Ruth O'Regan, MD
Endocrine therapy has long been a standard approach for patients with estrogen receptor (ER)-positive breast cancer, but there is an unmet need for the patients who develop resistance to this treatment.
The FDA approvals of the 3 CDK4/6 inhibitors palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio) have provided oncologists with new treatment options to add to their armamentarium, said Ruth O’Regan, MD.
These agents have shown promise when used in combination with endocrine therapy or an aromatase inhibitor (AI) as frontline treatment for patients with metastatic disease in clinical trials such as PALOMA-2, MONALEESA-3, and MONARCH 3.
Most recently, the FDA approved upfront ribociclib in July 2018 for use in combination with an AI for the treatment of pre/perimenopausal or postmenopausal women with hormone receptor (HR)-positive/HER2-negative advanced or metastatic breast cancer. Ribociclib was also approved in combination with fulvestrant (Faslodex) for the treatment of postmenopausal women with HR-positive/HER2-negative advanced or metastatic breast cancer, in the frontline setting or after disease progression on endocrine therapy.
O’Regan, a professor of Medicine at the University of Wisconsin School of Medicine and Carbone Cancer Center, said the next steps for CDK4/6 inhibitors will be to test their efficacy in an earlier stage of treatment.
In an interview with OncLive
, O’Regan discussed the current landscape of HR-positive breast cancer and the unanswered questions that still need to be addressed.
OncLive: What are the updates in HR-positive breast cancer treatment?
: The most dramatic thing that has happened in ER-positive breast cancer is that most patients do not need chemotherapy. More than 70% of patients with ER-positive, node-negative breast cancer do not need chemotherapy. From the TAILORx study led by Dr Joseph Sparano, what we know is that women under the age of 50 benefit from chemotherapy if they have recurrence scores over 16. Therefore, the question is, “How can we manage those patients?” If we are going to give them chemotherapy, there are several trials suggesting that you can use a less aggressive regimen.
The other choice is to use ovarian suppression, which is a pretty traditional approach. We now have follow-up of 8 years on the SOFT and TEXT trials, showing that in patients who receive chemotherapy, AI therapy is better than tamoxifen. Ovarian suppression with an AI seems to be the most optimal therapy for these patients. For patients who don't receive chemotherapy, they seem to do fine on tamoxifen alone—at least it looks that way with these 8-year data.
One of the things we struggle with is that whether a patient gets chemotherapy or not is somewhat of a physician's choice. It would be nice to have a molecular assay to tell us which patients need ovarian suppression. It does have some toxicities. At the 2018 ASCO Annual Meeting, we saw the composite risk score. It considers the patient's age, the nodal status of the tumor, the level of ER/HR expression, and more importantly, the grade or proliferation of the cancer. If the composite risk score is low, it is like having a low recurrence score based on the 21-gene assay. What we saw from this presentation was that the patients who received chemotherapy on the SOFT and TEXT trials all tend to have a higher composite risk score.
Another somewhat controversial topic is how much endocrine therapy is needed. The standard has been 5 years, but there are ongoing trials looking at a longer duration. It is interesting because it seems pretty clear that patients who get 5 years of tamoxifen should be considered for 10 years; there are several trials that support that approach. On the other hand, for patients who receive 5 years of tamoxifen or tamoxifen followed by an AI, the benefit of extending endocrine therapy is murkier. There are some rising molecular assays looking at this, but none that are ready for clinical use.
Lastly, whatever we find works in the metastatic setting, we want to try to test that in an earlier treatment setting. There are several studies looking at CDK4/6 inhibitors and we await the results of those.
If approved in an early-stage breast cancer setting, how will CDK4/6 inhibitors impact sequencing?
Right now, the CDK4/6 inhibitors are not being used for early-stage breast cancer. There are some preoperative data suggesting they can increase tumor response using Ki-67 when given with endocrine therapy, but there are not yet any data in the early settings. When there are data, and if these agents are approved, that it is going to be a really interesting question.