Dr. Erika Hamilton:
Welcome to The ASCO Post Roundtable Series on Updates in Early-Stage Breast Cancer. I'm Dr. Erika Hamilton. I'm the Director of the Breast Cancer Research Program at Sarah Cannon Research Institute in Nashville, Tennessee, and I'm joined by two of my fantastic colleagues today. Dr. Danso, would you introduce yourself?
Dr. Michael Danso:
Yes. I'm Michael Danso. Thank you very much for the invitation to join in this case discussion. I'm Medical Director and Research Director at Virginia Oncology Associates in Norfolk and also part of the Sarah Cannon Research Institute.
Dr. Hamilton:
Thank you so much for being here and Dr. Jhaveri?
Dr. Komal Jhaveri:
Hi, this Komal Jhaveri, happy to be here today joining you too. And I'm a breast medical oncologist at Memorial Sloan Kettering Cancer Center. I'm the Patricia and James Cayne Chair for Junior Faculty here. I serve as a Section Head for our Endocrine Therapy Research Program and Clinical Director for Early Drug Development Service.
Dr. Hamilton:
Happy to join both of you. Today, we're going to be discussing the treatment of early breast cancer with three patient cases. This is our second installment, and it will focus on the treatment of early node-negative, HER2-positive breast cancer.
Let's dive into this second case. This is a 53-year-old Caucasian female who works as a PACU nurse and she noted an abnormality in the right breast on screening mammogram. Nothing palpable that she felt prior to this. This is biopsied. It looks to be about 1.1 cm. It is ER positive with PR loss and also shows HER2 amplification by FISH. She ultimately goes on to have a lumpectomy due to the small size of this lesion, she has a 1.2-cm invasive ductal carcinoma. Again, that is HER2 amplified with zero out of two sentinel nodes involved.
So let's dive right into what you're thinking about this case, Dr. Danso. What would be your choice of adjuvant therapy for a HER2-positive cancer that's right at around a centimeter: weekly paclitaxel with trastuzumab, followed by endocrine therapy, TCH followed by endocrine therapy, TCHP followed by endocrine therapy, or T-DM1 for 1 year with endocrine therapy.
Dr. Danso:
Thank you, Dr. Hamilton. So as this is a tumor measuring less than 2 cm and is ER positive, I'd be very comfortable treating with adjuvant paclitaxel and trastuzumab based, followed by endocrine therapy, based on the results of a phase II APT trial published by Sara Tolaney. There are excellent disease-free survival outcomes of well over 90% with a 10-year follow-up. So I'm very comfortable with paclitaxel/trastuzumab in this setting. So although T-DM1 is as efficacious as paclitaxel/trastuzumab in this patient population, based on a number of trials including the recently published ATEMPT trial, T-DM1 is associated with higher rates of clinically relevant toxicities including resulting in dose delay or early discontinuation. For that reason, I think I'd be very comfortable with paclitaxel/trastuzumab.
Dr. Hamilton:
Yeah, absolutely. Dr. Jhaveri, what are you thinking about this case?
Dr. Jhaveri:
Yeah, I think we really look at a HER2-positive early-stage patient and it's really either the nodal involvement, which makes it easy to think about neoadjuvant chemotherapy and if it's no nodal involvement, then we're thinking about the tumor size. So given that this tumor size is less than 2 cm or closer to the 1 cm as you pointed out and is node negative, she obviously was treated very appropriately so with upfront surgery, and then we're thinking about the most optimal adjuvant regimen. And I think given the data that we have, this is one of those scenarios that despite not having a randomized dataset, but given a single arm study, which has been so, so wonderful in terms of getting great outcomes for our patients, which is the APT trial with weekly paclitaxel and trastuzumab with excellent disease-free survival rates of nearly 93% in this patient population and breast cancer–free survival rates of close to 99%. I mean, it cannot get any better to be able to justify anything more. So I think it seems like the right approach in this patient to offer that based on the APT data outcomes.
Dr. Hamilton:
Yeah, absolutely. Like our last case, Dr. Jhaveri, does age play into this at all? Is there a woman that's young enough that you feel less comfortable or how does age play into this decision, if any?
