Clinical validation of the EndoPredict test in node-positive, chemotherapy-treated ER+/HER2− breast cancer patients: results from the GEICAM 9906 trial

INTRODUCTION: EndoPredict (EP) is an RNA-based multigene test that predicts the likelihood of distant recurrence in patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2–negative (HER2−) breast cancer (BC) who are being treated with adjuvant endocrine therapy. Herein we report the prospective-retrospective clinical validation of EP in the node-positive, chemotherapy-treated, ER+/HER2− BC patients in the GEICAM 9906 trial. METHODS: The patients (N = 1,246) were treated either with six cycles of fluorouracil, epirubicin and cyclophosphamide (FEC) or with four cycles of FEC followed by eight weekly courses of paclitaxel (FEC-P), as well as with endocrine therapy if they had hormone receptor–positive disease. The patients were assigned to EP risk categories (low or high) according to prespecified cutoff levels. The primary endpoint in the clinical validation of EP was distant metastasis-free survival (MFS). Metastasis rates were estimated using the Kaplan-Meier method, and multivariate analysis was performed using Cox regression. RESULTS: The molecular EP score and the combined molecular and clinical EPclin score were successfully determined in 555 ER+/HER2− tumors from the 800 available samples in the GEICAM 9906 trial. On the basis of the EP, 25% of patients (n = 141) were classified as low risk. MFS was 93% in the low-risk group and 70% in the high-risk group (absolute risk reduction = 23%, hazard ratio (HR) = 4.8, 95% confidence interval (CI) = 2.5 to 9.5; P < 0.0001). Multivariate analysis showed that, in this ER+/HER2− cohort, EP results are an independent prognostic parameter after adjustment for age, grade, lymph node status, tumor size, treatment arm, ER and progesterone receptor (PR) status and proliferation index (Ki67). Using the predefined EPclin score, 13% of patients (n = 74) were assigned to the low-risk group, who had excellent outcomes and no distant recurrence events (absolute risk reduction vs high-risk group = 28%; P < 0.0001). Furthermore, EP was prognostic in premenopausal patients (HR = 6.7, 95% CI = 2.4 to 18.3; P = 0.0002) and postmenopausal patients (HR = 3.3, 95% CI = 1.3 to 8.5; P = 0.0109). There were no statistically significant differences in MFS between treatment arms (FEC vs FEC-P) in either the high- or low-risk groups. The interaction test results between the chemotherapy arm and the EP score were not significant. CONCLUSIONS: EP is an independent prognostic parameter in node-positive, ER+/HER2− BC patients treated with adjuvant chemotherapy followed by hormone therapy. EP did not predict a greater efficacy of FEC-P compared to FEC alone

Prognostic ability of EndoPredict compared to research-based versions of the PAM50 risk of recurrence (ROR) scores in node-positive, estrogen receptor-positive, and HER2-negative breast cancer. A GEICAM/9906 sub-study

There are several prognostic multigene-based tests for managing breast cancer (BC), but limited data comparing them in the same cohort. We compared the prognostic performance of the EndoPredict (EP) test (standardized for pathology laboratory) with the research-based PAM50 non-standardized qRT-PCR assay in node-positive estrogen receptor-positive (ER+) and HER2-negative (HER2−) BC patients receiving adjuvant chemotherapy followed by endocrine therapy (ET) in the GEICAM/9906 trial. EP and PAM50 risk of recurrence (ROR) scores [based on subtype (ROR-S) and on subtype and proliferation (ROR-P)] were compared in 536 ER+/HER2− patients. Scores combined with clinical information were evaluated: ROR-T (ROR-S, tumor size), ROR-PT (ROR-P, tumor size), and EPclin (EP, tumor size, nodal status). Patients were assigned to risk-categories according to prespecified cutoffs. Distant metastasis-free survival (MFS) was analyzed by Kaplan–Meier. ROR-S, ROR-P, and EP scores identified a low-risk group with a relative better outcome (10-year MFS: ROR-S 87%; ROR-P 89%; EP 93%). There was no significant difference between tests. Predictors including clinical information showed superior prognostic performance compared to molecular scores alone (10-year MFS, low-risk group: ROR-T 88%; ROR-PT 92%; EPclin 100%). The EPclin-based risk stratification achieved a significantly improved prediction of MFS compared to ROR-T, but not ROR-PT. All signatures added prognostic information to common clinical parameters. EPclin provided independent prognostic information beyond ROR-T and ROR-PT. ROR and EP can reliably predict risk of distant metastasis in node-positive ER+/HER2− BC patients treated with chemotherapy and ET. Addition of clinical parameters into risk scores improves their prognostic ability.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-016-3725-z) contains supplementary material, which is available to authorized users

