Debu Tripathy, MD: What I’d like to do is move on to the emerging area of using these biological combinations, particularly the CDK [cyclin-dependent kinase] inhibitors, in the adjuvant setting for a clinical benefit, and also in the neoadjuvant setting to possibly understand something about the biology and provide us some baseline data and justification for these trials. Ian, there were several studies looking at both the neoadjuvant model and defined subsets. Do you want to comment on those findings?

Ian E. Krop, MD, PhD: Yes. We’ve already known that in the pre-CDK era that in the neoadjuvant setting for ER [estrogen receptor]-positive breast cancer that neoadjuvant hormonal therapy was at least equivalent to neoadjuvant chemotherapy in aggregate and unselected ER-positive breast cancers in terms of clinically important things like increasing rates of breast conservation. Those are old data. Now that we have the advent of CDK4/6 inhibitors, which clearly improve the efficacy of hormonal therapy, it’s certainly worth revisiting this and to see if now this combination is even superior to chemotherapy. There was this interesting study in the neoadjuvant setting, the CORALLEEN study from the SOLTI Breast Cancer Research Group, which actually follows up on the PEARL study that you were talking about in the metastatic trial.

This trial looked specifically at luminal B, ER-positive cancer. We’re stacking the deck essentially against hormonal therapy, randomizing patients to ribociclib and hormonal therapy, an AI [aromatase inhibitor] for 6 months versus a neoadjuvant chemotherapy regimen, basically Q3 [every 3] week AC [doxorubicin cyclophosphamide] with weekly paclitaxel. Again, these are luminal B cancers, but when they looked at their primary end point, which was ROR [risk of recurrence] low-risk score, essentially equivalent effects. I think they’re certainly supportive of this idea that for patients with ER-positive breast cancer, that neoadjuvant hormonal therapy can be a very effective approach.

I think the 1 caveat that was brought up at the meeting was that this particular primary end point of ROR score was generated and validated in pretreatment patients. In this particular setting where they’re using it as a post treatment end point, my understanding is there’s not a lot of validation for that.

Hope S. Rugo, MD: Or any.

Ian E. Krop, MD, PhD: Or any. I was trying to give them the benefit of the doubt. But I think that that’s something that we need to follow up with, and there needs to be potentially longer-term outcomes data and also other end points. But it’s certainly encouraging. We already know from other preoperative studies that hormonal therapy plus CDK 4/6 inhibitors are essentially 100% effective at leading to drop in Ki-67. So, they’re effective. I think what we need to do now is really try to focus on which patients benefit most with ER-positive disease from chemotherapy, and which can get by very well with neoadjuvant hormonal therapy. My guess is for the vast majority hormonal therapy is going to be fine. But there probably are patients who still benefit from chemotherapy, and it will be nice to figure that out.

Debu Tripathy, MD: Certainly the large national, international randomized trials going on now, many of them are biomarker rich. That’s not only to answer the global question of the benefit in the adjuvant setting, but hopefully some about the biology and maybe patient selection as well.

Hope S. Rugo, MD: If we get data from the adjuvant trials, we have 4 trials that will someday report. One is still ongoing, NATALEE, with 3 years of ribociclib. We have the 2-year studies of MONARCH and PALLAS. Then we have the 1-year post neoadjuvant study of PENELOPE, which we thought would report earlier than the others. All of these trials, probably NATALEE the least, really focus on high risk of disease and try to amplify that. MONARCH probably is the highest-risk population and PENELOPE-B. This is trying to make it not be a 10-year difference in recurrence but more 5 or 3, or 4. But if those are positive, it’s going to be interesting to see what it does in terms of changing our neoadjuvant approach as well.

Adam M. Brufsky, MD, PhD: I was going to mention this, none of those trials, they’re all high-risk populations, and high-risk patients will get the chemotherapy. None of them address the problem, the question of, in a high-risk patient do you take the CORALLEEN way of just endocrine therapy and the CDK4 and nothing else?

Joyce A. O’Shaughnessy, MD: The West German Study Group is going to do that.

Adam M. Brufsky, MD, PhD: They’re going to do that, but it’s a smaller trial.

Joyce A. O’Shaughnessy, MD: It will be done. We’re going to get….

Adam M. Brufsky, MD, PhD: Assume for a minute it’s a couple of years from now, and PALLAS turns out to be positive for the CDK4/6, or PENELOPE-B, where I agree with you, where are the data? This trial closed a year or two ago. Assume they’re positive. Would that make us not use chemotherapy in the neoadjuvant setting?

Hope S. Rugo, MD: No, I just think that you might select a group of patients that would feel even more confident about a West German Study Group-type trial. This is because maybe we feel a little anxious now, and then when they get their neoadjuvant therapy and they have a lot of diseases at surgery, we still give them chemotherapy, you know?

Adam M. Brufsky, MD, PhD: Right.

Hope S. Rugo, MD: They all have Ki-67 less than 5%, but we don’t want to not give them chemotherapy. Also of course, the ongoing RxPONDER trial will give us some information about that too.

Transcript Edited for Clarity