Metformin- A Promising Agent for Chemoprevention in BRCA1 Carriers.

Women who carry germline mutations in the BRCA1 gene (BRCA1 carriers) have the highest individual lifetime risk for breast cancer (BCa) known [1-3], with 50% of carriers developing breast cancer by age 50. BRCA2 carriers also have a higher risk but relatively lower than BRCA1 carriers. Currently available options for both BRCA1 and BRCA2 carriers include high-risk surveillance, risk reducing mastectomy or chemoprevention with the ant-estrogens Tamoxifen (TAM) and Raloxifene. Chemoprevention has been controversial in that BRCA1 carriers tend to make estrogen receptor negative tumors. Selective estrogen receptor modulators (SERMs) such as tamoxifen and raloxifene reduce the risk of estrogen receptor positive breast cancers. For example, results from the National Surgical Adjuvant Breast and Bowel Project (NSABP1) Tamoxifen chemoprevention study suggested that TAM is not effective in carriers of a BRCA1 mutation [4]. Regardless, there is conflicting evidence on this point and both TAM and Raloxifene are offered to BRCA1 carriers as well as BRCA2 carriers [5]. As a chemoprotective agent in the general population, Raloxifene shows a similar reduction in risk for invasive breast cancer to TAM, but not for in situ cancers, which comprise >20% of newly diagnosed cases; the incidence of noninvasive breast cancer is approximately 40% lower for women on TAM compared with Raloxifene [6,7]. Both TAM and Raloxifene are effective only against estrogen receptor-positive tumors [8], and Raloxifene is typically only prescribed in women who are postmenopausal and have decreased bone density [9]. Both drugs increase risk for serious side effects, including venous thrombosis and pulmonary embolism [10,11]. TAM is also associated with an increased risk for endometrial cancer and stroke [12-14]. Other side effects of both drugs include dyspareunia, cataracts, musculoskeletal complaints including leg cramps, weight gain, hot flashes, vaginal discharge, bone loss in premenopausal women and bladder control problems [15]. More recently, long-term administration of TAM was observed to cause hepatic tumors in rats, induced via a genotoxic mechanism [16]. Compounding the unfavorable side affect profile studies have determined that approximately 5 – 10% of the population carries a homozygous variant of the CYP2D6 gene that imparts low activity to convert TAM from its less active form to its active metabolite [17]. This research led the FDA to require a change in the labeling of Tamoxifen to include this information [18]. Concerns about the risk: benefit ratio have thus limited the use of TAM for prevention. Recent evidence suggests that only approximately 8.4% of BRCA carriers who have not undergone prophylactic mastectomy and are eligible to take Tamoxifen or Raloxifene [19], for risk reduction do so [20]. Certainly, there is an urgent need to identify other agents for breast cancer prevention in this high-risk group. In fact, data from our own Inherited Cancer Registry (ICARE) at Moffitt indicated that of 253 female BRCA1 and BRCA2 mutation carriers, 127 had remaining at risk breast tissue (including 40 with a prior breast cancer diagnosis). Of these women, 18.1% indicated that they had taken either TAM or Raloxifene (including 7/60 (11.7%) of BRCA1 carriers and 16/67 (23.9%) of BRCA2 carriers. Consequently, the poor uptake of existing breast cancer prevention options, which appears to be more marked in those with BRCA1 compared to BRCA2, serves to illustrate the urgent need to identify other agents for breast cancer prevention in this high-risk group.