Criteris per a l'avaluació de la gestió dels risc de contaminació per micotoxines a la indústria alimentària

Micotoxines; Contaminació alimentària; Indústria alimentària; Control oficialMicotoxines; Contaminació alimentària; Indústria alimentària; Control oficialMycotoxins; Food contamination; Food industry; Official controlLa contaminació d’aliments per micotoxines és un risc emergent, ateses les condicions climàtiques actuals. En dur a terme l’activitat inspectora ens trobem amb empreses alimentàries que gestionen el risc de contaminació per micotoxines segons un criteri propi, sense cap fonament clar ni objectivable, i que no s’adequa al mètode de mostreig que marca el Reglament 401/2006 amb l’argument que està dirigit al control oficial. D’una banda, el fet que determinades empreses estiguin implicades en alertes per superar els límits de micotoxines que marca el Reglament 1881/2006 i, de l’altra, els resultats positius obtinguts en mostres oficials, evidencien que els plans d’autocontrol que tenen implementats aquestes empreses no són prou efectius per controlar aquest perill. Aquesta Comunitat de Pràctica (CoP) pretén unificar una sèrie de criteris que permetin avaluar els programes de gestió del risc de micotoxines de les empreses alimentàries afectades per aquests contaminants. L’abast d’aquest treball inclou els sectors de la fruita seca, les espècies, els cereals, el vi, el cafè i la fruita i derivats. En un marc normatiu complex i canviant, és necessari disposar d’una eina que faciliti la seva interpretació i aplicació durant el control oficial de micotoxines. Els diferents apartats previstos en el qüestionari poden ajudar les empreses i els inspectors a prendre consciència dels factors afavoridors de la contaminació i creixement de les micotoxines en totes les etapes del procés dels aliments, i a aplicar les mesures preventives i de control necessàries.La contaminación de alimentos por micotoxinas es un riesgo emergente, dadas las condiciones climáticas actuales. Al llevar a cabo la actividad inspectora nos encontramos con empresas alimentarias que gestionan el riesgo de contaminación por micotoxinas según un criterio propio, sin fundamento claro ni objetivable, y que no se adecua al método de muestreo que marca el Reglamento 401/2006 con el argumento de que está dirigido al control oficial. Por un lado, el hecho de que determinadas empresas estén implicadas en alertas para superar los límites de micotoxinas que marca el Reglamento 1881/2006 y, por otro, los resultados positivos obtenidos en muestras oficiales, evidencian que los planes de autocontrol que tienen implementados estas empresas no son suficientemente efectivos para controlar ese peligro. Esta Comunidad de Práctica (CoP) pretende unificar una serie de criterios que permitan evaluar los programas de gestión del riesgo de micotoxinas de las empresas alimentarias afectadas por estos contaminantes. El alcance de este trabajo incluye los sectores de los frutos secos, las especias, los cereales, el vino, el café y la fruta y derivados. En un marco normativo complejo y cambiante, es necesario disponer de una herramienta que facilite su interpretación y aplicación durante el control oficial de micotoxinas. Los distintos apartados previstos en el cuestionario pueden ayudar a las empresas y los inspectores a tomar conciencia de los factores favorecedores de la contaminación y crecimiento de las micotoxinas en todas las etapas del proceso de los alimentos, ya aplicar las medidas preventivas y de control necesarias.Food contamination by mycotoxins is an emerging risk, given the current climatic conditions. When carrying out the inspection activity, we come across food companies that manage the risk of contamination by mycotoxins according to their own criteria, without a clear or objective basis, and that does not conform to the sampling method established by Regulation 401/2006 with the argument that it is intended for official control. On the one hand, the fact that certain companies are involved in alerts to exceed the mycotoxin limits established by Regulation 1881/2006 and, on the other, the positive results obtained in official samples, show that the self-control plans implemented by these companies are not effective enough to control this danger. This Community of Practice (CoP) aims to unify a series of criteria that allow evaluating the mycotoxin risk management programs of food companies affected by these contaminants. The scope of this work includes the sectors of nuts, spices, cereals, wine, coffee and fruit and derivatives. In a complex and changing regulatory framework, it is necessary to have a tool that facilitates its interpretation and application during the official control of mycotoxins. The different sections provided in the questionnaire can help companies and inspectors to become aware of the factors that promote mycotoxin contamination and growth at all stages of the food process, and to apply the necessary preventive and control measures

High Proliferation Predicts Pathological Complete Response to Neoadjuvant Chemotherapy in Early Breast Cancer.

