Improved Patient Selection Needed to Advance HER2+ Breast Cancer Care

Lisa Carey, MD

Immunotherapy and chemotherapy are options physicians should not dismiss for patients with HER2-positive breast cancer, according to Lisa Carey, MD, even with the available targeted agents trastuzumab (Herceptin), pertuzumab (Perjeta), lapatinib (Tykerb), and ado-trastuzumab emtansine (T-DM1; Kadcyla).

Recent evidence has shown that signs of promise for immunotherapy in triple-negative breast cancer (TNBC). Therefore, altering the tumor microenvironment in HER2-positive disease could also be a logical option, says Carey.

Moreover, chemotherapy—and its suggested synergy when partnered with HER2-targeted treatment—will likely continue to have a role, though a cytotoxic one for patients.

But the main goal, Carey explains, is to pinpoint the patients who may be best suited for immunotherapy, chemotherapy, HER2-targeted agents—or all 3.

OncLive: Is it worth exploring immunotherapy in HER2-positive breast cancer?

With agents such as ONT-380 and neratinib coming down the pipeline, how do you think they might change the treatment paradigm?

In an interview with OncLive, Carey, associate director, Clinical Research at UNC Lineberger Comprehensive Cancer Center, and Richardson and Marilyn Jacobs Preyer Distinguished Professorship for Breast Cancer Research at UNC-Chapel Hill, discussed the potential for immunotherapy in HER2-positive patients, improving identification of patients likely to benefit from dual-targeted treatment, and the future role of chemotherapy in HER2-positive disease.Carey: Immunotherapy is likely to be studied in all of the subtypes. We don’t really know how to select for immunotherapy. What I can say is the same studies that are showing restriction in the B-cell receptor—suggestive of clonal expansion in an actual antigenic response—are highest in TNBC and HER2-enriched breast cancers. If that is an argument, then that is an argument for HER2-enriched breast cancer—which does make up about half of hormone receptor (HR)¬—negative, HER2-positive breast cancer, and about 20% of triple-positive breast cancer. There absolutely is a rationale for looking at immunotherapy. To be honest, manipulating the microenvironment of the tumor may matter across all types of tumors.The paradigm for HER2-positive breast cancer has been such an incredible trajectory over the last few years if you think about it. I remember [the approval of] trastuzumab; I was just coming out of my fellowship. If you move through most of the realm of HER2 targeting, the things that are coming and, are particularly exciting, include better small molecule inhibitors—neratinib being one of them.

Some of these drugs may be easier to combine with monoclonal-based therapy or may be better than them. However, I suspect that combinations may be the way to go. Part of what we are going to learn in the future is also how to be more strategic about who needs all of these drugs.

One of the problems with HER2-directed therapies, while it has been such a success story, is that all of the drugs are very expensive. We have essentially priced it out of reach for low-income countries. Therefore, as we want to get smarter about this, it is true that some patients may do exceptionally well with just a biologically equivalent trastuzumab. On the other hand, there are others who need dual therapy with multiple HER2-targeted drugs.

I do think that the landscape for understanding that, from a standpoint of both DNA and RNA analyses and figuring out who benefits from multiple targeted therapies, is likely to hit in HER2-positive breast cancer, if anything, earlier than some of the other kinds. This is because it is so heterogeneous and there is already evidence of ways in which we can do better, by looking more carefully at the biology of using all of these drugs.

If you think about it, the landscape is so broad right now. It is an area I would have thought that pharmaceutical companies and drug developers would move away from, but HER2 is such an attractable target. The oncogene addiction theory seems to hold true, in that you keep targeting and it keeps working. That has been a great success story.

Are there still questions left unanswered with approved agents such as pertuzumab, lapatinib, or T-DM1?

Also, the biomarkers will improve past HER2 and incorporate a lot of these other markers.Who needs dual therapy? Who can get by with 1 agent? Who needs chemotherapy? In truth, chemotherapy is added to HER2 targeting because there is evidence, in the early and late stage, that patients do better with chemotherapy onboard; there is clearly some synergy there.

You mentioned these targeted agents have synergy with chemotherapy for a lot of patients. Will chemotherapy always have a role in this subset?

However, some patients do really well with just HER2-targeted therapy and then you can avoid the cytoxic therapy. Who are they? Those are some of the fundamental questions in HER2-positive breast cancer.I would never bet against chemotherapy. In truth, we always talk about chemotherapy as if it is something to be eliminated. However, one of the truisms is that HER2 targeting without chemotherapy is generally inferior to HER2 targeting with chemotherapy. We have a lot of drugs that are effective in TNBC; most patients with HR-positive metastatic breast cancer receive chemotherapy before they stop being treated. It is a real, important component of care for every subtype of breast cancer that we have.

One of our challenges, and an important goal, is to do it better. Sure, [it would be great] if we could eliminate chemotherapy; it is the most toxic thing that we give. Although, there was a reasonably large study done that compared molecularly targeted therapy against chemotherapy. The precision medicine arm, admittedly, is in its infancy, but with the drugs available at the time, the precision medicine-directed approach was no more effective than chemotherapy. The likelihood of toxicity was higher, but we can manage chemotherapy.

As an expert in the field, what have you seen in practice, anecdotally, with regard to this disease?

We can give chemotherapy safely with minimal side effects—not always, but there are strategies. Chemotherapy is important. I would always like to get rid of it, but I don’t think we will anytime soon. We can manage it well, and it is an important part of the armamentarium.I had a patient with HER2-positive breast cancer. She had easy-to-follow disease because she had hepatic metastases; every time she progressed, she had a visible hepatic metastasis that hurt. I could always tell that she was going to progress.

She was initially coming in for treatment as we were starting to realize that ongoing HER2 targeting after progression was a good idea. She received a trastuzumab-based regimen, then she progressed and I gave her lapatinib plus capecitabine. Everything bought her about 9 months to 1 year. Then, she progressed and I would have to change her regimen. Her timing was impeccable, because every time she progressed was right around when something new was approved. I managed to get her pertuzumab, right after added to trastuzumab and a taxane, and then T-DM1.

She was the history of improvements in advances in HER2-targeted breast cancer. She lived with visceral, progressive, HER2-metastatic disease for about 5 years or so. She really was quite an exceptional woman.