There are two main sources of estrogen, the ovaries and body fat. There are three perhaps major classes of hormonal medications to treat breast cancer: LHRH agonists, or GnRH agonists as they are also called, selective estrogen receptor modulators, SERMs, and aromatase inhibitors. Dr. Anton Titov, MD.: How to choose between these medications to reduce estrogen effects in breast cancer? You are correct, and your list is incomplete because now people separate drugs like tamoxifen or SERMs, selective estrogen receptor modulators from a class of drugs called SERDs, selective estrogen receptor degraders (down regulators), Fulvestrant is the main drug of SERD class. There will shortly be orally available SERDs over the next couple of months. They are even more active than fulvestrant. Oral SERDs are very exciting. Dr. Marc Lippman, MD.: But the exact answer to your question is randomized clinical trials. These are empiric questions that look at both efficacy and toxicity and try to make statements about the most effective drug. In metastatic breast cancer for postmenopausal women aromatase inhibitors are somewhat more effective than Tamoxifen. They are usually the first line. Now there are other well done randomized clinical trials of another class of drugs, CDK4/6 inhibitors. CDK4/6 inhibitors block one pathway of drug resistance. It has been proven overwhelmingly that, when combined with an aromatase inhibitor, CDK4/6 inhibitors dramatically increase both response rates and double response duration. So that's extremely exciting. And those drugs have now been promoted to adjuvant clinical trials, where they are also very encouraging. So the single-use of tamoxifen or aromatase inhibitors is probably going out of fashion. It seems that combinations of aromatase inhibitors or tamoxifen, at least with the CDK4/6 inhibitors are vastly more effective. Why are these medications, such as tamoxifen or aromatase inhibitors, LHRH or GnRH agonists, used in combination? What is the rationale for their use together? And perhaps there are some instances when they should not be used in combination? The best answer your question, you need to separate whether we are talking about metastatic breast cancer or the adjuvant treatment of breast cancer. We are giving these drugs to prevent recurrence in the metastatic disease setting unless toxicity intervenes, which is pretty uncommon. Pretty uncommon. The drugs continue till the patient progresses. There's no reason to stop them. For the most part, as I've already said, the toxicities of these therapies are very minimal, vastly offset by the risks of progressive metastatic disease. So endocrine therapies can be given endlessly until patients progress. In the old days, breast cancer patients were treated by ovariectomy, oophorectomy. There were certainly patients who responded for more than a decade. So, obviously, you would continue with the current therapy until patients didn't respond to treatment anymore. In the adjuvant chemotherapy of breast cancer, most of these studies have been done empirically over many decades. When Tamoxifen was first used to prevent a recurrence of breast cancer, people gave it for a year. And it worked. So then people did studies that have compared two years to one year. And two years was better. Then people compared five years to two years of tamoxifen. Five years of tamoxifen therapy was better than two years . So five years became something of an established empirical standard for breast cancer treatment. Some of the new studies of the adjuvant chemotherapy of breast cancer with CDK4/6 inhibitors have been for shorter periods. And the reason for that is partly because the CDK4/6 inhibitors are so fiendishly expensive, and no one wants to pay $3,000, $4000, or $5,000 a month. So much of this isn't an efficacy issue but an expense issue. And that's, in my opinion, extremely unfortunate that that kind of decision is made under those circumstances. In terms of combining these therapies, recently a series of studies have proven that in premenopausal women. You can interfere with ovarian estrogen production with a GnRH drug, as you mentioned, or just by ovariectomy. Then, if you give an aromatase inhibitor or Tamoxifen, it's far more effective than giving the Tamoxifen alone. So that for poor prognosis or younger women, whom we are treating to prevent breast cancer recurrence. The fact is that usually tamoxifen or aromatase inhibitors are combined, when possible, with GnRH agents to suppress the ovary. And those treatments are usually for about three years because that's all people want to tolerate.