ABSTRACT
BACKGROUND: Metformin has been associated with antitumour activity in breast cancer (BC) but its mechanism remains unclear. We determined whether metformin induced a modulation of apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) overall and by insulin resistance status in a presurgical trial. METHODS: Apoptosis was analysed in core biopsies and in surgical samples from 100 non-diabetic BC patients participating in a randomised trial of metformin vs placebo given for 4 weeks before surgery. RESULTS: Eighty-seven subjects (45 on metformin and 42 on placebo) were assessable for TUNEL measurement at both time points. TUNEL levels at surgery were higher than that at baseline core biopsy (P<0.0001), although no difference between arms was noted (metformin arm: median difference surgery-biopsy levels +4%, interquartile range (IQR): 2-12; placebo arm: +2%, IQR: 0-8, P=0.2). Ki67 labelling index and TUNEL levels were directly correlated both at baseline and surgery (Spearman's r=0.51, P<0.0001). In the 59 women without insulin resistance (HOMA index<2.8) ,there was a higher level of TUNEL at surgery on metformin vs placebo (median difference on metformin +4%, IQR: 2-14 vs +2%, IQR: 0-7 on placebo), whereas an opposite trend was found in the 28 women with insulin resistance (median difference on metformin +2%, IQR: 0-6, vs +5%, IQR: 0-15 on placebo, P-interaction=0.1). CONCLUSION: Overall, we found no significant modulation of apoptosis by metformin, although there was a trend to a different effect according to insulin resistance status, with a pattern resembling Ki67 changes. Apoptosis was significantly higher in the surgical specimens compared with baseline biopsy and was directly correlated with Ki67. Our findings provide additional evidence for a dual effect of metformin on BC growth according to insulin resistance status.
Subject(s)
Apoptosis/drug effects , Breast Neoplasms/drug therapy , Carcinoma, Ductal, Breast/drug therapy , Hypoglycemic Agents/administration & dosage , Metformin/administration & dosage , Preoperative Period , Breast Neoplasms/pathology , Breast Neoplasms/surgery , Carcinoma, Ductal, Breast/pathology , Carcinoma, Ductal, Breast/surgery , Combined Modality Therapy , Double-Blind Method , Drug Administration Schedule , Female , Humans , Ki-67 Antigen/analysis , Middle Aged , Neoadjuvant Therapy , PlacebosABSTRACT
BACKGROUND: Early postoperative enteral nutrition with immune-enhancing supplements has helped to restore immune function and reduce infectious complications in patients with cancer undergoing major gastrointestinal operations. The aim of this study was to evaluate the effectiveness of similar supplements (containing arginine and arginine plus omega-3 fatty acids) given preoperatively for 1 week before cancer surgery. METHODS: In this randomized, double-blinded study, patients scheduled to undergo elective resection of upper gastrointestinal tumors were given one of three different oral liquid supplemental diets (control, arginine, arginine plus omega-3 fatty acids) to be taken each day for 7 days before surgery. Blood samples were obtained upon enrollment, on the morning of surgery, and on postoperative day 1 for analysis of immunologic function. RESULTS: Mean serum ornithine (a metabolite of arginine) levels were significantly higher compared with controls, but no significant increase in mean serum arginine levels was noted on the morning of surgery for those patients who received arginine as part of the supplement. In conjunction with these findings, there were no differences among groups in mean lymphocyte mitogenesis, mean peripheral blood mononuclear cell production of cytokines, or clinical outcomes. CONCLUSIONS: Use of oral liquid supplements in this fashion did not improve lymphocyte proliferation or monocyte functions in patients with cancer undergoing major surgery.
