Breast cancer is defined based on its drivers. Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) are the three most common drivers, and drugs are currently available for each. When breast cancer is driven by an unknown factor, few treatment options are available. In this case, breast cancer without ER, PR and HER2 is not considered to be driven by hormones, and this type of breast cancer is called triplenegative breast cancer (triplenegativebreastcancer). Ou Jianghua, Department of Breast Surgery, Xinjiang Cancer Hospital Ten years ago, researchers at the UniversityofColorado Cancer Center added another member, androgenreceptor (AR), to the list of breast cancer drivers. This week’s study marks an important milestone in a clinical trial targeting the growth of this type of breast cancer. In fact, 75 percent of breast cancers and about 20 percent of triple-negative breast cancers are positive for AR. Blocking AR may be able to stop the growth of some triple-negative breast cancers. Chemotherapy, radiation and surgery have long been the only treatment options for dealing with this very aggressive type of cancer. According to Anthony Elias, MD, head of the breast cancer program at the University of Colorado Cancer Center, “This work is a succinct example of the kind of oncology research that is now available. We notice something in the clinic and then study it in the lab. Now we are very pleased to report that the lab work is back in the clinic again with very real potential to benefit cancer patients.” The work began in 2001 when Elias observed in the clinic that ER-positive breast cancers were responding poorly or only temporarily to estrogen blockade therapy and told colleague Jennifer Richer, MD, about this phenomenon. In these cases, some other factor drove the cancer. What exactly was the pathway?Richer confirmed through her research that it was AR. It has long been agreed that androgens (including testosterone) are the drivers of prostate cancer. Dr. Richer first studied Medivation Pharmaceuticals’ then experimental drug MDV-3100 using cell culture and animal models. Typically, hormones act by binding to receptors in the cytoplasm, followed by the entry of the hormone and receptor complex into the MDV-3100, now known as enzalutamide, was recently approved by the FDA for the treatment of prostate cancer. MDV-3100 prevents AR from entering the nucleus and, therefore, the signal for cell growth cannot be delivered. Interestingly, ER-positive breast cancer is also susceptible to this drug, and Richer explained that estrogen signaling to the nucleus in this manner requires the presence of AR in the nucleus (which is counterintuitive). Thus, enzalutamine has multiple potential applications in the treatment of breast cancer: as a first-line drug for the treatment of AR-positive cancers with or without other hormonal drivers; as a second-line drug for tumors that adopt AR dependence due to mutations that result in ER- or HER-2-dependent loss; in combination with drugs that target other hormones to stop the cancer from moving toward AR dependence in the first place or to replace existing therapies for the treatment of estrogen-positive breast cancers, which are considered to be susceptible to such anti-androgen therapies. After observing “no additionaltoxicities,” Elias expects the ongoing Phase I Enzalutamide clinical trial in triple-negative breast cancer to advance to Phase II, from providing safety data to demonstrating efficacy data. In addition to CU Cancer Center, the trial will also be conducted at Memorial Sloan-Kettering Cancer Center and Karmanos Cancer Institute, and Richer and Elias will present additional research data from their work in androgen-positive breast cancer to the Breast Cancer Symposium in December. With the validation of the new target, Richer and Elias may soon offer a powerful new therapeutic agent for a class of breast cancers that can evade current therapies.