Andrew D. Seidman, MD: I want to present a case to you and close on a provocative note. A 61-year-old woman presents with a mammographically detected invasive ductal carcinoma in her right breast. It’s 80% ER [estrogen receptor]-positive, PR [progesterone receptor]-positive, and HER2-negative. She goes directly to surgery and ends up having a 2-cm tumor with 10 positive axillary nodes. Her extent of disease work-up is otherwise negative. Most of us would probably tell this woman she’s in for 10 years of adjuvant aromatase inhibitor, but given where we are now with the monarchE study, is the CDK4/6 inhibitor ready for prime time? This is a free-for-all. You guys can fight for the mic.

Hope S. Rugo, MD: First of all, I think that meeting was in Orlando, because I remember that there was a spillover meeting when we saw the trastuzumab adjuvant data. It was like watching a rock star. It was an amazing place to be. What was so unique about trastuzumab was that there were survival data very early and recurrences occurred very early in that population. We even saw a benefit when there was a tiny follow-up in the trial that was sequential from Europe, the HERA trial.

This is a different situation. We’ve been talking about how we need to see longer follow-up in all of these trials. We need to understand this carry-over effect looking at the H/I [HOXB13/IL17BR ratio] index and also understand other treatments in terms of the impact. The main question about the CDK4/6 inhibitors is exactly what Aditya very nicely outlined: We see 50% of recurrences occurring after 5 years. What is special about the monarchE trial is that they successfully identified a group of patients who seemed to have higher recurrence risk in the first 5 years. If we can identify those patients in practice, we should consider use.

At this year’s St. Gallen [International Breast Cancer Conference], a fair number of people would consider the use of abemaciclib in patients who have 4 or more positive nodes. In the 1 to 3 positive node group, it’s a little uncertain. By Ki-67 alone, an inherently unstable marker, we don’t know. Patients who have a lot of disease have such a high risk. We probably aren’t doing them a big disservice—no long-term toxicities—so we would consider it now while waiting for longer-term data.

Andrew D. Seidman, MD: We have these discussions among our own service at Memorial Sloan Kettering Cancer Center so that patients in the waiting room aren’t hearing different things when they have the same clinical circumstance. Nick, are you ready to give an adjuvant CDK4/6 inhibitor in June 2021 to a patient with 10 positive nodes, or should we sit tight?

Nicholas McAndrew, MD, MSCE: Up until we finished the enrollment of NATALEE, we were obviously trying to put patients onto the NATALEE trial. But as you mentioned, even with the addition of 1000 patients, it still completed enrollment slightly ahead of schedule. Now that the NATALEE trial isn’t an option at this point, I agree. From a practical standpoint, patients who have a large burden of nodal disease are at such high risk, and there are some patients who we’ve all met in practice who—it’s sad to say—were waiting for the other shoe to drop in many respects.

I have been recommending doing adjuvant abemaciclib in addition to endocrine therapy in my very high-risk patients because we’re concerned that they may have metastatic disease anyway and should be on the best therapy as early as possible. And if they don’t, based on what we know so far, before we learn about whether those curves are going to stay separated or are going to join up, hopefully we’ll be continuing to give benefit to patients who are still potentially curable with that combination. So I am recommending that. You mentioned the OlympiA trial. One of the patients I’m giving adjuvant abemaciclib to also has a BRCA2 mutation. She sent me a very interesting question over the weekend about it.

Andrew D. Seidman, MD: Aditya, I’ve sent a few patients up I-95 to Boston to get ribociclib on the LEADER trial. Thank you for that. Assuming there’s an adjuvant benefit for ribociclib, which we obviously have to wait for, how does the LEADER trial inform how we might use ribociclib in the early stage setting?

Aditya Bardia, MD, MPH: The question with the LEADER trial is the timing of the use of CDK4/6 inhibitors. It was designed as a trial that’s post-NATALEE, post-LEADER, and post-monarchE. Coming back to the question of dormancy, do we really know that the best time to use a CDK4/6 inhibitor is just after surgery? LEADER is for patients who have had at least 2 years of adjuvant endocrine treatment and then after that have access to a CDK4/6 inhibitor, with ribociclib. The first phase was everyone getting endocrine plus ribociclib. The second phase is ctDNA [circulating tumor DNA] driven. The trial has a pre-screening component to see if there’s evidence of disease based on ctDNA. If that’s present, then the patient would get a CDK4/6 inhibitor. It’s more of a timing question with the LEADER trial.

Andrew D. Seidman, MD: Great.

Transcript Edited for Clarity