Biomarker Data After Neoadjuvant Therapy for HER2+ Breast Cancer



Adam Brufsky, MD, PhD: Virginia, did you see the stuff from Carsten Denkert? He was the PI [primary investigator], and it was the KATHERINE investigators.

Virginia Kaklamani, MD:The bottom line was that they didn’t come up with anything that significant. PIK3CA mutation status did not seem to influence the outcome. The benefit from T-DM1 [trastuzumab emtansine] appeared to be independent of all the other biomarkers. We still don’t have a biomarker that tells us whom to use the T-DM1 on and whom not to.

Adam Brufsky, MD, PhD: I like to look at the parts that are trends. They’re not quite there yet. You see the CD8, PD-1, and those little things, and you’re going, “Maybe you if you had more power in their trial we would have seen something.” Do you think there could be an immune signature that could mean something here eventually?

Virginia Kaklamani, MD:If you look at the PD-L1 that was potentially important in the trastuzumab arm but not in the T-DM1 arm, moving toward the fact that T-DM1 might be doing the work regardless of the immune system, that’s good.

Adam Brufsky, MD, PhD: There was really nothing. Let me look back here, there’s a cytokine gene signature. It looks a little different but not a lot, and the hazard ratio between the 2 aren’t significant because the confidence intervals overlap but they clearly are a little different. Is it enough to make something of or just blow off?

Carey K. Anders, MD: My take-home was very similar to Virginia’s. Was the T-DM1 superior to the trastuzumab? It seems to overcome many of the differences that were seen in the trastuzumab arm by either CD8 or PD-L1, and there was no differentiation between PIK3CA. It told me to continue choosing T-DM1 in that setting until I know more.

Adam Brufsky, MD, PhD: I’m thinking more of the mechanism of what’s going on behind all this. There is no marker that can tell if T-DM1 or trastuzumab is better. That’s the clear bottom line to this. From a teaching standpoint, what is it going to teach us?

Virginia Kaklamani, MD:Most of the time we test the primary tumor and give neoadjuvant therapy. Then we find the results—and I guess a lot of institutes look at ER [estrogen receptor]/PR [progesterone receptor] and HER2 at the time of surgery, as well—the more you do it, you get discordant results. You have a patient who is ER negative and HER2-positive. You give them neoadjuvant TCHP [docetaxel, trastuzumab, pertuzumab, carboplatin]. They have some residual disease, but now the residual disease is triple negative. What do you do in that setting? It happens more and more; the more we check, the more we get these results.

Adam Brufsky, MD, PhD: I thought someone did an analysis on that a couple of years ago and found they had a worse prognosis. Is that correct? Someone presented it at ASCO [American Society of Clinical Oncology Annual Meeting] or San Antonio Breast Cancer Symposium a number of years ago. I just remember it saying that if you are discordant at surgery, you do worse. Maybe there’s something there. What do you do? What are we going to do? The answer to it, and this is where we’re probably going to see it, is going to be when we start using DS-8201 [fam-trastuzumab deruxtecan-nxki]. DS-8201 has activity in lower HER2 than T-DM1, right? Is that what we all believe, or no?

Mark D. Pegram, MD: It has a bystander effect. It can kill the tumor cells that aren’t even bound by the antibody backbone. They can still be killed.

Adam Brufsky, MD, PhD: Rashmi, what do you think? Is that a reasonable thing? Is this COMPASS or the other 1? This is B60, right? COMPASS is 1 where we use tucatinib. In B60 we are comparing DS-8201 to T-DM1, right? What do you think, Rashmi, will this help us out at all?

Rashmi K. Murthy, MD, MBE: Yes, definitely. There seems to be significant clinical activity of DS-8201 in the low HER2-expressing tumors. We actually had several of the trials open at our institution, and we definitely saw clinical benefit in our patients. It will really be interesting to see what type of role that has in the future in terms of bringing it to the earlier-stage settings.

