My presentation earlier was about developing treatments for premenopausal patients with breast cancer. This is an area that has been of interest because in many parts of the world a good proportion of patients with breast cancer present in their premenopausal years and much of the recent investigation in newer hormonal therapies has really focussed on postmenopausal patients. Historically the reason for this is that, interestingly, the initial endocrine therapy that was found to be effective over a hundred years ago was oophorectomy and this was, of course, before there was any knowledge of the biology of breast cancer or even the discovery of oestrogen for that matter. It was really based on the observation that the breast and the ovaries are both female organs and removal of the ovaries was something that was done for other reasons, mostly infectious complications. A surgeon by the name of George Beatson was the first person to report that removal of the ovaries actually results in transient responses in patients with advanced breast cancers.

So since that time we have, of course, developed more focused endocrine therapies that have been very important. Tamoxifen was discovered in the late ‘60s, early ‘70s, and this is a drug that works in both pre- and postmenopausal patients. So this was rapidly adopted into practice, both in advanced stage breast cancer but also in early stage breast cancer it was found to have a significant adjuvant benefit, reducing recurrence risk by 50%. So for many years the research in this area really did not distinguish between pre- and postmenopausal patients.

In later years newer compounds were developed as endocrine therapy, particularly aromatase inhibitors and fulvestrant. These are drugs that physiologically would only be expected to work in postmenopausal patients and that was known so most of the investigation was done in postmenopausal patients. In the United States and in most Western countries the majority of patients actually present in their postmenopausal years with breast cancer and we didn’t really know much about the treatment of patients with premenopausal breast cancer.

The last set of studies that were done in a coordinated fashion was twenty years ago and this was before we actually had developed postmenopausal specific therapies, we were still using tamoxifen. But even then it was shown that oophorectomy improved the outcome of even tamoxifen. So from that time forward there has been very little investigation until just the last few years and that’s really what I discussed in my lecture.

The last four years or so have witnessed a huge transformation in how we treat hormone receptor positive breast cancers. First of all we’re now using aromatase inhibitors and there has been a trend now to focus on the use of hormonal therapy as opposed to chemotherapy in patients with advanced breast cancer. Twenty or thirty years ago we were primarily starting off with chemotherapy which has much more toxicities with the belief that it was a more aggressive and potentially more effective therapy. But it turns out really not to be the case and the trend towards using endocrine therapy has become much more prominent. However, again with the introduction of some of these biological agents all of the research was focussed in postmenopausal patients.

Some of the recent trials with cyclin dependent kinase inhibitors did allow a few patients, maybe a third of the patients that were premenopausal, but based on the earlier data they all underwent medical oophorectomy, primarily with either leuprolide or goserelin.  Those studies suggested that the outcomes were the same as they were in postmenopausal patients, something that we hadn’t really appreciated.

The MONALEESA-7 trial which I presented yesterday was the first of the modern era trials that was dedicated to premenopausal patients with hormone receptor positive and HER2 negative breast cancer. This was a study that was done in the first line and the trial was similar to the postmenopausal patients in that they tested an aromatase inhibitor along with the cyclin dependent kinase inhibitor ribociclib versus placebo with an aromatase inhibitor. The difference was, of course, as these women were premenopausal that they all received goserelin. The other difference about this trial is that it also allowed the use of tamoxifen which is commonly used in premenopausal patients or sometimes it’s used in patients that have trouble tolerating aromatase inhibitors. That study, because it was dedicated to premenopausal patients, had sufficient size and power to look at subsets and, in fact, did show that the outcomes were similar, that we get the same results in premenopausal patients with ovarian suppression and that tamoxifen was just as suitable an endocrine partner as aromatase inhibitors in terms of producing this effect.

Now, it turns out that ribociclib can prolong the QT interval slightly and because of that patients need to be tested with an EKG although the number of patients that have to come off due to QT prolongation is very small and was not associated with any clinical events in the studies. However, interestingly, this study found that in tamoxifen treated patients, even without ribociclib there was a prolongation of the QT interval which had never been known to occur with tamoxifen because that drug was developed at a time when we really weren’t using drugs that had those conduction defects. So we really picked up on this serendipitously but we are not using that combination in clinical practice now because tamoxifen now plus ribociclib on top of it could prolong the QT interval more; even though, again, we didn’t see adverse clinical events from it in the trial, as it expands to much larger populations that is a concern.

So really the key message here is that ovarian suppression is important and while most of our data in the modern era is in CDK inhibitors we presume that this is going to be the same with drugs like fulvestrant where we know it really works primarily in postmenopausal patients. But now that when we are combining hormonal therapy with biological therapies that we can be reasonably assured that we will get the same impact in premenopausal patients. There is still much we need to learn; there are more side effects from ovarian suppression, we need to learn how to mitigate those. We need to still study whether or not the biology is different but clearly we now can treat these patients with more confidence with some of the newer emerging regimens.