Metformin in early breast cancer (BC): A prospective, multi- institutional, open-label, neo-adjuvant “window of opportunity” study.
Saroj Niraula, Ryan JO Dowling, Marguerite Enis, Martin Chang, Susan Done, Nicky Hood, Jaime
Escallon, Wey Leong, David R. McCready, Michael Reedijk, Vuk Stambolic, Pamela J Goodwin
Background: There is growing pre-clinical, clinical and epidemiological evidence that metformin,
being used in Canada for over 50 years, may exert anti-cancer effects through indirect (insulin-
mediated) or direct (AMPK/AKT-pathway) mechanisms and it costs about 50¢ Canadian per day.
Here, we report final results of a neo-adjuvant “window-of-opportunity” study of metformin in
Methods: Newly diagnosed, untreated, non-diabetic BC patients received solitary treatment with
metformin 500 mg tid after diagnostic core-biopsy until definitive surgery (no other antineoplastic
agents). Clinical characteristics [weight, symptoms, European Organization for Research and
Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C-30)] and biologic
characteristics [insulin, glucose, homeostatic model assessment (HOMA), C-reactive protein (CRP),
leptin] were compared pre- and post-metformin as were Terminal deoxynucleotidyl transferase-
mediated dUTP nick end labeling (TUNEL, an apoptotic marker) and Ki67 (our primary end-point)
scored blinded by manual count of positive nuclear-staining. The planned sample-size of 40 patients
gave 90% power to detect a 5.5 percentage point change in Ki67.
Results: Thirty-nine patients were enrolled and mean age was 51 years; metformin was given for a
median of 18 days, range 13-40 days. Twenty patients had T1 and 19 patients had T2 or T3 tumors;
16 tumors were grade III; 24 were node negative; 32 were ER/PR positive and 5 were HER-2
positive. No major toxicities were encountered - grade 1-2 self-resolving diarrhea, anorexia and
abdominal distention occurred in 50%, 41% and 32%. EORTC QLQ scores were stable in all
function domains and in overall scores. The main study outcome variables are tabulated below.
Conclusions: Short-term preoperative metformin was well-tolerated and resulted in clinical and
cellular effects in keeping with beneficial anti-cancer effects as demonstrated by improved insulin
resistance (HOMA), increased apoptosis (TUNEL) and decreased proliferation (ki67).
Variable (units) Pre-metformin Mean change p (Change) mean (SD) Weight (Kg) <0.0001 BMI (kg/m2) <0.0001 CRP (mg/L) Glucose (mmol/L) Insulin (pmol/L) Leptin (ng/ml)
I was involved in the reported project starting right from the conception, protocol writing, ethics approval process, trial initiation in all involved sites, recruitment of patients, collection of data,
analysis of data and preparation of the abstract along with the upcoming manuscript. Contribution percentage:
L’heLLÉnisme en France dans Le prÉsentil serait très utile de faire une synthèse globale sur l’enseignementet la recherche du Grec en France à tous les niveaux, ainsi que sur lesgrands problèmes qui se posent. il n’existe actuellement aucune synthèsede ce genre, car les différentes actions qui peuvent être menées soit dansles institutions officielles soit dans diverses associatio
DEPARTAMENTO DE HUMANIDADES Y CIENCIAS SOCIALES TECNICATURA UNIVERSITARIA EN CEREMONIAL y PROTOCOLO Cátedra: 2734 1º y 2º CUATRIMESTRE 2012 CEREMONIAL Y PROTOCOLO I Prof. Adjunto: Lic. Diego L. MONASTERIO Carga horaria cuatrimestral: 4 (cuatro) horas semanales. 1) Fundamentación Según narra la historia, aproximadamente desde el año 3100 a de Cristo, exis