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Dr. Hurvitz: Welcome to The ASCO Post Roundtable Series on Updates in Breast Cancer. I'm Dr. Sara Hurvitz, professor of medicine and director of the medical oncology program at the University of California, Los Angeles Jonsson Comprehensive Cancer Center. And joining me today are two of my colleagues, Dr. Bill Gradishar and Dr. Sara Tolaney. Dr. Bill, can you introduce yourself please?
Dr. Gradishar: Sure. I'm Bill Gradishar, a breast medical oncologist, chief of Hem/Onc at Northwestern University.
Dr. Hurvitz: Welcome today, Bill. And Sara?
Dr. Tolaney: I'm Sara Tolaney. I'm a breast medical oncologist at Dana-Farber Cancer Institute in Boston.
Dr. Hurvitz: Welcome, thanks for being here. Today, we will be discussing recent updates in breast cancer, including data presented at the 2021 ASCO Annual Meeting, and integrating these new developments into four patient case studies. Our third installment will focus on treatment options for HER2-positive breast cancer, including adjuvant therapy for residual disease. So let's get started. We have a patient who is a 62-year-old woman who was diagnosed with high-grade cT1N1, ER-positive, PR-negative, HER2-positive left breast cancer. So let's just get right down to the question. Sara, what neoadjuvant therapy do you recommend for her?
Dr. Tolaney: So this is a patient with node-positive, HER2-positive disease. And so I usually do give preoperative therapy to anyone who has a cancer over 2 cm or has nodal involvement. And generally I have been using a non-anthracycline–based therapy at this point, and really using TCHP for most patients who I'm giving preoperative therapy to.
Dr. Hurvitz: Would you agree, Bill, TCHP? Or are you still using ACTH-based therapy in the neoadjuvant setting?
Dr. Gradishar: No, I think I am in complete agreement with Sara again. We've really transitioned over the last several years away from anthracyclines in the setting. And even the thought that you're somehow compromising the effectiveness by avoiding an anthracycline has been proven not to be the case based on a clinical trial that looked at a comparison and found that the pCR rate was identical, whether you're on anthracycline or not. So you avoid the potential cardiac toxicity without compromising efficacy.
Dr. Hurvitz: Yeah, the TRAIN-2 data I think were quite compelling to many people. Sara, do you want to take us through the more recent EFS data from that trial?
Dr. Tolaney: Yeah. So this is nice to see, because I think prior to this, the only data we really had came from BCRG006, which certainly had supported that TCH seemed to do just as well as ACTH, but this is now in the era of dual HER2-directed therapy. So TRAIN-2 was really nice to see because it compared paclitaxel/carboplatin with trastuzumab/pertuzumab, to anthracycline-based therapy with taxane and trastuzumab and pertuzumab. It really not just looked at results in terms of pCR, but also in terms of EFS. And so while there is no difference in terms of pCR, I think we're all anxious to see how that would hold up with long-term outcomes.
And in fact, what we saw was there was also no difference in terms of event-free survival. And this was true regardless of which subgroup you looked at. So even if you looked at the really high-risk multi-node–positive patients, you still see no difference in event-free survival. Again, really suggesting that there's no benefit for anthracyclines even in the very high-risk patients. And so this data really was very reassuring to me because it sort of confirmed that we don't need to use anthracyclines even in high-risk patients, that their outcomes are really just as good, and we're sparing them potential toxicities such as cardiac toxicities and even potential secondary leukemias.
Dr. Hurvitz: Yeah, it's interesting. This year, the National Comprehensive Cancer Network guidelines indicated this sort of sentiment with moving the anthracycline-based regimens in HER2-positive disease from the preferred section down to the “useful in certain circumstances.” And so I think people are coming to terms with this. I think the one situation where I'm still using anthracyclines are in a pregnant woman with HER2-positive breast cancer, because we know taxanes and trastuzumab-based therapy are not safe for the baby.
So this particular woman does go on and receive neoadjuvant TCHP. She has breast-conserving surgery. She has a great response, but there is 5 mm of residual invasive disease in the breast and her nodes are completely clear. The residual breast cancer is actually tested again, it's ER-positive, PR-negative and HER2 2+ by IHC, but remains FISH positive. So Bill, can you take us through sort of how you would treat this patient in the adjuvant setting? She's had a great response. Her nodes are negative, but there is a little bit of disease that's remaining.
