Case 1

Dr. Chau Dang:

Welcome to a new installment in the JNCCN Video Roundtable series. I’m Dr. Chau Dang from Memorial Sloan Kettering Cancer Center. Joining me today are two of my colleagues, Dr. Shanu Modi and Dr. Anthony Elias. Dr. Modi?

Dr. Shanu Modi:

Hi, so great to be with all of you today. My name is Shanu Modi, and I’m a breast medical oncologist from Memorial Sloan Kettering Cancer Center.

Dr. Chau Dang:

Dr. Elias?

Dr. Anthony Elias:

I’m Anthony Elias from the University of Colorado, also a breast medical oncologist.

Dr. Chau Dang:

Great, thank you. Today we will be discussing the management of patients with HER2-positive breast cancer, focusing on the use of monoclonal antibodies, antibody-drug conjugates, and tyrosine kinase inhibitors in combination regimens in three case studies across different clinical settings.

Let’s start with case 1. This is a 52-year-old postmenopausal woman with a clinical T2 N1, ER/PR-positive, HER2-positive right-sided breast cancer. She presented after experiencing right breast pain for 2 months. Otherwise, she’s healthy and fit. She has no preexisting medical conditions. On exam, she has a large 4- cm right-sided breast mass and a movable right axillary nodal mass.

Breast imaging with mammography, ultrasound, and MRI showed a 4-cm right upper outer quadrant mass and a right axillary nodal mass. Biopsy of the breast mass showed it was an invasive ductal carcinoma, ER 90%, PR 50%, HER2/neu IHC 3+, and Ki67 90%. The FNA of the right axillary mass showed cancer cells with the same immunostains as the breast biopsy.

What would you recommend for this patient, Dr. Modi? Upfront surgery, neoadjuvant therapy with paclitaxel plus trastuzumab, known as TH, or neoadjuvant therapy with dose-dense AC followed by THP or docetaxel plus carboplatin and HP, known as TCHP. Dr. Modi, what is your recommendation?

Dr. Shanu Modi:

Thanks, Chau. This is a case we commonly see in the clinic. It’s a patient with a larger-sized breast mass and positive lymph nodes. In this setting, my preference would be to use neoadjuvant therapy with polychemotherapy and dual HER2 blockade, so choice C here. Really this is based on a couple of key clinical neoadjuvant studies for the HER2-positive early breast cancer field. It’s already been well established that adding HER2 blockade to chemotherapy improves outcomes for patients with early-stage breast cancer, and using the neoadjuvant approach in particular has some advantages. It allows us to give patients a more accurate prognosis, and it also allows us to escalate therapy in the adjuvant setting for those patients who are at higher risk. We’ve seen now from two meta-analyses that for patients who are at an individual level, patients who achieve a pathologic CR, a complete remission or regression of all their cancer in the breast and lymph nodes, those patients tend to have better long-term survival outcomes.

The first trial in the HER2-positive breast cancer arena was the NeoSphere study, which showed that by adding a second HER2-targeted agent, so pertuzumab to trastuzumab, and this was in conjunction with taxane therapy, we could double the pathologic CR rate, which is really meaningful for these patients. The follow-up study in some ways was TRYPHAENA. TRYPHAENA, another neoadjuvant study for patients with early-stage HER2-positive breast cancer, used a more traditional polychemotherapy backbone. [In] two of the arms, patients got anthracyclines and taxanes, plus dual blockade. In the third arm, they got a nonanthracycline regimen that was carboplatin, docetaxel, and dual blockade. We saw consistently in all three arms, pathologic CRs of around 60%. This has really set the bar today for neoadjuvant therapy in HER2-positive breast cancer. We saw, again, more confirmation in the BERENICE trial.

