Dr. Carey Anders:
Welcome to The ASCO Post Roundtable Series on updates on HER2-positive breast cancer. My name is Carey Anders, and I'm the Medical Director of the Duke Center for Brain and Spine Metastasis, Interim Division Chief of Medical Oncology, and a practicing breast medical oncologist. Joining me here today are two of my colleagues, Dr. Erika Hamilton and Dr. Sara Hurvitz, and I'll let them introduce themselves.
Dr. Erika Hamilton:
Hello, I'm Erika Hamilton. I'm a medical oncologist and I direct the Breast Cancer Research Program at Sarah Cannon Research Institute at Tennessee Oncology here in Nashville, Tennessee. Happy to join you two today.
Dr. Sara Hurvitz:
Hi there, I'm Sara Hurvitz. I'm a medical oncologist at David Geffen School of Medicine at UCLA Jonsson Comprehensive Cancer Center, where I direct the Breast Cancer Trials Program. Really happy to be here today.
Dr. Anders:
Excellent. Thank you both. We're going to be moving into case number four, which is the really challenging space of HER2-positive residual disease. I think we all hope that every patient we treat with locally advanced HER2-positive disease will have a pathologic complete response, and many will. But the reality is that not all of our patients will have a pathologic complete response at surgery, and we know they're at higher risk for recurrence.
We wanted to talk through a case to really highlight what's being done in this space, now and also in the future. This is a 39-year-old premenopausal dentist who self-palpated a mass in her left breast. She brought this to medical attention and her workup revealed a T2 or 3.6 centimeter breast mass with a positive lymph node on core needle biopsy. The pathology revealed that her malignancy was ER/PR-negative and HER2-positive. Fortunately, her staging CT and bone scan were negative and she had no evidence of distant metastatic disease at diagnosis.
So, she presents to our multidisciplinary clinic for discussion regarding neoadjuvant chemotherapy and HER2-directed therapy approaches. One of the key pieces of her story is that she is a pediatric dentist, so she is around children, and is hopeful to maintain her practice in some form. She is also concerned about alopecia just based on the fact that she works with children.
She goes on to receive our traditional TCHP (docetaxel, carboplatin, trastuzumab, and pertuzumab) for six cycles with very good tolerance. She's able to work through her treatment and at surgery, she is found to have residual disease, 1.6 centimeters, in the breast. Fortunately, she did clear her lymph node, so ypN0 disease. She asks about some of the options that we have in the adjuvant setting to decrease her risk of recurrence. I'll start with Dr. Hurvitz to see what her approach to this case would look like and what the discussion with the patient would center around in the clinic visit.
Dr. Hurvitz:
Yeah, absolutely. First of all, her desire to avoid hair loss. I think many women, especially women with children or are working around children wish to avoid alopecia associated with chemo.
I was ever hopeful that the KRISTINE study of neoadjuvant T-DM1 (trastuzumab emtansine) with pertuzumab would be a positive trial. It actually did show a pathologic complete response rate of 44%, but unfortunately, the TCHP regimen that she received was associated with a 56% pathologic complete response rate. So it is not standard to give a T-DM1-based regimen in the neoadjuvant setting at this time. I'm hopeful that the T-DXd (trastuzumab deruxtecan) antibody-drug conjugate will prove to be beneficial in this realm. It doesn't have full hair loss, but we'll have to see how that clinical trial ends up reporting out.
But in this particular patient who did have residual disease after standard neoadjuvant TCHP, which is a regimen I use routinely in this setting, I would recommend trastuzumab emtansine based on the results of the KATHERINE trial that showed in patients who had received neoadjuvant trastuzumab and chemotherapy and had residual disease at the time of surgery. Fourteen cycles of T-DM1 significantly improves the invasive disease-free survival with the hazard ratio around 0.5. This is sort of the standard accepted regimen now in the adjuvant setting for those patients who do have residual disease, and I think that this would be exactly what I would recommend for her.
