The effect of metformin on apoptosis in a breast cancer presurgical trial

• Published in: British journal of cancer Vol. 109; no. 11; pp. 2792 - 2797
• Main Authors: Cazzaniga, M, DeCensi, A, Pruneri, G, Puntoni, M, Bottiglieri, L, Varricchio, C, Guerrieri-Gonzaga, A, Gentilini, O D, Pagani, G, Dell'Orto, P, Lazzeroni, M, Serrano, D, Viale, G, Bonanni, B
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.11.2013; Nature Publishing Group
• Subjects: 631/80/82/23; 631/92/609; 692/699/67/1347; 692/700/565/1436; Apoptosis - drug effects; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Breast Neoplasms - surgery; Cancer Research; Carcinoma, Ductal, Breast - drug therapy; Carcinoma, Ductal, Breast - pathology; Carcinoma, Ductal, Breast - surgery; Clinical Study; Combined Modality Therapy; Double-Blind Method; Drug Administration Schedule; Drug Resistance; Epidemiology; Female; Gynecology. Andrology. Obstetrics; Humans; Hypoglycemic Agents - administration & dosage; Ki-67 Antigen - analysis; Mammary gland diseases; Medical sciences; Metformin - administration & dosage; Middle Aged; Molecular Medicine; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoadjuvant Therapy; Oncology; Placebos; Preoperative Period; Tumors; breast cancer; metformin; apoptosis; neoadjuvant study; Ki67; insulin resistance; Endocrinopathy; Pancreatic hormone; Breast disease; Biological marker; Metabolic diseases; Breast cancer; Malignant tumor; Insulin; Neoadjuvant treatment; Mammary gland diseases; Target tissue resistance; Hypoglycemic agent; Biguanides; Cancerology; Cell death; Ki67 antigen; Clinical trial; Insulin resistance; Metformin; Preoperative; Cancer; Apoptosis
• ISSN: 0007-0920; 1532-1827; 1532-1827
• DOI: 10.1038/bjc.2013.657

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.