Then finally, the most recent study, TRAIN-2, a European trial, once again neoadjuvant dual HER2 blockade plus polychemotherapy looking at anthracycline and nonanthracycline regimens. And, again, really consistent pathologic CR rates. That was the first trial to also show us that in both arms, we saw similar event-free and overall survival. I think today we have options, as oncologists, to use dual blockade with an anthracycline-based backbone chemo regimen or a nonanthracycline carboplatin-based backbone regimen. The key thing in all of these studies is they included patients who had stage II and III HER2-positive breast cancer, so tumors at least 2 cm or positive lymph nodes. I think that’s exactly the case we’re looking at today. All these data suggest we can give these patients the best chance at a long-term outcome with neoadjuvant HER2 blockade and polychemotherapy. I would certainly pursue that option for this patient.

Dr. Chau Dang

That’s great, Shanu. You discussed the key trials with anthracycline-based treatment followed by taxane HP. What would compel you to choose one or the other? Would it be patient factors like age and comorbid conditions or treatment toxicity factors like neuropathy that are inherent in taxanes and heart failure? Can you comment on that?

Dr. Shanu Modi:

I think the whole motivation for testing a nonanthracycline-based regimen in this field was the fact that some of the more long-term toxicities we see in survivors of our treatments are related to the anthracycline backbone. Particularly now that we are adding in HER2-targeted therapies that also have potential for cardiac toxicity. There’s been a real drive to try to minimize the side effects of these regimens. The carboplatin and taxane regimen was borne out of this desire. I think particularly from the TRAIN-2 trial, we’ve seen there is less febrile neutropenia. There are fewer cardiac events and fewer long-term secondary cancers when we use the nonanthracycline regimen. It has become a more widely adopted backbone for neoadjuvant therapy in HER2-positive breast cancer. It tends to be the one I use as well.

I think there are always exceptions, particularly patients who have heterogeneous cancers, where the backbone is chemotherapy. You may want to cover other subtypes of breast cancer, or patients who have really challenging GI baseline comorbidities, who really struggle with the diarrhea side effects of taxanes. That’s how I tend to choose between the two. In general, I tend to use the nonanthracycline approach for most of my patients.

Dr. Chau Dang:

Thanks. Dr. Elias, would you agree?

Dr. Anthony Elias:

Yes, I completely agree with Dr. Modi. I just want to point out that in general, I do not favor upfront surgery in these situations and treat almost exclusively with preoperative treatment for T2 and greater or node-positive. Part of the reason is you want to try to clear the axilla of the positive nodes because that can simplify the surgical management of the axilla and free the patient from a full axillary node dissection and instead utilize something called the targeted axillary dissection, which is basically a sentinel node biopsy plus the clipped axillary node that was positive.

The second, of course, is in this patient, the size of the mass is pretty large, and therefore breast-conserving surgery might be challenging. And given the extensive response we expect with preoperative therapy, most of these patients probably, if they wanted, could get breast-conserving surgery. The evidence for the use of TH or option B is essentially nonexistent in node-positive disease. It is certainly a fairly common regimen for node-negative tumors. Of course, we would administer antiestrogen therapy postoperatively for this patient. I typically give TCHP as well instead of the THP-AC regimen, largely to avoid secondary leukemias and heart failure risks. Although admittedly, TCHP is not an easy regimen. Occasionally, one has to adapt depending on what the toxicities are that are then encountered.

Dr. Chau Dang:

Right. Thank you so much. I want to comment on the risks with the anthracyclines. I know the world is concerned about cardiac toxicity, but thank goodness, based on trial evidence, at least from what we’ve seen from the BERENICE study, the neoadjuvant study with anthracyclines, HP was really only 1% to 1.5%. Even the APHINITY study, that large adjuvant study was about the same 1%. It is really lower than what we had seen historically with trastuzumab back 20 years ago. Acknowledging that it is less with the taxane-based treatment. It’s [about] 0.4% or 0.5%.

Dr. Anthony Elias:

Actually lower, of course, if you then look into whether the patient has hypertension, cardiac risk factors, and so forth, because they all confounded or increase the toxicity risk.

