Insulin, lipids and Breast Cancer in a Randomised Clinical Trial. The Energy and Balance Aspects studies (EBBA I +II)

-The project is running according to what was planned regarding the two studies, EBBA-I and EBBA-II. In the EBBA-I study, we have had nine publications studying the associations between low-penetrence gene, growth factors (i.e. Insulin Growth Factor, IGF-1 and GH, Growth Hormone), adult stature, life style (alcohol intake, obesity) associated with level of estrogen and progesterone. Estrogens and progesterone are two key factors associated with breast cancer development. These finding will be used, and followed in new studies based on data collected in the EBBA-II study. The EBBA-II (NBCG14) is a multicenter study including newly diagnosed breast cancer patients (N=600, www.clinicaltrials.com , NCT02240836), at Oslo University hospital, and in 2014 also including patients at St. Olavs hospital, Trondheim and Vestre Viken Drammen. Several studies evaluating the methods used have been fulfilled, and have so far resulted in a total of 10 fulfilled master projects (8 projects: UIO/NIH/OUS, and 2 projects NTNU/St.Olav). In addition, two more projects are ongoing (marks on master projects, 4 with A, 5 with B, and one with C). The EBBA-II study is an ongoing study, with 10 years follow-up, and results will be presented and published along with collection of data. We are now studying the association between metabolic profile, including Insulin and IGF-1, among breast cancer patients in relation to the tumor micro environment, in a new collaboration with researcher at the University in Tolouse, France, and researcher at the Fred Hutch Cancer Research Center, US. We have already observed that the serum level of Insulin and IGF-1 among breast cancer patients at diagnosis, may be associated with the cell proliferations activity (Ki67) in the breast tumor. Thus, we are now studying the importance of Insulin, IGF-1 and lipids in relation to the aggressiveness of the breast tumor, and also how physical activity may influence the serum levels of these factors during adjuvant treatment. In another study, we have analysed the importance of pre-diagnostic dyslipidemia In relation to tumor characteristics. By development of new methods, we have studied how subfractions of lipids by using metabolomics, are associated with progesterone and estrogen receptors of breast tumors. Our findings have so far resulted in new knowledge on how genetic susceptibility interact with lifestyle factors (obesity, alcohol intake), and growth hormone of importance for level of sex hormones and mammographic density. These findings will be focused in new studies, in relation to breast cancer development, including the EBBA-II (www.clinicaltrials.com NCT02240836).

There is a growing concern regarding obesity, insulin and lipids in relation to the development and treatment of breast cancer. Moreover, breast cancer seems to cluster in a smaller subset of the female population supporting gene -environment interaction . Parallel to this knowledge, observational studies support an adverse effect of insulin and lipids on breast cancer and use of anti diabetic drug metmorfin has observed to induce tumor response following neoadjuvant therapy. However, results from rando mized clinical trials are missing. The project aims to test whether variation in insulin and lipid profiles in reponse to variation in physical activity are associated with specific low penetrance gene, patient and breast tumor characteristics of impor tance for breast cancer recurrence and survival. Part A, In EBBA-I healthy women aged 25-35 years are included. We hypothesise that single nucleotide polymorphisms (SNPs) in candidate genes may alter the womens susceptibility to a high insulin level a nd unfavorable lipid profiles, and influence levels of daily free estradiol throughout one entire menstrual cycle. Part B, In the EBBA- II , including female breast cancer cases, we will compare insulin levels and lipid levels in relation to physical ac tivity intervention (250 women) vs. control (250 women). The intervention group (12 months) receives a detailed training program based on their own VO2max at baseline (starting 2-4 weeks after operation). The control group will follow the standard care gi ven by our national guidelines and both groups will receive standard breast cancer treatment. If these studies along with international studies demonstrates that physical activity influence levels of insulin and lipid profiles in subset or among all wome n of importance for breast cancer recurrence, insulin and lipid profile should be assessed and physical activity should be prescribed as an integral part of breast cancer treatment and rehabilitation