Abstract ES9-3: Targeted interventions: Metformin and lifestyle change
Authors: Goodwin PJ 
Published: May 2016

Abstract
Obesity is associated with increased risk of premenopausal (triple negative) and postmenopausal [primarily estrogen receptor (ER) positive] breast cancer (BC). Higher Body Mass Index [BMI = weight (kg)/height (m)2] and lower physical activity have been associated with increased risk of distant recurrence and death in both pre- and postmenopausal BC, regardless of ER status; some recent studies nested in clinical trials have found an association only in ER+ BC. There is growing evidence that obese women may have less benefit from aromatase inhibitors (AIs) other than letrozole. Translational and preclinical research suggests that obesity associated alterations in systemic physiology (higher estrogens, insulin resistance leading to higher insulin and glucose, altered adipokines and inflammation) or changes in the tumor microenvironment (localized inflammation) may mediate effects of obesity on BC outcomes.
The presence of an association of obesity with breast cancer outcomes is not necessarily causal (non-causal associations may reflect healthy person bias, under-treatment of obese patients, or presentation of BC at more advanced stage in obese women). Even if the association is causal it may not be reversible (ie: adverse effects may be reflected in the biology of the BC that develops and may not be amenable to change). Evidence that an association is both causal and reversible can be obtained from any intervention research. Potential interventions include weight loss and targeted drugs such as metformin.
Metformin, a biguanide commonly used to treat type 2 diabetes, may act (i) indirectly to improve obesity associated systemic physiology (e.g. by lowering circulating insulin leading to reduced insulin receptor mediated activation of PI3K and ras pathways), (ii) directly via an effect on the mitochondrium leading to an LKBI mediated AMPK activation and downstream mTOR inhibition or (iii) directly via other non-AMPK mediated direct effects. Metformin has been associated with lower BC risk and improved BC outcomes in observational studies that may be susceptible to survival biases. It has led to reduced proliferation and increased apoptosis in some neoadjuvant studies (similar to effects seen in preclinical studies). Despite this epidemiologic, clinical, translational and preclinical research, definitive evidence of benefits from Phase III trials is needed. A Phase III adjuvant trial (NCIC MA.32) testing metformin (vs placebo) in the adjuvant BC setting has completed accrual and is anticipated to report BC outcome data in 2017.
Lifestyle based weight loss interventions (involving calorie restriction and enhanced physical activity) have been shown to lead to 5-7% weight loss in BC populations (and to improvement in potential systemic mediators noted above). Most ongoing or completed studies of weight loss in have been underpowered for BC outcomes and have focused primarily on weight loss. An adequately powered US Intergroup study (led by the Alliance) using a telephone based intervention involving over 3000 subjects is in advanced stages of planning. Results of this trial, anticipated 6-8 years after initiation, should provide rigorous evidence regarding possible benefits of the degree of weight loss that can be achieved through lifestyle change on BC outcomes.
Citation Format: Goodwin PJ. Targeted interventions: Metformin and lifestyle change. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr ES9-3.