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Title: Neoadjuvant Metformin Added to Systemic Therapy Decreases the Proliferative Capacity of Residual Breast Cancer
Author: López Bonet, Eugeni
Buxó, Maria
Cuyàs, Elisabet
Pernas, Sònia
Dorca, Joan
Álvarez López, Isabel
Martinez, Susana
Pérez García, José Manuel
Batista López, Norberto
Rodríguez Sánchez, César A.
Amillano, Kepa
Domínguez, Severina
Luque, Maria
Morilla, Idoia
Stradella, Agostina
Viñas, Gemma
Cortés, Javier
Oliveras, Glòria
Melendez, Cristina
Castillo, Laura
Verdura, Sara
Brunet, Joan
Joven, Jorge
Garcia, Margarita
Saidani, Samiha
Martin Castillo, Begoña
Menendez, Javier A.
Keywords: Càncer de mama
Breast cancer
Issue Date: 1-Dec-2019
Publisher: MDPI
Abstract: The proliferative capacity of residual breast cancer (BC) disease indicates the existence of partial treatment resistance and higher probability of tumor recurrence. We explored the therapeutic potential of adding neoadjuvant metformin as an innovative strategy to decrease the proliferative potential of residual BC cells in patients failing to achieve pathological complete response (pCR) after pre-operative therapy. We performed a prospective analysis involving the intention-to-treat population of the (Metformin and Trastuzumab in Neoadjuvancy) METTEN study, a randomized multicenter phase II trial of women with primary, non-metastatic (human epidermal growth factor receptor 2) HER2-positive BC evaluating the efficacy, tolerability, and safety of oral metformin (850 mg twice-daily) for 24 weeks combined with anthracycline/taxane-based chemotherapy and trastuzumab (arm A) or equivalent regimen without metformin (arm B), before surgery. We centrally evaluated the proliferation marker Ki67 on sequential core biopsies using visual assessment (VA) and an (Food and Drug Administration) FDA-cleared automated digital image analysis (ADIA) algorithm. ADIA-based pre-operative values of high Ki67 (>= 20%), but not those from VA, significantly predicted the occurrence of pCR in both arms irrespective of the hormone receptor status (p = 0.024 and 0.120, respectively). Changes in Ki67 in residual tumors of non-pCR patients were significantly higher in the metformin-containing arm (p = 0.025), with half of all patients exhibiting high Ki67 at baseline moving into the low-Ki67 (<20%) category after neoadjuvant treatment. By contrast, no statistically significant changes in Ki67 occurred in residual tumors of the control treatment arm (p = 0.293). There is an urgent need for innovative therapeutic strategies aiming to provide the protective effects of decreasing Ki67 after neoadjuvant treatment even if pCR is not achieved. Metformin would be evaluated as a safe candidate to decrease the aggressiveness of residual disease after neoadjuvant (pre-operative) systemic therapy of BC patients.
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It is part of: Journal of Clinical Medicine, 2019, vol. 8, num. 12
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Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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