Neoadjuvant Therapy for HR+ Breast Cancer

Transcript:

Adam M. Brufsky, MD, PhD, FACP: Let me bring this into the neoadjuvant setting, because this is a really important point. Let me give you a case. This happened to me yesterday, actually. She came to see me before I flew out here last night. A woman walks in the door, she’s 62 years old, and she has a 12-cm tumor that’s fairly ER-positive, probably about the equivalent of 60%. We use semi-quantitative evaluation. Let’s say the ER equivalent of 60%, PR of 60%, Ki-67 of 15%, and a 12-cm grade 2 tumor that’s touching the chest wall. So, how would you treat that patient? Would you give her chemotherapy up front?

Lee Schwartzberg, MD, FACP: How old is the woman?

Komal Jhaveri, MD, FACP: How old is she?

Adam M. Brufsky, MD, PhD, FACP: 62 years old; she’s postmenopausal.

Hope S. Rugo, MD: And grade 2 ER-positive?

Adam M. Brufsky, MD, PhD, FACP: Grade 2 ER-positive, and her Ki-67 is around 15%. Our Ki-67 score guys are good. We don’t know if it’s node negative, but Ki-67 is 15%, on the low end.

Hope S. Rugo, MD: I just saw a patient like that yesterday.

Adam M. Brufsky, MD, PhD, FACP: So, here we go. What do you give this woman? I’ll tell you what I do, but will you give this woman endocrine therapy and a CDK4/6 inhibitor? Or would you give her chemotherapy up front? That’s the decision.

Hope S. Rugo, MD: We don’t have that approval for neoadjuvant therapy.

Adam M. Brufsky, MD, PhD, FACP: We don’t, but one could argue it’s unresectable disease; so yes, we do have approval. It’s unresectable.

Hope S. Rugo, MD: So, this patient has unresectable disease?

Adam M. Brufsky, MD, PhD, FACP: She has unresectable disease, and you want to make it resectable.

Hope S. Rugo, MD: Do you send genomic tests in that setting? Because we do.

Adam M. Brufsky, MD, PhD, FACP: Not in that setting. It’s too early for me to use genomic testing, which is a whole other conversation. Would you treat her? How would you treat her, Lee?

Lee Schwartzberg, MD, FACP: Those are the problem cases every time. I don’t think about using CDK inhibitors. I haven’t done that yet. I have used genomic tests in that setting, and there was actually a study at San Antonio that looked at Oncotype to help guide that decision.

Adam M. Brufsky, MD, PhD, FACP: Oh, genomic testing meaning multiparametric Oncotype.

Hope S. Rugo, MD: That’s what I meant.

Adam M. Brufsky, MD, PhD, FACP: Oh, I thought you meant NGS [next-generation sequencing].

Lee Schwartzberg, MD, FACP: No, no, not NGS.

Hope S. Rugo, MD: See, we use that to decide about using chemotherapy or not because of the I-SPY study.

Adam M. Brufsky, MD, PhD, FACP: Let’s say she’s low risk.

Lee Schwartzberg, MD, FACP: If she’s low risk, I would consider endocrine therapy there, but if I was going to start that patient on a neoadjuvant endocrine therapy, I’d get a repeat Ki-67 at 2 weeks.

Adam M. Brufsky, MD, PhD, FACP: You would do that?

Hope S. Rugo, MD: I get it at 1 month.

Lee Schwartzberg, MD, FACP: Well, at 2 to 4 weeks, depending on when we can schedule the biopsy.

Adam M. Brufsky, MD, PhD, FACP: You would use that even though, for me, it’s kind of a research thing? You’d use that clinically?

Lee Schwartzberg, MD, FACP: In this particular case, I would.

Adam M. Brufsky, MD, PhD, FACP: Really?

Lee Schwartzberg, MD, FACP: Yes, but not in an 80-year-old who has a bad surgical risk, where I’m using neoadjuvant endocrine therapy all the time now to try to shrink the tumor.

Adam M. Brufsky, MD, PhD, FACP: But this is someone you’d normally give chemotherapy to.

Lee Schwartzberg, MD, FACP: That’s right.

Hope S. Rugo, MD: If I’m trying to decide if I am going to jump ship and give chemotherapy in a patient like this, I would look at Ki-67 if I could at 4 to 6 weeks, or something like that; 2 weeks is a little bit early for us. Now, if she’s going to go to surgery at 4 to 6 weeks, I don’t need to do that. But if I’m going to try and keep her on that therapy to try and shrink it and if this patient has unresectable disease…

Adam M. Brufsky, MD, PhD, FACP: She does.