Dr. Jhaveri:
I think in my mind here, it's more that the APT trial really had a cutoff of 3 cm, but I usually think about the APT regimen regardless of the age, if the tumors are really small. So if it's a 1-cm tumor, less than 1.5-cm tumor, or even something that is even smaller, I feel a lot more comfortable with the APT regimen. I'm not necessarily thinking that if this patient was a younger woman that I would give her neoadjuvant just because of the age, unlike what we discussed in case one. So I think it's more the tumor size and the nodal involvement that drives my decision for neoadjuvant therapy with HER2-positive cancer.
Dr. Hamilton:
That makes a lot of sense. Dr. Danso, how high will you go in terms of tumor size? Obviously in the APT trial they included patients that had up to 3-cm tumors, but really the majority of patients on the trial had 2 cm or less. How far do you feel comfortable taking that?
Dr. Danso:
Yeah, I tend to be quite a little bit rigid about this. So if the tumor size is greater than T2, so greater than 2 cm, I will offer a more aggressive therapy with a TCHP-like regimen. So node positive or greater than T2, T2 or greater, I will offer TCHP chemotherapy. But I'm very comfortable with the tumor size less than 2 cm, node negative, to offer the paclitaxel/trastuzumab combination regardless of age.
Dr. Hamilton:
I feel exactly as you do on this. So Dr. Jhaveri, that brings up an important question. So if TCHP is really indicated 2 cm or larger or node positive and we feel pretty comfortable with paclitaxel/trastuzumab for less than 2 cm, does that mean that TCH is more a regimen of the past?
Dr. Jhaveri:
I would think so. I think here we are trying to make a determination about who gets neoadjuvant therapy and how should we optimally treat that, and we have data now that dual HER2-targeted therapy has been useful. The places where I've really now thought about TCH is one of those situations where you have two separate masses and perhaps two different clones of breast cancer, if you will. One's an ER-positive clone or if you have something which is HER2, which was not a 2+ and the FISH was just barely, the ratio was barely high and you're trying to figure out if this is truly an ER-positive tumor or a HER2-driven tumor, or if there are two clones, one is really being ER-positive tumor and the other one is barely making the HER2 criteria, but you want to just be sure that you're appropriately treating both clones. That's when I would think about even a docetaxel/cyclophosphamide/trastuzumab-based regimen. But short of that, if I am thinking about treating a HER2-positive tumor in the neoadjuvant setting, I'm going with dual HER2-targeted therapy.
Dr. Hamilton:
Thanks. So let's talk just briefly about APT. So this trial was really looking at deescalating, or as I like to call it, right-sizing adjuvant therapy for stage I HER2-positive breast cancer.
You'll see that paclitaxel was given at standard 80 mg/m2 dosing for 12 weeks with trastuzumab, and then it was followed essentially by 13 cycles of trastuzumab alone. So 12 weeks of the combination with chemotherapy and then patients were done with their chemotherapy and went on to antibodies alone.
When we look at the data, as Dr. Jhaveri really pointed out, excellent disease-free survival outcomes even at 7 or 10 years of follow-up, 93% vs 91% at the 10-year follow-up and really deescalating therapy in these patients that have very small node-negative, HER2-driven breast cancers doesn't compromise outcome. You'll note here that the 10-year breast cancer free survival is really approaching 99%.
So very hard to sell a patient on wanting to do more when outcomes are already so good. You can imagine the incremental benefits here to be exceedingly small.
I guess another question that comes up, Dr. Jhaveri, is who do you give neoadjuvant-directed therapy to? Is there a certain size you're thinking about or are you thinking about nobody tolerates chemotherapy better after surgery than before surgery? How do you make the decision about when you would give neoadjuvant therapy vs waiting in the adjuvant setting?
Dr. Jhaveri:
Yeah, I think I agree with what Dr. Danso said. Even though the APT trial did allow tumors up to 3 cm in size, I kind of follow the 2-cm rule in some ways when I'm thinking about neoadjuvant, when it's node-negative tumor size that I'm relying on.
So essentially given that we have the data for any tumor that is more than 2 cm or 2 cm and higher or node positive, I would be thinking about neoadjuvant therapy given the benefit that we've seen in those patients who, despite that neoadjuvant regimen might have residual disease for which we have options such as trastuzumab emtansine or T-DM1 to offer at the backend, right? The KATHERINE trial did offer us that benefit with a disease-free survival improvements of nearly 11%, the delta benefit. So given that data, I think if I'm thinking neoadjuvant, I'm thinking a 2 cm or a bigger tumor or a node-positive tumor.
