Choosing an Endocrine Partner: Metastatic HR+ Breast Cancer - Episode 6
Sara Hurvitz, MD: At this point, we don’t have any validated predictive biomarkers of response or sensitivity to CKD4/6 inhibitors in the frontline setting. Nick Turner has presented some very nice data looking at cell-free DNA from the PALOMA-3 trial. This was a trial that compared fulvestrant versus fulvestrant plus palbociclib. They took samples at the end of treatment and looked at sequencing of the tumor cells, or the cell-free DNA, to determine whether or not there was any marker amplification or mutation that occurred in those cells that might predict resistance to disease and actually showed that there are a number of markers of resistance to fulvestrant—DSR1 mutations, for example; the accumulation of PIK3CA mutations. But the accumulation of RB1 mutations is actually pretty uncommon, on the order of less than 5%.
At this point, we’re not ready for us to be doing tumor sequencing or cell-free DNA testing in our clinical patients prior to starting therapy to tell us whether or not treatment’s going to work. That may be a future way that we’re going to be able to go. For example, there are some data accumulating that cyclin E1 amplification may predict for resistance to CDK4/6 inhibitors. But at this point, I’m not sequencing a patient’s tumor to tell me that they should not receive a CDK4/6 inhibitor; it’s just too early for that.
Hatem Soliman, MD: If you’re going to use monotherapy fulvestrant, the patients whom you should select would be those who are similar to the FIRST and FALCON population, with low-burden, nonvisceral disease, or potentially de novo patients or those who have had a very long period of time between their adjuvant therapy, initial presentation, and their metastatic relapse. So, that indolent population is probably the one—if there was a toxicity concern, or a cost, or access issue—that I would consider doing monotherapy for.
Sara Hurvitz, MD: As of right now, fulvestrant monotherapy is being used in my own clinic for patients who are unable to follow the very complicated oral dosing regimen that the CDK4/6 inhibitors generally have. Patients need to be able to keep track of their days because 2 of these drugs are being given days 1 through 21 with a week off. I’ve had patients inappropriately forget to take their week off if they’re not good at keeping track of their pills. Abemaciclib requires twice-daily dosing, which can be complicated for some patients and causes diarrhea. Fulvestrant is nice as a single agent because you come into the clinic once a month to get your injections. We know the patient is being compliant with therapy, and so I will often choose this for an elderly patient or a patient who’s unable to comply with a sort of complicated oral regimen schedule or patients with very indolent bone-only metastases. The issue is that we don’t know whose disease is going to behave in an indolent fashion in the majority of cases. We don’t know who is going to require combination therapy to get that long PFS. So, for the most part, I’m using fulvestrant either in combination with the CDK4/6 inhibitor or in combination with an mTOR inhibitor like everolimus, which has shown benefit in patients with AI-resistant disease, if I can’t, obviously, enroll my patients on a clinical trial because most clinical trials are now pairing their agents with fulvestrant.
Hatem Soliman, MD: The best time to start fulvestrant, based on its mechanism of action, appears to be, for some patients, in the first-line setting. The way the drug works against degrading and directly targeting the estrogen receptor as opposed to an aromatase inhibitor, which works by lowering the circulating level of estrogen in a postmenopausal woman’s body to very low levels, is by selecting for a different kind of resistance in breast cancer. So, women who are on an aromatase inhibitor, especially in the metastatic setting and then progress, have almost a 33% chance of getting a mutation in the ESR1 gene, leading to constitutive activation of that receptor and independence from estrogen. Whereas with fulvestrant, it appears that those events happen with a lower frequency. And there’s a lot of interest now in the emerging class of oral SERDs, as well, that are potentially going to be more potent or allow us to dose those drugs at higher levels to overcome other forms of resistance, so that they may become our preferred class of antiestrogen agents in the first-line setting.
Transcript Edited for Clarity