Breast Cancer Clinical Case Review

Deborah Toppmeyer, MD, director of the Stacy Goldstein Breast Center and professor of medicine at Robert Wood Johnson Medical School, Rutgers Cancer Institute of New Jersey, discusses the treatment options for locally advanced or metastatic HR-positive breast cancer.

Editor’s note: The following is an automatically generated transcript of the above video.

"First-Line treatment in terms of treatment options without question endocrine therapy, plus a CDK4/6 inhibitor based on data that I will share with you is First-Line recommended treatment for most patients. However, we can certainly in a select patient population, although sometimes it's a little challenging to identify who that may be, that really compromising their overall survival is to start with endocrine monotherapy. That may be a patient with a solitary metastases, oligometastatic disease that was radiated that you really don't want to embark on systemic therapy with a CDK4/6 inhibitor because it does add toxicity to the patient's life.

Once again, chemotherapy is only recommended for visceral crisis at this point. So as many of you know, CDKs are key regulators of controlled progression through the cell cycle and CDK4-cyclin D1, the Rb pathway is a aberrant in many cancers, which leads to loss of cell cycle control. And in breast cancer amplification or overexpression of cyclin D1 can be found up to 75% of tumors. But again, remember the only biomarker for the use of these agents is estrogen receptor and progesterone receptor.

So these are the three options and as many of you know, there has been extensive data on palbo, ribo, and abemaciclib in various studies, which I will share with you. And the indications for palbociclib, ribociclib, and abemaciclib are first or second line, first with an AI or after progression, after endocrine therapy with fulvestrant in terms of ribociclib first or second line with fulvestrant. And it is also approved first line premenopausal with ovarian suppression and an AI. Abemaciclib, unlike the other two, is the only agent that has been approved as monotherapy after progression on endocrine therapy and chemotherapy. Here's just another schema of the overview of the phase trials, endocrine therapy, sensitive or naive. You can see that all three agents have shown efficacy in combination with AI. Second line is typically with fulvestrant, and again, only abemaciclib is approved as single agent in a highly pretreated patient population.

I think this is an incredibly important slide because there has been a lot of controversy in terms of the overall survival data, which I'm going to speak to next relative to CDK4/6 inhibitor choice as first line therapy. If you look at the hazard ratio for progression-free survival, all three agents are essentially identical. And if you look at the Kaplan-Meier curves, they're almost all super imposable compared to control. And again, if you look at the progression-free survival in months, it's almost a nine to 10 month increase in progression-free survival, in certain cases, a doubling of progression-free survival.

Again, it's not appropriate to do cross study comparisons, but I think what we can take away from this is that all three agents are active in this patient population and any of the three agents can be chosen as first line therapy. The overall survival data in particular gonna focus on the MONALEESA data. This particular trial did show a survival benefit in women treated with ribociclib, goserelin and AI or fulvestrant or letrozole. These data are important in this particular trial, obviously, in MONALEESA-7, it was a younger patient population.

There were not as many premenopausal patients included in the other trials, and I would say that by and large people are more inclined in a younger patient to start with ribociclib based on these data. However, I will say that there were certain issues with the studies and in terms of the PALOMA-2 and 3 trials that the control arms, there was a loss of patients and follow up was somewhat flawed. Again, impacting the overall survival data in these trials. If you look at the rest of the world data or real-world data of these agents, they're all very equivalent. So there is not a wrong choice if you choose palbo over ribo, over abema or abema over ribo.

So again, all of these agents are very active agents and there is not a wrong choice. And your choice of first line therapy really has to be dictated by a number of factors, particularly factors related to the patient comorbidities, potential drug drug interactions, et cetera. And again, the toxicity profile of these agents are somewhat different. If you look at ribo and palbociclib, they both have neutropenias, a fairly significant AE, where with abemaciclib, that rate of neutropenia significantly less. However, if you look at diarrhea and fatigue, certainly GI side effects are more significant with abemaciclib compared to palbociclib and ribociclib.

Additionally, it is critically important that we obtain EKG monitoring with ribociclib compared to palbociclib or abemaciclib has been associated with prolongation of the QTC interval, particularly at the 600-milligram dosing, which is approved in the metastatic setting as opposed to the 400-milligram dosing that was tested in the NATALEE trial. That was also positive in the adjuvant setting. The recommendation is that an EKG is obtained before treatment and day 14 of cycle one and cycle two, day one as well. Also important to understand is that the QTC interval was significantly increased inpatients on tamoxifen, and we do not give ribociclib and tamoxifen together."