Dr. Anders:
Excellent. Dr. Hamilton, I'm curious to your response, and also if either of you would recommend scalp cooling for her in this setting.
Dr. Hamilton:
Yeah, absolutely. I completely agree with Dr. Hurvitz. I would be thinking about T-DM1 for this patient. I also have to put a plug in for clinical trials, that there's multiple clinical trials looking at this space. Certainly the KATHERINE data was really transformative and quite impressive for us, but we're seeing if we can't improve upon this, either with trastuzumab deruxtecan or adding agents like tucatinib to T-DM1.
But in the KATHEINE trial, we really took our very highest risk patients. Our patients that had residual disease after good neoadjuvant HER2 therapy and those that did not receive T-DM1 and continued on standard therapy, their disease-free survival was about 77%, and we were able to increase that up to 88%. So, really to get to almost 90% cure rate, even in these ultra-high-risk patients, really was quite encouraging and just goes to show how much progress we’ve made in the HER2-positive arena.
Dr. Anders:
Excellent. So, would either of you have offered scalp cooling to this patient?
Dr. Hurvitz:
Yeah, I think scalp cooling is certainly very reasonable here. There are many different scalp cooling devices from which one can choose. Unfortunately, insurance doesn’t usually cover this, so it is an out-of-pocket expense. But in my own experience, I think that it’s effective, I would guesstimate somewhere around 80% of the time, and allows women to have their normal appearance. There will be significant hair thinning, but they are able to look like themselves. If they’re willing to put in the time, the extra time on the infusion day, and the extra cost, I have no problem with scalp cooling, and we offer it to all our patients receiving cytotoxic chemo.
Dr. Hamilton:
I agree. We too offer it. I do find it tends to be more effective when you're in this situation, getting maybe taxane and carboplatin sometimes with anthracycline. It can prove a little bit more challenging in the other population, but it's not quite as effective as we would hope. In some of our African American patients, they tend to have more hair loss and scalp cooling is not as effective for them either.
Dr. Anders:
Interesting. No, absolutely. And that's been our experience as well. I think with anthracycline-taxane, we see more hair loss despite scalp cooling, but not the complete alopecia. I think it is really important to set the expectation that, while we won't see complete alopecia, we certainly see hair thinning. I know that can be quite distressing for some of my own patients, but it certainly is something to offer and discuss with patients. Absolutely very important for the quality-of-life perspective.
This particular patient is very involved in her treatment. She's been in contact with many patients with HER2-positive breast cancer on several forums and has learned that HER2-positive disease can portend a higher rate of brain relapse. So, as you're thinking through and talking with her about some of the options that we have, I think we were a bit disappointed that we didn't see lower rates of brain relapse in KATHERINE in the T-DM1 compared to the trastuzumab arm. Albeit they're low numbers, less than 10%, but we didn't really see a significant differential there. So, I'm curious as to what some of the strategies in clinical trials are to help prevent brain relapse for patients in the post-neoadjuvant setting.
Dr. Hurvitz:
I'll just jump in here. I think that the ExteNET study of neratinib given in the extended adjuvant setting was certainly intriguing to many of us. Neratinib was given for a year and was shown to improve the invasive disease-free survival for patients treated with trastuzumab-based therapy, and that benefit really did appear to be largest in those high-risk patients with lymph node-positive disease or residual disease after neoadjuvant chemotherapy. And the benefit really did appear to be restricted to those with hormone receptor co-expression on their tumors. This particular patient has hormone receptor-negative breast cancer, so it's unclear whether or not neratinib would really benefit this particular patient. But an interesting thing about neratinib is it does seem to penetrate that blood-brain barrier, and numerically, there were lower rates of CNS (central nervous system) recurrences. Again, this was a very exploratory finding. It certainly isn't level one evidence, but it's something that some patients are choosing to do.
