survival from 9 months onwards was assessed by Cox proportional hazards models. The trial is registered, number ISRCTN11883920. It has completed accrual and follow-up is continuing for enrolled participants. FINDINGS: After a median follow-up of 91·0 months (IQR 83·0-99·2), carpal tunnel syndrome had been reported for 66 (2·8%) of 2319 patients in the exemestane group compared with 13 (0·6%) of 2338 in the tamoxifen group (odds ratio [OR] 5·23, 99% CI 2·39-11·49; p

Background: A regimen of docetaxel, doxorubicin, and cyclophosphamide (TAC) is superior to a regimen of fluorouracil, doxorubicin, and cyclophosphamide (FAC) when used as adjuvant therapy in women with node-positive breast cancer. The value of taxanes in the treatment of node-negative disease has not been determined. Methods: We randomly assigned 1060 women with axillary-node-negative breast cancer and at least one high-risk factor for recurrence (according to the 1998 St. Gallen criteria) to treatment with TAC or FAC every 3 weeks for six cycles after surgery. The primary end point was disease-free survival after at least 5 years of follow-up. Secondary end points included overall survival and toxicity. Results: At a median follow-up of 77 months, the proportion of patients alive and disease-free was higher among the 539 women in the TAC group (87.8%) than among the 521 women in the FAC group (81.8%), representing a 32% reduction in the risk of recurrence with TAC (hazard ratio, 0.68; 95% confidence interval [CI], 0.49 to 0.93; P=0.01 by the log-rank test). This benefit was consistent, regardless of hormone-receptor status, menopausal status, or number of high-risk factors. The difference in survival rates (TAC, 95.2%; FAC, 93.5%) was not significant (hazard ratio, 0.76; 95% CI, 0.45 to 1.26); however, the number of events was small (TAC, 26; FAC, 34). Rates of grade 3 or 4 adverse events were 28.2% with TAC and 17.0% with FAC (P

To assess the efficacy of exemestane as neoadjuvant treatment, 55 postmenopausal women ( mean age: 76 years; range: 66-86) with oestrogen-positive non-metastatic breast tumour and ineligible for conservative surgery were recruited into this phase II trial to receive oral exemestane ( 25 mg day(-1)) for 6 months. Tumour response was evaluated by clinical examination, mammography and breast ultrasound every 2 months (RECIST criteria). Overall clinical response to treatment was observed in 33/54 patients (61.1%; 95% CI: 48.1-74.0). Radiological responses in 45 evaluable patients were partial response in 23, stable disease in 21 and disease progression in one. Median time to surgery from the commencement of treatment was 7 months; conservative surgery in 24 patients (55.8%) and mastectomy in 19 patients (34.5%); no surgery ( patient choice or considered not suitable by attending physician) in 12 patients. Pathologic complete response was observed in breast and axilla in one patient (2.3%) and different forms of persistent disease in 23 (53.5%) patients. Treatment tolerance was good. No patient withdrew from the study because of toxic events. We conclude that exemestane as a primary treatment is feasible and very active in elderly patients with large-sized breast cancer tumour. Conservative surgery is feasible in responding patients. No severe adverse events were detected. The optimal hormonal treatment schedule remains to be determined.