Dr. Chau Dang:

Right, and one more comment about the anthracyclines. As we all know, across the different trials, they were not powered to compare the taxane-based treatment against an anthracycline-based treatment for disease-free and overall survival outcomes. However, the signals look very similar. We can exclude the benefit of anthracyclines in certain subsets of patients, especially if we’re going to be considering a dose-dense fashion. It’s just a comment there.

Dr. Anthony Elias:

There are subtypes of HER2-positive breast cancer that we still are not sure about. For example, there are, of course, heterogeneous clones. And the second is the HER2 basal type, where the HER2 expression is not clearly driving the gene-expression profile. It’s not yet in clinical use, but it’s certainly a question that remains to be investigated.

Dr. Chau Dang:

Absolutely. Let’s move on to the case. She did receive polychemotherapy plus HP followed by breast conservation. She had a terrific response, but there was residual disease with a 0.2-cm invasive ductal carcinoma, and there were zero out of five nodes identified, and two of them had a treatment effect. She did have a great response.

In this case, now we move on to adjuvant therapy, as we all know that our patients need to complete 1 year of any HER2 regimen. For her in the adjuvant setting, would it be continuation of the HP plus endocrine therapy because she’s ER/PR-positive? Or is it HP plus endocrine therapy followed by neratinib from the ExteNET trial? Or is it T-DM1 plus endocrine therapy? Or is it T-DM1 plus endocrine therapy followed by neratinib? Dr. Elias, I’d love to hear your thoughts on this. What would you recommend for your patient?

Dr. Anthony Elias:

Yes, I would typically choose the T-DM1 plus endocrine therapy option, so option C. This patient had a really good response, but it wasn’t complete in the residual cancer burden scale. It would be a class I response, which typically does carry a good prognosis. The KATHERINE trial looked at patients with residual disease after standard neoadjuvant treatment, and essentially it was T-DM1 to complete the year of anti-HER2 therapy vs the standard HP. There is an overall survival advantage that was updated by Dr. Loibl at San Antonio in 2023 that demonstrated a 7-year overall survival of 89.1% with T-DM1 vs 84.4%, which is a substantial benefit. There’s also a sustained disease-free survival benefit that corresponds to that overall survival. Given that overall survival, I have a difficult time not choosing T-DM1.

Dr. Chau Dang:

Sure.

Dr. Anthony Elias:

Some patients don’t tolerate T-DM1 particularly well. In those patients, I might give them T-DM1 and then go back to HP for the last couple of cycles if they’re really having a tough time.

Dr. Chau Dang:

Sure, yes. In the KATHERINE study, about a third of patients could not complete T-DM1 because of toxicities, and they transitioned to trastuzumab alone. I think in the modern era, we would all just transition back to HP. That would make sense. Shanu, what would you recommend? I specifically would love your thoughts on neratinib. Is there a role here?

Dr. Shanu Modi:

This is a great case and like Anthony said, I would favor the adjuvant T-DM1 approach. We’re now seeing a survival advantage, and that’s really great to see. Although I would add, it’s still sobering that 20% of these patients will have a recurrence after 7 years in spite of our best HER2-targeted therapies today. There’s still room for improvement, and there are ongoing studies looking to do just that. I think we’re going to talk about them later. To come to one of the options, which was to look at adding neratinib in this setting. This brings up the ExteNET study from a few years ago. This was almost a 3,000-person study. It was done for patients with stage I to III, early-stage, HER2-positive breast cancer who all got standard-of-care chemotherapy and 1 year of trastuzumab.

That was the standard in this trial back then. Then they were randomized to either a year of the neratinib TKI or placebo. The primary endpoint of that trial was invasive disease–free survival at 2 years. And it was positive. The hazard ratio was 0.67, but the absolute benefit was just over 2 years. It was a little clinically questionable at the time. Longer follow-up continued to show that same benefit, which was really reassuring. That was worth 5 years of follow-up. More recently, we’ve seen even 8-year follow up from this trial. One of the clear messages we’re getting from the ExteNET trial when we looked at subgroups was the patients who really benefited from adding neratinib were the hormone receptor–positive subpopulation and those with positive lymph nodes. We’ve since then seen even more interesting descriptive subgroup studies, where they’ve looked at using neratinib soon after completing the trastuzumab within a year. We’ve seen certainly that patients also seem to have fewer CNS events with the adjuvant neratinib. There was, I should mention, a small group of patients in this trial who were treated with the neoadjuvant approach. They got chemo and trastuzumab and then finished trastuzumab for a year after treatment. Those patients could also enroll. We saw even for the patients without a pathologic CR in ExteNET, a nice advantage from the adjuvant therapy.