In the neoadjuvant setting, changes in the proliferation marker Ki67 are associated with primary endocrine treatment efficacy, but its value as a predictor of response to chemotherapy is still controversial. We analyzed 262 patients with centralized basal Ki67 immunohistochemical evaluation derived from 4 GEICAM (Spanish Breast Cancer Group) clinical trials of neoadjuvant chemotherapy for breast cancer. The objective was to identify the optimal threshold for Ki67 using the receiver-operating characteristic curve method to maximize its predictive value for chemotherapy benefit. We also evaluated the predictive role of the defined Ki67 cutoffs for molecular subtypes defined by estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2). A basal Ki67 cutpoint of 50% predicted pathological complete response (pCR). Patients with Ki67 >50% achieved a pCR rate of 40% (36 of 91) versus a pCR rate of 19% in patients with Ki67 ≤ 50% (33 of 171) (p = .0004). Ki67 predictive value was especially relevant in ER-HER2- and ER-HER2+ patients (pCR rates of 42% and 64%, respectively, in patients with Ki67 >50% versus 15% and 45%, respectively, in patients with Ki67 ≤ 50%; p = .0337 and .3238, respectively). Both multivariate analyses confirmed the independent predictive value of the Ki67 cutpoint of 50%. Basal Ki67 proliferation index >50% should be considered an independent predictive factor for pCR reached after neoadjuvant chemotherapy, suggesting that cell proliferation is a phenomenon closely related to chemosensitivity. These findings could help to identify a group of patients with a potentially favorable long-term prognosis. The use of basal Ki67 status as a predictive factor of chemotherapy benefit could facilitate the identification of a patient subpopulation with high probability of achieving pathological complete response when treated with primary chemotherapy, and thus with a potentially favorable long-term prognosis

High Proliferation Predicts Pathological Complete Response to Neoadjuvant Chemotherapy in Early Breast Cancer

BACKGROUND. In the neoadjuvant setting, changes in the proliferation marker Ki67 are associated with primary endocrine treatment efficacy, but its value as a predictor of response to chemotherapy is still controversial. PATIENTS AND METHODS. We analyzed 262 patients with centralized basal Ki67 immunohistochemical evaluation derived from 4 GEICAM (Spanish Breast Cancer Group) clinical trials of neoadjuvant chemotherapy for breast cancer. The objective was to identify the optimal threshold for Ki67 using the receiver-operating characteristic curve method to maximize its predictive value for chemotherapy benefit. We also evaluated the predictive role of the defined Ki67 cutoffs for molecular subtypes defined by estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2). RESULTS. A basal Ki67 cutpoint of 50% predicted pathological complete response (pCR). Patients with Ki67 >50% achieved a pCR rate of 40% (36 of 91) versus a pCR rate of 19% in patients with Ki67 ≤50% (33 of 171) (p = .0004). Ki67 predictive value was especially relevant in ER-HER2− and ER-HER2+ patients (pCR rates of 42% and 64%, respectively, in patients with Ki67 >50% versus 15% and 45%, respectively, in patients with Ki67 ≤50%; p = .0337 and .3238, respectively). Both multivariate analyses confirmed the independent predictive value of the Ki67 cutpoint of 50%. CONCLUSION. Basal Ki67 proliferation index >50% should be considered an independent predictive factor for pCR reached after neoadjuvant chemotherapy, suggesting that cell proliferation is a phenomenon closely related to chemosensitivity. These findings could help to identify a group of patients with a potentially favorable long-term prognosis. IMPLICATIONS FOR PRACTICE: The use of basal Ki67 status as a predictive factor of chemotherapy benefit could facilitate the identification of a patient subpopulation with high probability of achieving pathological complete response when treated with primary chemotherapy, and thus with a potentially favorable long-term prognosis

Characterisation of microbial attack on archaeological bone

As part of an EU funded project to investigate the factors influencing bone preservation in the archaeological record, more than 250 bones from 41 archaeological sites in five countries spanning four climatic regions were studied for diagenetic alteration. Sites were selected to cover a range of environmental conditions and archaeological contexts. Microscopic and physical (mercury intrusion porosimetry) analyses of these bones revealed that the majority (68%) had suffered microbial attack. Furthermore, significant differences were found between animal and human bone in both the state of preservation and the type of microbial attack present. These differences in preservation might result from differences in early taphonomy of the bones. © 2003 Elsevier Science Ltd. All rights reserved