In clinical practice, it is possible to classify breast tumors according to estrogen receptor (ER), progesterone receptor (PgR), and HER2 overexpression: ER negative, PgR negative, and HER2 overexpressing; ER negative, PgR negative, and HER2 negative; ER positive, PgR positive, and HER2 negative; ER positive, PgR positive, and HER2 overexpressing; and the less frequent remaining 4 combinations. The aim of this study was to determine the percentage of pathologic complete response (pCR) in patients with locally advanced breast cancer (LABC) treated with neoadjuvant or primary chemotherapy with anthracyclines and taxanes grouped according to ER, PgR, and HER2 status.Patients with LABC treated with primary chemotherapy including anthracyclines and taxanes were grouped according to ER, PgR, and HER2 status; pCR rates were analyzed using the chi(2) test; and correlations with a P value ofor = 0.05 were considered statistically significant.A total of 103 patients were treated. Only 100 patients were included for the analysis of pCR. Eighteen patients exhibited pCR. The pCR rate for each subgroup was as follows: 39.1% (9 of 23) had ER-negative, PgR-negative, and HER2-negative disease (P0.01); 35.7% (5 of 14) had ER-negative, PgR-negative, and HER2-overexpressing disease; 33.3% (3 of 9) had ER-positive, PgR-positive, and HER2-overexpressing disease; and 2.8% (1 of 36) had ER-positive, PgR-positive, and HER2-negative disease (P0.01).In patients with LABC, grouping breast tumors according to ER, PgR, and HER2 status can help predict pCR to primary chemotherapy.

5547 Background: PROC describes a heterogeneous group of patients (pts) with a variable but generally poor prognosis and low response to chemotherapy. Predicting OS in PROC would help stratify pts ...

Purpose: To evaluate the efficacy and safeness of patients with advanced ovary cancer resistant to platinum-based drugs receiving a regime of liposomal adriamycin 35 mg/m 2 and cyclophosphamide 600 mg/m 2 day 1 every 28 days, up to a maximum of 8 cycles. Material y methods: Twenty two evaluable patients were enrolled using the indicated phase II methodology. Results: A response was achieved in 5 out of 21 evaluable patients (23.8%; IC: 5.6-42), with 4 PR (19%; IC: 2.3-35.8) and 1 CR (4.8%; IC: 0-13.9). Hematological toxicity was grade 1,2 anemia in 12 (59%), and 3 (4%), and grade 1-2 neutropenia (26%). Significant non-hematological toxicity was grade 3 fatigue (4%), nausea (4%), and palmoplantar erythrodisesthesia (4%). The mean time was 3.03 months (IC: 0.96-5.11). The median of survival was 6.13 months (IC: 4.32-7.95). The mean duration of the response in patients responding to treatment was 4.73 months (IC: Conclusion: The pegilated liposomal doxorubicin and cyclophosphamide regime administered to patients with advanced ovary cancer resistant to platinum-based drugs is relatively effective and shows low toxicity.

This phase II study was designed to evaluate the efficacy of vinorelbine in combination with estramustine in patients with chemotherapy-naïve hormone-refractory prostate cancer.Patients received vinorelbine (i.v. 25 mg/m2) on days 1 and 8 every 3 weeks and estramustine (oral, 600 mg/m2) daily. Eligible patients were required to have progressive metastatic disease following the first hormonal manipulation.Of the 51 patients enrolled (median age = 69 years), 84% presented bone involvement and 75% had at least two organs involved at the time of study entry and 47 were evaluable for treatment efficacy. Prostate specific antigen (PSA) response (or =50% decrease) which was the primary efficacy criterion was reported in 21 patients (41.2%) in the intent-to-treat (ITT) population and in 20 patients (48.8%) in the per protocol (PP) population. Of the 7 patients with measurable disease, 2 achieved partial response. Median progression-free survival and overall survival were 4.7 months (range: 1.9-8.6) and 14.3 months (range: 4.2-21.2), respectively. Grade 3-4 neutropenia was reported in 6.1% of patients and in 1% of cycles. The incidence of complicated neutropenia (febrile neutropenia reported in 1 patient and septic shock with severe neutropenia reported in 2 patients) was 5.8%. The most frequent grade 3-4 non-haematological events (% of patientsor =5%) included anorexia (10%), thrombosis/embolism (8%), vomiting and hypotension (6% each). There were 3 toxic deaths (5.9 %) resulting from pulmonary embolism, angina pectoris, and septic shock. The impact of combined chemotherapy on the quality-of-life (QL) of the patients was assessed between baseline and the first evaluation scheduled at 6 weeks indicated a marked reduction in pain while the rest of the symptoms remained stable. Overall, health status improved slightly over the treatment period.This study confirmed that the combination of vinorelbine and estramustine is an active regimen in patients with hormone-resistant prostate cancer who had not been treated previously with chemotherapy. Main toxicities included complicated neutropenia even though the incidence of severe neutropenia was low. We observed a higher incidence of toxic deaths which could have been related to the regimen of estramustine used in the study.