Dr. Gradishar: Sure. So if she had a pCR and she's almost there, but not quite, we would've probably continued HP. And when APHINITY was originally reported, we were thinking that it's really only the node positive. And then there was even a suggestion that the ER-negative are the only ones that benefit. With longer follow-up, both subgroups of ER expression benefited—ER negative or positive. But in this case, even though the area of residual disease is pretty minute, there was no threshold for which T-DM1, based on the KATHERINE study, didn't confer a benefit. So I would consider switching the patient to T-DM1. Even though she's had a very good response, it's not a pCR.
Dr. Hurvitz: Yeah. I agree with you. Completely. And I think even the small tumors on the subgroup analysis of KATHERINE seemed to benefit from the use of T-DM1 in this setting. You mentioned that if she'd had a path CR you would have used HP in the adjuvant setting. Are there any patients in the adjuvant setting where you'd use trastuzumab alone who received neoadjuvant therapy and had a path CR? If her nodes had been negative clinically prior to starting neoadjuvant therapy, would that have changed your adjuvant approach?
Dr. Gradishar: Well, I think in this setting, if there's any question about the patient not tolerating the drug, I would feel comfortable giving her trastuzumab alone. That said, if you look at the data from the APHINITY trial, it's a year of therapy. So I would be more inclined to move forward towards a year of therapy, but be willing to discontinue if there was any side effects that were prohibitive.
Dr. Hurvitz: Sounds good. What about you, Sara? And the adjuvant setting, I want to, in particular, ask you about the use of neratinib. This patient has ER-positive, HER2-positive breast cancer, she started out as node positive, great response. Assuming you're going to give her T-DM1, what about neratinib?
Dr. Tolaney: That's a good question because the data that we saw from ExteNET was in an era prior to us using pertuzumab or T-DM1. And so while that study did show that there was benefit in terms of preventing recurrence only really in the ER-positive subgroup of that trial. Again, we don't know what the benefits would be in someone who's had prior pertuzumab or T-DM1. And so it's challenging, but I think in this case this is a patient who had ER-positive disease. She did have a really good response to therapy with just a teeny bit of cancer left at the time of surgery. And so she's not the typical person that I'm going out on a limb for to recommend neratinib in a data-free zone. Because again, she's going to get T-DM1 here and likely going to have a good outcome.
Whereas if it was a patient who had node-positive disease after preoperative therapy, that makes me a little more anxious because those patients do have higher risk. And even in KATHERINE, the patients who had node-positive residual disease do have higher risk of recurrence still, even after T-DM1. I think we have room to improve on in those patients. And so those are patients, if they have ER-positive disease and residual node-positive disease after T-DM1, sometimes I have considered giving them a year of neratinib.
Dr. Hurvitz: Okay. Thank you for that. I do want to highlight something about this particular case. The HER2 was 2+ at the time of surgery and it was tested again by FISH and was found to be FISH positive. I want to ask each of you, first of all, are you routinely testing residual disease for biomarkers again? So let's first get that question addressed. Bill, what are you doing at your center?
Dr. Gradishar: The answer's no, but occasionally we end up with one, one way or the other, but usually no.
Dr. Hurvitz: And Sara?
Dr. Tolaney: Our pathologists uniformly do retest the surgical tissue. So we do end up getting the repeat receptors.
Dr. Hurvitz: Okay and if in this case the residual disease demonstrated HER2-negative, nonamplified residual disease that you are confident that it was originally HER2-positive, does that change how you think about the adjuvant regimen and the benefits of T-DM1? Do we have any data here? Bill?
Dr. Gradishar: We have very little data, but we do have a subset of the patients in the KATHERINE study, 70 who had that sort of change reported change in their HER2 status. So it's not a big number, but among the patients who continued on T-DM1, there were no subsequent events. Whereas there were some events in the other patients who did not get T-DM1.
Dr. Hurvitz: Okay. Thank you very much. Both of you. This has been very helpful and enlightening. I'll now sum up some of our key clinical takeaways. Neoadjuvant therapy should be considered for HER2 breast cancer. T2 certainly, some people even in T1c are considering it a node positive for sure, given that the pathologic response to therapy is both prognostic as well as predictive for benefit in the adjuvant setting from T-DM1. Anthracycline-based regimens are no longer considered a standard or preferred based on the NCCN guidelines, so they should be used only in special circumstances. T-DM1 remains the standard for those with residual disease, and the benefit appears to be maintained regardless of residual disease, HER2 expression, although the data are a small. And deescalation strategies continue to be explored in clinical trials with Sara Tolaney’s APT regimen being accepted as standard in small tumors in the adjuvant setting.
So this brings us to the end of our case. Please see the other segments for further discussion about the latest data in breast cancer or visit ASCOpost.com. Thank you both so much.