The other caveat about this trial is that ExteNET did not allow patients who had received pertuzumab or T-DM1, so we don't know if there is any incremental benefit to adding neratinib in a patient who has already had these therapies.
At this point, I think it's something we can discuss for this particular patient. I don't think that a full year of neratinib is worthwhile given her tumor was ER/PR-negative and she did receive T-DM1, trastuzumab, and pertuzumab, but it is something that one could discuss, especially in a patient with hormone receptor co-expression.
Dr. Anders:
Excellent. Wonderful summary and agree on all those points. Dr. Hamilton, I'm curious about the next generation TKI with tucatinib. What might be on the horizon for our patients with residual disease?
Dr. Hamilton:
Yeah. That's a great point. You bring up the CompassHER2 RD, or residual disease, trial, and that's really looking at these patients that don't have a pathologic complete response and randomizing them to standard T-DM1, per KATHERINE, or T-DM1 with the combination of tucatinib. So, we’re seeing if we can improve on the already pretty good job we're doing for our patients.
Dr. Anders:
That's fantastic and I think we're all very excited about trastuzumab deruxtecan. I'm curious about any strategies to incorporate trastuzumab deruxtecan into this space.
Dr. Hurvitz:
Yeah. There's the DESTINY-Breast05 clinical trial looking at T-DXd head-to-head against T-DM1. There's also a study looking at neoadjuvant T-DXd. So, I think in the next few years, we're going to have so much more data to inform our decisions and the landscape of treatment may be completely altered. It's really interesting that we have four agents available that are HER2-directed in the curative setting, the early-stage setting, but it's possible we'll have six or more in the next 2 to 3 years. So, I think we all have to fasten our seat belts because it's going to get bumpy.
Dr. Anders:
Absolutely. I think we're becoming very comfortable with the use of immunotherapy in our patients who need neoadjuvant treatment for triple-negative breast cancer based on the KEYNOTE-522 data really nice data at ASCO, looking at the benefit based on RCB (residual cancer burden) status. I’m curious about the potential for immunotherapy in this setting and whether or not their investigations evaluating HER2-directed therapy with IO (immuno-oncology).
Dr. Hurvitz:
Yeah. There's sound rationale to do so. Certainly HER2-positive breast cancer has been shown to have tumor infiltrating lymphocytes and may be amenable to HER2-directed therapy combined with immune therapy. There was a study in the metastatic setting called KATE2, where T-DM1 was combined with atezolizumab. And while the overall study was a negative clinical trial in the subset of patients whose tumors had PD-L1 expression, there was a striking benefit by adding atezolizumab to T-DM1. So, this strategy is being evaluated in the ongoing adjuvant ASTEFANIA study, in which patients with residual high-risk disease, which is residual disease in the lymph nodes, are randomly assigned to receive T-DM1 with or without atezolizumab.
Dr. Anders:
Excellent. Wonderful discussion. Well, I think we will close this session with some key clinical takeaways. I think that it's very apparent that residual disease post-neoadjuvant care for our patients with locally advanced HER2-positive breast cancer is an active area of research. We've made great strides, but we can always do better. Of course, we want to maximize our preoperative therapy, but if our patients don't achieve a pathologic complete response, which we would hope, we really want to maximize their postoperative therapy or their adjuvant therapy to prevent recurrence, because we know they're at higher risk for recurrence.
Unique to the HER2-positive space is the concern for CNS recurrence. And I'm really happy to report that we have several strategies evaluating ways to decrease CNS recurrence in the post-neoadjuvant space with the Compass RD study, as we've discussed with tucatinib. We've also reviewed the neratinib data, and hopefully in the future, we'll have some biomarker or collection of biomarkers that will help us better predict which patients are at higher risk of recurrence, and particularly those who are at higher risk of CNS recurrence to help tailor our strategies.
So, that brings us to the end of case four. Please see the other segments for further discussion about the latest data in breast cancer, or you can also visit ASCOPost.com. Thank you.