The aim of this study was to determine whether the response rate for the paclitaxel-carboplatin combination is superior to carboplatin alone in the treatment of patients with platinum-sensitive recurrent ovarian carcinoma.Patients with recurrent ovarian carcinoma, 6 months after treatment with a platinum-based regimen and with no more than two previous chemotherapy lines, were randomized to receive carboplatin area under the curve (AUC) 5 (arm A) or paclitaxel 175 mg/m(2) + carboplatin AUC 5 (arm B). The primary end point was objective response, following a 'pick up the winner' design. Secondary end points included time to progression (TTP), overall survival, tolerability and quality of life (QoL).Eighty-one patients were randomized and included in the intention-to-treat analysis. The response rate in arm B was 75.6% [26.8% complete response (CR) + 48.8% partial response (PR)] [95% confidence interval (CI) 59.7% to 87.6%] and 50% in arm A (20% CR + 30% PR) (95% CI 33.8% to 66.2%). No significant differences were observed in grade 3-4 hematological toxicity. Conversely, mucositis, myalgia/arthralgia and peripheral neurophaty were more frequent in arm B. Median TTP was 49.1 weeks in arm B (95% CI 36.9-61.3) and 33.7 weeks in arm A (95% CI 25.8-41.5). No significant differences were found in the QoL analysis.Paclitaxel-carboplatin combination is a tolerable regimen with a higher response rate than carboplatin monotherapy in platinum-sensitive recurrent ovarian carcinoma.

This randomised, open-label trial compared oral tegafur (FT)/leucovorin (LV) with the intravenous bolus 5-fluorouracil (5-FU)/LV as first-line chemotherapy for advanced colorectal cancer (CRC). Patients were randomised to receive oral FT 750 mg/m2/day for 21 days and LV 15 mg/m2 every 8 h in cycles repeated every 28 days (n=114), or intravenous LV 20 mg/m2 followed by 5-FU 425 mg/m2 daily for 5 days every 4 weeks for 2 cycles, and later every 5 weeks (n=123). Response rate was significantly higher in the FT/LV arm (27%, 95% CI 19-35) than in the 5-FU/LV arm (13%, 95% CI 7-19) (p0.004). The median time to progression was 5.9 months (95% CI, 5.3-6.5; FT/LV arm) and 6.2 months (95% CI, 5.4-6.9; 5-FU/LV arm). Median overall survival was 12.4 months (95% CI, 10.3-14.5 months; FT/LV arm) and 12.2 months (95% CI, 8.9-15.7 months; 5-FU/LV arm) (p=n.s.; hazard ratio FT/LV:5-FU/LV=1.02). 5-FU/LV showed a higher incidence of grade 3/4 neutropenia (4.1 vs. 0%). Non-hematological toxicities showed similar incidences in the two treatment arms. Oral FT/LV was more active than IV 5-FU/LV in terms of objective response rate with similar overall survival, and with a favorable toxicity profile. This makes FT/LV a valid alternative to the IV 5-FU schedule in CRC patients.