The one thing that throws a wrench into all these great positive results is the fact that this trial was done in an era where we were using single-agent trastuzumab. Now today, in a more modern era, we are using at least triple HER2-targeted therapy in this population. They’re getting dual blockade upfront and then T-DM1 on the back end. It’s hard to be confident or hard to know whether neratinib would truly add an advantage in that pretreated setting or pretreated population. The other downside [is that] this is a drug that causes a lot of diarrhea. It was almost 40% grade 3 diarrhea in the ExteNET trial. Although, we have learned how to deliver neratinib a little more safely using a more gradual dose-escalation approach.

And finally, they didn’t see an overall survival advantage in the ExteNET trial. I think there are limited data to suggest that we would have the same benefits we’ve seen with ExteNET using a year of adjuvant neratinib in patients treated today. Having said that though, there are those really high-risk patients. In very selected patients, those with a very high burden of disease upfront, those with a lot of residual disease after neoadjuvant therapy who are hormone receptor–positive, who you feel have probably still a high risk of recurrence as we saw in KATHERINE; there is that population out there. I think on a select basis with open discussion, I would be willing to consider adding neratinib in that setting, but certainly I would not call that a standard-of-care option.

Dr. Chau Dang:

Thanks so much. And before we wrap up, Dr. Elias, what’s on the horizon for neoadjuvant trials in terms of escalation or de-escalation? Can you comment on a few trials?

Dr. Anthony Elias:

We’ve established that pCR is associated with excellent outcomes, long-term, with following standard neoadjuvant approaches. The question then becomes if you achieve pCR with something less aggressive and less toxic, will pCR still have an excellent outcome? The answer is probably yes.

The COMPASS-HER2 trial, for example, treated patients with just 12 weeks of THP without the carboplatin, went to surgery, and then if you had a pathologic CR, you got HP plus endocrine therapy because these were ER-positive as well. The 3-year relapse-free survival is well in excess of 92%. This was a phase II single-arm study. The answer at least not at 10 years, but at 3 years. Other studies have 5-year relapse-free or disease-free survival. It looks very good.

Other trials are intensifying treatment for patients with residual disease. For example, [COMPASS HER2 RD] is taking women who had a residual disease after preoperative therapy and randomizing to T-DM1, which would be the standard of care according to KATHERINE with or without tucatinib as a placebo-controlled trial.

Other trials such as DESTINY-Breast11 are comparing [T-DXd] alone as preoperative therapy vs T-DXd followed by THP vs dose-dense AC-THP in high-risk patients, so T3 or 4 or node extensively positive. Then finally, DESTINY-Breast05 is looking at the nonpathologic CRs and looking at T-DXd vs T-DM1 with the hypothesis that T-DXd is in fact much more potent than T-DM1 and may provide an advance over the KATHERINE trial.

Finally, I-SPY 2 is an innovative trial of preoperative therapy. Their concept is patients are assigned to experimental arms and if they actually have a pathologic complete response or are suspected to have pathologic complete response to just that experimental therapy, they go to surgery early and bypass all the rest of the toxicity. Many of the patients have either a pathologic complete response or near-complete response with that type of approach. I think there’s a major emphasis on decreasing toxicity both in the short term and the long term and molding the treatment based on response.

Dr. Chau Dang:

Great. Thank you so much for that wonderful response. I think with all these available drugs, we’ve moved them from the metastatic setting into the early setting and hopefully curing more patients with HER2-positive early breast cancer and preventing metastasis.