Hope S. Rugo, MD: I would add a CDK4/6 inhibitor.

Lee Schwartzberg, MD, FACP: Based on the POETIC trial, if they go from high to low Ki-67, or if you’re low to low, which is what your case is…

Adam M. Brufsky, MD, PhD, FACP: Describe POETIC for the audience. They need to know what that is.

Lee Schwartzberg, MD, FACP: In my opinion, it was a little audacious. The primary endpoint was actually a clinical endpoint, which I suspect had more to do with the funding authorities than with the scientific design, but I don’t know that. So, it was 2 weeks of perioperative hormonal therapy with an AI [aromatase inhibitor] to see if there’s a clinical change. But there were lots of correlative sciences. Basically, it just confirmed what we’ve known from all the other small trials. If you have high Ki-67 and you go low, you do well. If you have low-low you do well. If you go low-high, you do poorly. If you’re high-high, you do poorly, with 20% disease progression within 5 years.

Hope S. Rugo, MD: Matt Ellis has shown this, Matt Ellis and Cynthia Ma’s work. I think Cynthia Ma has an ongoing trial with this. I actually think that there are a fair bit of data out that move it a little bit outside of the research setting and suggest that people who don’t drop their Ki-67 don’t do well. We believe that those patients may actually benefit from chemotherapy. So, I think that if you’re going to start with neoadjuvant endocrine therapy in a patient where the decisions are going to be close, that might be helpful. I actually use it in patients where I’m trying to make a decision.

Lee Schwartzberg, MD, FACP: I agree.

Hope S. Rugo, MD: If somebody said to me, “She has a second cancer, she doesn’t want chemotherapy, and she has a low-high risk on MammaPrint,” I would say, “OK, well, we’ll do endocrine therapy. Her Ki-67 is 20%.” We’ve got to see what’s going to happen in this first month.

Komal Jhaveri, MD, FACP: The caveats with Ki-67 and the reproducibility…

Adam M. Brufsky, MD, PhD, FACP: Right. You’ve got to trust your Ki-67 people.

Hope S. Rugo, MD: Yes.

Adam M. Brufsky, MD, PhD, FACP: You’ve got to trust who does it.

Komal Jhaveri, MD, FACP: Where I come from, we don’t report that, so I wouldn’t know.

Adam M. Brufsky, MD, PhD, FACP: It’s Memorial Sloan Kettering. And you don’t trust your pathologist? You shouldn’t say that on TV.

Komal Jhaveri, MD, FACP: Many institutions, including ours, do not use Ki-67 as a part of their pathology report to guide treatment, for the various caveats that are known to everyone. Just out of curiosity, I find all these data very intriguing and relevant in many ways, as we’re discussing, but the cut points have always confused me. The POETIC trial used 10%, the POL study used 10%, there are data for 14% cut points, and subgroup analyses have looked at 20%. How have you decided on a baseline Ki-67 of 15%, and how much of a decline makes you feel like you want to adapt therapy if you use it in clinic?

Adam M. Brufsky, MD, PhD, FACP: They say you have to decline below a certain number. All the trials say below 4.7%.

Lee Schwartzberg, MD, FACP: Below 5%.

Adam M. Brufsky, MD, PhD, FACP: It’s 5%, roughly.

Hope S. Rugo, MD: Based on neoMONARCH and all the neoadjuvant studies looking at CDK4/6 inhibitors, people used a complete cell cycle suppression of 2.7% or something like that.

Adam M. Brufsky, MD, PhD, FACP: I always forget what it is. Let’s say 2.7% or whatever it is.

Hope S. Rugo, MD: It’s an interesting question because that is a research question. You’re looking at complete cell cycle suppression. I don’t know if we need that.

Francisco Esteva, MD, PhD: I agree with Komal.

Adam M. Brufsky, MD, PhD, FACP: So, do you use it at New York University?

Francisco Esteva, MD, PhD: I think this is still a research question.

Komal Jhaveri, MD, FACP: It’s a research question.

Lee Schwartzberg, MD, FACP: You have to trust your Ki-67, absolutely.

Francisco Esteva, MD, PhD: It’s not validated. I think it’s very dangerous to go by a test that is unreliable.

Lee Schwartzberg, MD, FACP: Don’t try this at home.

Komal Jhaveri, MD, FACP: When I have reports of Ki-67, I use that information in some way, but I don’t know if I rely on Ki-67 to make a decision.

Hope S. Rugo, MD: You’re looking at change. That’s what I look at. I don’t care about the number.

Francisco Esteva, MD, PhD: But the change is a different biopsy in different areas. Breast cancer is very heterogeneous, and you’re not biopsying the same place.

