Michael Untch, MD: I would like to point out that the data are very convincing from the neratinib study, and it fits quite well with the GeparQuinto trial, which actually used a similar therapeutic principal but with another drug. It’s a tyrosine kinase inhibitor, lapatinib. So, basically, the GeparQuinto trial is a negative trial because it was powered for pCR—pathologic complete response. Trastuzumab plus chemotherapy is better than the combination of lapatinib plus chemotherapy, period. But this trial happened to have 18 months of anti-HER2 therapy starting with a tyrosine kinase inhibitor, lapatinib, and then continued 12 months post-neoadjuvant—so, after surgery with trastuzumab versus trastuzumab treatment alone.

And what happened actually when we saw the update of the data—and I’m going to present it here in ESMO again—that the hormone receptor-positive cohort had a survival benefit, although it was not the primary endpoint for the combination of the sequence of a tyrosine kinase inhibitor followed by trastuzumab. So, basically, a reverse sequence like in the neratinib trial. But it is reinforcing that HER2-positive hormone receptor-positive disease is different. And we had a talk actually yesterday at the end of the breast cancer session where Hope Rugo focused, or summarized, very nicely all these data, and I think, Hope, it seems to fit, that it matches.

Hope S. Rugo, MD: I think it really does. And there are a lot of things we know about hormone receptor-positive HER2-positive disease, which suggest that using an agent like this while you’re overlapping with endocrine therapy improves response to endocrine therapy and, therefore, outcome.

Adam M. Brufsky, MD, PhD: And the mechanism for that is what? I had to bring it up. We always need the mechanisms to try to understand this.

Hope S. Rugo, MD: Yes, absolutely. Signaling through HER2 actually increases signaling through the estrogen receptor pathway, upregulates estrogen receptor. And so, you have signaling through HER2. If you don’t block the signaling through HER2, your hormone therapy is relatively less effective. So, blocking both together makes a difference.

Now that said, there are also very interesting data from Sherene Loi in the HERA trial that shows that if you have a low FISH ratio and you’re ER-positive, you actually have less trastuzumab responsiveness, which is quite intriguing, and those patients had less benefit from trastuzumab overall—ER-positive, low FISH ratio-positive. And that was between 2.1 and less than 5; greater than equal to 2, up to less than 5. And that’s a ratio that we all think of as being positive, so I think they were quite interesting data.

Joyce A. O’Shaughnessy, MD: There is a nice publication that shows that when an ER-positive breast cancer cell is signaling down through HER2, it leads this transcription factor FOXO to leave the nucleus, and FOXO’s very involved with ER signaling. And then when you inhibit the HER2 signaling, FOXO goes back into the nucleolus and works with the estrogen receptor to transcribe all the ER-positive genes. So, it’s really a very nicely worked out mechanism actually. And there’s a very important, I think, poster here at ESMO by the Lambertini Group. They looked at the importance of treatment-induced amenorrhea in the HER2-positive ER-positive premenopausal group, and it was with chemotherapy and trastuzumab. And trastuzumab didn’t make any difference in terms of increasing the risk of treatment-induced amenorrhea, but women who were premenopausal who achieved that amenorrhea had a marked improvement in disease-free survival. The hazard ratio was 0.6 in favor of amenorrhea. Interestingly, they had an ER-negative cohort. It didn’t do anything in the ER-negative HER2-positive, as we would expect, but really highlights the importance of both blocking HER2 and ER in the effect of the ER-positive setting.

Adam M. Brufsky, MD, PhD: That’s interesting. Just to skip around for a minute to bring in something else, if that’s true, then why didn’t NSABP-B52 have a positive result?

Joyce A. O’Shaughnessy, MD: Because of what Michael said: Path CR is not the endpoint.

Hope S. Rugo, MD: Right.

Adam M. Brufsky, MD, PhD: Is that what we think? So, NSABP-B52 was a trial of HER2-directed neoadjuvant therapy, with or without endocrine suppression, and there was no difference in pCR rate. You’re saying it was just the wrong endpoint to look at?

Joyce A. O’Shaughnessy, MD: Right. That’s my opinion.

Hope S. Rugo, MD: Way too short. I think you want to look at long-term outcomes, not short-term outcomes, in that population.

Michael Untch, MD: It’s a good endpoint for high-risk breast cancer patients. But HER2-positive hormone receptor-positive, as it has been shown in GeparQuinto, is not the right patient population to have pCRs as an endpoint. And, again, although it was a secondary endpoint survival from the trial, it biologically fits quite well that HER2-positive hormone receptor-positive disease seems to have a benefit from a sequence of a tyrosine kinase inhibitor and trastuzumab.

Adam M. Brufsky, MD, PhD: Fair enough.

Transcript Edited for Clarity