Neoadjuvant Metformin Added to Systemic Therapy Decreases the Proliferative Capacity of Residual Breast Cancer.

Eugeni López-Bonet ,Idoia Morilla,Javier Cortés,Joan Dorca,Gemma Viñas,Isabel Álvarez,Joan Brunet,Kepa Amillano,Elisabet Cuyàs,Norberto Batista-López,Agostina Stradella,Severina Domínguez,Jorge Joven,Laura Castillo,Javier A Menendez,Samiha Saidani,Susana Martínez,Sara Verdura,César Augusto Rodríguez-Sánchez ,María Buxó ,C Meléndez ,Glòria Oliveras ,Sònia Pernas ,Margarita García ,M Luque ,Begoña Martin-Castilló ,José Manuel Pérez-García

doi:10.3390/jcm8122180

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.

Highlights

Pathological complete response, the primary endpoint for a majority of neoadjuvant trials in breast cancer (BC), has been commonly adopted as a surrogate marker of long-term treatment benefit [1,2,3]
The present study was designed to evaluate the therapeutic activity of neoadjuvant metformin with respect to Ki67 on sequential core biopsies obtained from patients belonging to the ITT population of the METTEN trial (Figure 1), which included all randomly assigned HER2-positive BC patients who received at least one dose of study medication (n = 79; Table 1)
The mean Ki67 suppression was similar between the two treatment arms, a statistically larger decrease in the proliferative capacity of residual tumor cells from baseline values was observed only in the non-pathological complete response (pCR) patients belonging to the metformin-containing arm, thereby suggesting that metformin might be considered as a safe candidate to prevent and/or treat the proliferative potential of residual BC disease after neoadjuvant therapy

Summary

Introduction

Pathological complete response (pCR), the primary endpoint for a majority of neoadjuvant trials in breast cancer (BC), has been commonly adopted as a surrogate marker of long-term treatment benefit [1,2,3]. In patients with BC who fail to achieve pCR and have a worse prognosis, other biological markers are urgently needed to identify those at high-risk who could benefit from additional, customized therapeutic strategies. Central to these issues is Ki67, a nuclear protein associated with cellular proliferation, which is a well-established prognostic and predictive biomarker in patients with BC treated with neoadjuvant therapies. The potential prognostic value of Ki67 after neoadjuvant therapy has been less characterized, there is strong evidence to suggest that changes in Ki67 index between pre- and post-neoadjuvant hormonal and chemotherapy might be a strong predictor of outcome for patients who do not achieve a pCR. The evaluation of absolute Ki67 values, and of any differences in specific Ki67 levels between pre- and

Results

Discussion

Conclusion