The purpose of this study was to assess the toxicity and efficacy of gemcitabine and docetaxel administered every other week as first-line therapy in metastatic breast cancer. Fifty-one patients with histologically confirmed metastatic breast cancer were enrolled. Patients received docetaxel 65 mg/m(2) followed by gemcitabine 2,500 mg/m(2), both on day 1 of a 14-day cycle, for 10 cycles without granulocyte-colony stimulating factor support. Thirty-five patients were evaluable for toxicity and 32 for efficacy. Median age was 65 years (range, 37 to 72 years), and median performance status was 90 (range, 60 to 100). The number of disease sites was 2 or > or =3 in 39% and 44% of patients, respectively, with visceral involvement in the liver and/or lung in 44% of patients. A total of 45% had received prior adjuvant chemotherapy. So far, 267 cycles have been administered. Twenty-five percent of the docetaxel and gemcitabine doses were reduced or delayed due primarily to neutropenia, giving a median dose intensity of 90% of the planned dose for both drugs. Grade 3/4 toxicities were mainly hematologic, with neutropenia in 46% of patients (two patients experienced neutropenic fever). Other toxicities were asthenia, diarrhea, transaminase elevation, and nausea. Overall response rate was 66% (four complete responses, 17 partial responses), with 22% of patients achieving stable disease. Responses were observed in all disease sites, including lung (60%) as well as liver (37.5%). In conclusion, preliminary evaluation from our phase II study shows that the combination of docetaxel and gemcitabine given every 2 weeks is a tolerable and highly active combination in patients with metastatic breast cancer. These data compare favorably with those obtained with other docetaxel schedules.

9620 Background: In order to improve the risk stratification of patients with febrile neutropenia (FN), we previously developed a prognostic score predicting major complications in patients with so...

e12558 Background: LORENA is an ambispective observational study evaluating B-based therapy in a real world setting which purpose is to assess clinical features, treatments and prognosis of HER2-negative MBC pts with ≥12 months (mo.) of PFS to 1st-line B-based chemotherapy (CT). Methods: Pts with MBC receiving 1st-line CT and B are enrolled. No prespecified schedules, doses or assessments. Data since the introduction of the treatment with B were collected at inclusion (retrospective phase), and prospectively at 18 mo. after enrollment for the patients alive at the time of inclusion, including B-targeted adverse events (AEs). Relevant baseline and on-study variables were analyzed by Cox model to identify independent effects on PFS. Results: By Jan 2013, complete retrospective data were available for 84 pts, 33 (39.3%) of them having stage III-IV at diagnosis. Median age, 50 years (r: 29–77); age ≥65 years, 13%; triple negative, 20.2%; bone/liver/lung metastases (%), 55/27/40; ≥2 metastases sites: 46.4%; ECOG status 0-1: 91.7%, ≥2: 5.9%, UK: 2.3%. 67% of pts have received prior (neo)adjuvant CT, with 56 and 30% of them with anthracyclines and taxanes, respectively. The objective response was 78%, including complete responses in 23%. A further 22% had stable disease. Median duration of B-based therapy was 12.4 mo. PFS events had been recorded in 44% of pts. Median PFS: 19.5 mo. (95%CI: 15.6-23.2). Cox proportional hazard multivariate regression model showed that B-based therapy ≥15 vs

10500 Background: The Basal-like subtype is generally associated with high chemo-sensitivity, but not all tumors respond and/or benefit to the same extend. In this study, we sought to identify gene expression predictors of neoadjuvant chemotherapy sensitivity in Basal-like breast cancer. Methods: Expression of 542 genes was measured using the Nanostring nCounter platform from 69 FFPE pre-treated samples of the GEICAM/2006-03 phase II trial, which were treated with epirrubicin/cyclophosphamide followed by docetaxel+/-carboplatin. Research-based PAM50 and Claudin-low predictors were also evaluated. The association between response (Miller-Payne criteria) and gene/signature expression was assessed by multivariable ordinal logistic regression. Significant findings were evaluated in 109 independent triple-negative and Basal-like tumors treated with anthracycline/taxane-based chemotherapy (Hatzis et al.). Finally, interaction tests were performed to identify genes/signatures associated with carboplatin response. Results: In GEICAM/2006-03, 61/69 (88%) tumors were identified as Basal-like by PAM50. High correlation to the Basal-like centroid, or high expression of proliferation-related genes (i.e. FANCA), were found to be significantly associated with high chemo-sensitivity, whereas high expression of genes associated with mesenchymal/stem cell biological processes (i.e. SNAI1 and IL6) and/or luminal differentiation (i.e. MUC1 and FOXA1) were significantly associated with chemo-resistance; similar findings were observed in Hatzis et al. Finally, high expression of genes associated with proliferation/DNA-repair (i.e. ATR) and tight junctions (i.e. CLDN3/4/7) were found associated with carboplatin response, whereas expression of the Claudin-low signature was found associated with carboplatin resistance. Conclusions: High expression of Basal-like and/or proliferation-related genes and low expression of luminal/mesenchymal/stem cell-like biological processes were consistently identified as predictive of chemotherapy response. Our data suggests that gene expression profiling might help shed light into the biological and clinical heterogeneity of Basal-like breast cancer.