Adam Brufsky, MD, PhD: Is anybody using T-DM1 instead of TH [paclitaxel, trastuzumab] right now, based on the ATEMPT trial that was presented? Didn’t they publish that? I didn’t see it published. I’m assuming it is going to be out sometime. Does anyone use T-DM1 now, or not?

Mark D. Pegram, MD: Our group decided that during the COVID-19 [coronavirus disease 2019] pandemic, we would consider it, especially for elderly patients and patients who have high-risk factors for COVID-19 mortality. It keeps them away from a high-risk area, which is a medical center. By definition, a medical center is high risk for the virus transmission. As a group, we decided that we would at least consider the ATEMPT approach during the pandemic.

Adam Brufsky, MD, PhD: If there weren’t a pandemic, would you have done it?

Mark D. Pegram, MD: No, probably not. Even the authors who presented the paper in San Antonio, in their conclusion did not endorse it.

Adam Brufsky, MD, PhD: Any other comments before we move on to something else?

Carey K. Anders, MD: It is interesting. I know it was a non—

Rashmi K. Murthy, MD, MBE: I think in select patients, elderly patients, or those who have—

Adam Brufsky, MD, PhD: Obviously, you don’t lose your hair. That’s a biggie with women. They don’t want to lose their hair, and they still want therapy. It’s reasonable. Carey, you were going to say something. I’m sorry.

Carey K. Anders, MD: It’s interesting that the trial design was clearly noncomparator. It’s hard not to do that by human nature when you’ve got 2 arms in the same study. The results were not that much different, but the discontinuation rate of the T-DM1 was not insubstantial. Even though we think of it as a gentler, kinder regimen, many of the women did transition over to complete their year with trastuzumab. I do agree, if I had a woman who said to me, “I will not take anything for a small node negative, HER2-positive breast cancer that would cause me to lose my hair,” I would strongly consider, based on the ATEMPT data, offering her T-DM1 over nothing. That would be a very reasonable option based on the data we have.

Adam Brufsky, MD, PhD: If she’s got tumor heterogeneity, I’m not going to do that.

Carey K. Anders, MD: Correct.

Adam Brufsky, MD, PhD: That’s 1 thing I will not do it because I understand those are the people who are not going to do well with this. That’s a very good point.

In this COVID-19 era, what do you think about the FeDeriCa data that was presented at San Antonio? I don’t know if it’s been approved, the combo subcutaneous trastuzumab and pertuzumab? Has that been approved?

Mark D. Pegram, MD: No, not yet. There is a capacity-use trial that’s open, and it allows home administration of a fixed-dose combination of pertuzumab, trastuzumab, and recombinant hyaluronidase by a home-visiting nurse. We have a trial open at our center, and that trial was developed mainly for the COVID-19 issue.

Adam Brufsky, MD, PhD: Have you had anybody on it yet?

Mark D. Pegram, MD: I haven’t, personally. I have to ping my colleagues at the next tumor board. I don’t recall.

Adam Brufsky, MD, PhD: I’m really curious because the preference trials from Europe—the HannaH, PrefHER—where they have half trastuzumab subcutaneous and half regular trastuzumab, the women loved it. Patients loved this. Approximately 90% of the people wanted the subcutaneous instead of the IV [intravenous].

Mark D. Pegram, MD: For the subcutaneous, if somebody’s getting the APT [adjuvant paclitaxel and trastuzumab] regimen during the COVID-19 era, subcutaneous is a faster amount of time in your infusion area. Therefore, it will be a lower risk of virus transmission because that’s also time dependent. Acute trastuzumab is already available, and I would use it in a heartbeat during the COVID-19 era.

Adam Brufsky, MD, PhD: Let’s look ahead to 2027. Tesetaxel gets approved as an oral taxane. Can you imagine treating women with an oral taxane and subcutaneous pertuzumab-trastuzumab as their therapy for 4 months? No hair loss, and it’s equally as good. That’s the future we’re probably looking at, at some point.

Transcript Edited for Clarity

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