Adam M. Brufsky, MD, PhD, FACP: Well, that’s the point I was going to raise.

Hope S. Rugo, MD: Some of these ER-positive cancers are not that heterogeneous. I think we just have to be cautious and individualize.

Francisco Esteva, MD, PhD: For a patient like this, I would probably use chemotherapy to downstage and then use hormone therapy in an adjuvant setting. But having said that, I agree that a combination of endocrine therapy and CDK4/6 inhibition may be as effective as paclitaxel. We don’t know for sure, but it seems like some patients can actually do very well. The other problem with neoadjuvant endocrine therapy is the duration, because we know we give endocrine therapy for 5 or 10 years and 3 months may not be enough.

Hope S. Rugo, MD: No, it’s clearly not enough.

Francisco Esteva, MD, PhD: You’re using the Ki-67 to guide you, and that’s where I have a problem.

Lee Schwartzberg, MD, FACP: That’s right.

Komal Jhaveri, MD, FACP: That is why pCR is not prognostic in the ER-positive subtype the way it is for HER2-positive and triple-negative disease.

Francisco Esteva, MD, PhD: For example, in the abemaciclib study, neoMONARCH, the pCR rate was 3.7% at San Antonio. It’s not the greatest.

Lee Schwartzberg, MD, FACP: But there’s the NeoPAL study that was presented at ESMO, which is a small trial that compared chemotherapy to palbociclib and an AI.

Adam M. Brufsky, MD, PhD, FACP: Right. That’s what I’m remembering when I think about this.

Lee Schwartzberg, MD, FACP: You can either read that as glass half full or glass half empty.

Adam M. Brufsky, MD, PhD, FACP: We’re oncologists. It’s always half full.

Lee Schwartzberg, MD, FACP: Right, but here’s the point to your patient. If a patient got chemotherapy, they still only had a 5% pCR rate, and they got the same amount with the combination.

Adam M. Brufsky, MD, PhD, FACP: That’s exactly right. When I thought of this patient, I thought of NeoPAL, exactly.

Komal Jhaveri, MD, FACP: The breast conservation rate was similar, which means you could get away with the endocrine therapy combination.

Adam M. Brufsky, MD, PhD, FACP: That’s the point. The response with these drugs is high. We said it in metastatic disease; we said it in the neoadjuvant setting.

Komal Jhaveri, MD, FACP: Having said that, I don’t think this is a very clinically approved approach and indication yet, but on a patient-to-patient basis…

Adam M. Brufsky, MD, PhD, FACP: No, unresectable disease is approved. They would have been eligible for the trials.

Hope S. Rugo, MD: They would have been eligible for the first-line studies.

Lee Schwartzberg, MD, FACP: That’s true.

Adam M. Brufsky, MD, PhD, FACP: That’s in the label.

Hope S. Rugo, MD: I personally would take that approach instead of chemotherapy. When I give neoadjuvant endocrine therapy, if I’m really giving it—I’m not just giving it to decide about whether or not somebody should get chemotherapy after surgery, which we also do, but giving it as an induction by using more of Matt Ellis’s drop in proliferation—I try and give it for 6 months. I think that’s where, for lobular cancer, there are really good data from the United Kingdom suggesting that you see really much better responses with longer duration.

Adam M. Brufsky, MD, PhD, FACP: They do it for a year.

Komal Jhaveri, MD, FACP: I do that for a year.

Adam M. Brufsky, MD, PhD, FACP: I think American women will not want to go on hormone therapy for a year.

Hope S. Rugo, MD: Some people do.

Komal Jhaveri, MD, FACP: I did it for a woman with unresectable disease, with letrozole alone for a year, under close observation with a surgeon, and she actually made it to surgery.

Adam M. Brufsky, MD, PhD, FACP: Good for her.

Francisco Esteva, MD, PhD: I’ve done it in patients who are fragile, who are not good candidates for chemotherapy, and you can do it for a long time.

Adam M. Brufsky, MD, PhD, FACP: We’re not talking fragile. We’re talking regular patients.

Hope S. Rugo, MD: I try and get people to surgery by around 6 months, unless they are really continuing to have a great response. But in some of these people, you see phenomenal responses to endocrine therapy. And then, you get patients with lobular cancer who have been on it for 6 months and they have 26 positive nodes, which you couldn’t see from anything.

Adam M. Brufsky, MD, PhD, FACP: They would have had those 26 nodes regardless.

Hope S. Rugo, MD: They would have had them anyway. So, now you know you need chemotherapy.

Transcript Edited for Clarity