10616 Background: Ki67 proliferation biomarker determined by immunohistochemistry (IHC) has been studied as a prognostic and predictive factor in Operable Breast Cancer (OBC). Ki67 modifications after neoadjuvant endocrine therapy have been correlated with long term outcome. However, there is no robust data about its predictive role in Neoadjuvant Chemotherapy (NC). In this study, we investigated Ki67 value as predictor of NC efficacy. Methods: 193 patients (pts) from 2 GEICAM phase II randomized trials (2006-03 and 2006-14) were included: 78 (40%) received epirubicine plus cyclophosphamide followed by docetaxel (EC-D), 41 (21%) EC-D plus carboplatin, and out of the 74 HER2+ pts, 37 (19%) received EC-D plus tratuzumab and 37 (19%) EC-D plus lapatinib. Median age was 49 years. From series, 87% were invasive ductal carcinoma, 58% premenopausal, 50% grade III, 23% luminal , 39% basal and 38% HER2+. Ki67 was centrally assessed by IHC (MIB1 clone) and median score was 40% (range 1-100%). Pathological Complete Response (pCR), defined as absence of invasive cells in breast and lymph nodes, was achieved in 56 pts (29%). Univariate and multivariate logistic regression models were used to study the association of each clinical-pathological variable with pCR. ROC curves were used to determine the most accurate ki67 cut-off for predicting NC response. Results: Ki67≥50% was defined as the most accurate threshold to select patients obtaining benefit from NC. In the univariate analysis, histological grade (p=0.01), treatment (P=0.006), ER (p

e15590 Background: To evaluate the safety and efficacy of bevacizumab (BEV) alone or combined with chemotherapy (CT) in a compassive use program sponsored by the Spanish Ovarian Cancer Research Gro...

Fifty-three patients with advanced non-small cell lung cancer (NSCLC) were trerated with alternating two-drug schedules cisplatin/vindesine and ifosfa-mide/mitomycin. Objective response (complete and partial response) was obtained in 31 % (confidence limits 18.6-44%) of patients. The mediam duration of response was 26 weeks. The median survival was 25 weeks, with 24% of patients alive at 1 year. The toxicity was acceptable. The still poor antitumor activity of the chemotherapy schedules used and the lack of non-cross-resistance are factors that could explain the low antitumor activity of alternating chemotherapy.

500 Background: Luminal breast cancer is a highly endocrine responsive disease. However, the therapeutic benefit of CT in this population is not fully characterized. This study investigates the value of CT versus HT in this luminal subgroup in a neoadjuvant setting. Methods: Patients (Pt) with operable breast cancer (T2/T3) and immunophenotypically defined luminal disease (ER+/PR+/HER2-/cytokeratin 8/18+ assessed in a central laboratory) were recruited. Pts were randomized to CT (epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 × 4 cycles [cy] followed by docetaxel 100 mg/m2 × 4 cy [EC-T]) or HT (exemestane 25 mg daily × 24 weeks [combined with goserelin in premenopausal pts]). The primary end point was clinical response measured by magnetic resonance image. Secondary end points were pathological complete response (pCR), toxicity, type of surgery, and axillary status at surgery. Adjuvant treatment was provided in an individualized manner. Results: 95 pts were randomized (47 CT, 48 HT) from March 07 to ...