Dr. Hamilton:
Yeah, absolutely. Dr. Danso, how does KATHERINE interplay in your decision about offering neoadjuvant therapy? Obviously if we're not offering neoadjuvant, we're not getting to see that biology, whether somebody's going to have a great outcome and have a pathologic complete response, does that influence you to give more patients neoadjuvant? So you kind of got that KATHERINE data in your back pocket and tell us how you really integrate KATHERINE into your clinical practice.
Dr. Danso:
Absolutely. So my preference is to give neoadjuvant chemotherapy if the patient clearly fits criteria for the neoadjuvant trial. So 2 cm of node positive and clearly the reason to do that is prognostication and knowing whether the patient will therefore, if they have less than the path CR benefit from adjuvant T-DM1 or a clinical trial.
So based on the results of the KATHERINE trial that showed a relative risk reduction of 50% of invasive disease recurrence for patients with residual disease after preoperative HER2 neu–directed therapy, I do routinely offer adjuvant T-DM1 in this setting. And subgroup analysis in the KATHERINE trial demonstrate benefit in all subgroups regardless of age, receptor status or stage. So that definitely influences my decision making in offering preoperative TCHP.
Now, occasionally a patient with T2 disease or node-positive disease comes to me already having had surgery, but this is quite a rare occurrence as most patients are presented at a prospective tumor conference. Also, patients who are clinically staged as node negative with less than a 2 cm, with less than 2 cm of disease occasionally found to have more extensive disease after surgery. And in those patients, I do offer adjuvant TCHP based on the results of the APHINITY trial. That demonstrated a real but modest benefit of TCHP over TCH.
Dr. Hamilton:
Yeah, that's a great point. I too was very struck by the KATHERINE data. Essentially it's our very highest risk population, our population that doesn't have a pathologic complete response and to really be approaching disease-free survival of 90% in this high-risk population. This is really what's influencing this shift of almost half of our patients with metastatic HER2-positive disease now present with de novo disease. If we can kind of give them neoadjuvant or adjuvant therapy, the majority of these patients have a good outcome. So I think that that's really important to keep in mind.
Dr. Jhaveri, if we talk about APT as deescalation, and if we talk about KATHERINE as kind of escalation, offering those patients that we're worried about more therapies, another form of escalation really is the adjuvant neratinib data. Tell me how you think about this and who, if any, you're thinking about neratinib for.
Dr. Jhaveri:
Yeah, I think the neratinib data are very appealing in some ways because when we saw the benefit, the benefit was largest seen in the ER-positive patient population that were node positive as well, or those that had neoadjuvant therapy and then still had residual disease and were ER positive, node positive. I think that was a subset that derived the most benefit.
The part that we struggle with that dataset is that those tumors did not have HER2 blockade with pertuzumab, which is what we use for our patients. So if we're giving neoadjuvant therapy, we are thinking about a pertuzumab-based regimen. We now have KATHERINE, which has also shifted our standard of care practice for those patients with neoadjuvant therapy who then also get a T-DM1 in the post residual disease setting. And those were not the dataset that the neratinib data that we got from the ExteNET study provided. Having said that, for the highest-risk patient population who despite getting the pertuzumab, who despite getting the T-DM1 nodal involvement with ER positive, I do think I might consider for that particular patient population. But again, that would be something that we're doing outside of the clinical trial, given what we've seen and the benefit we've seen. But for the majority of our patients and especially the ER-negative patients, I'm not necessarily offering neratinib.
Dr. Hamilton:
Yeah, absolutely. I think we are very lucky in the breast cancer space that we have so many new therapies, but it can be challenging when these clinical trials are really done in similar times, and so it makes it tough to integrate data with other changes that have already happened.
In terms of this case, our key clinical takeaways, the APT trial showed excellent outcomes with only weekly paclitaxel in conjunction with trastuzumab for patients with stage I HER2-positive breast cancer, a so-called deescalation of therapy. Lower-risk patients may be able to receive less chemotherapy in the setting of HER2-positive disease, but higher-risk patients with residual disease after neoadjuvant HER2-directed therapy are also eligible for adjuvant T-DM1 per KATHERINE, and we can also consider neratinib for those patients as well.
In conclusion for case two, this brings us to the end of the case. Please see the other segments for further discussion about the latest data in breast cancer or visit ASCOPost.com. Thank you.
