Gradishar Sheds Light on Treatment Trends in Breast Cancer

William J. Gradishar MD

The field of breast cancer has seen momentous progress over the last decade, particularly with novel agents for patients with HER2-positive disease.

OncLive: With the novel agents that have emerged in the HER2-positive setting, has an optimal sequence been determined?

In an interview with OncLive, William J. Gradishar, MD, interim chief of hematology and oncology at Northwestern University’s Feinberg School of Medicine, discussed the latest developments in the HER2-positive setting, as well as biomarker development and the potential for immunotherapy in breast cancer.Gradishar: HER2-positive cancer has been an area that has evolved over the last decade with the introduction of several new agents. They apply to patients both in early-stage and late-stage settings, as well as preoperatively. One of the challenges we have, particularly in patients with metastatic disease is how to optimally use these drugs, extend the time that patients have, and to really convey benefit to them.

So, one of the things that we base our decision-making on, certainly in metastatic disease, is the results of clinical trials. And what the clinical trials have demonstrated is that we should be using pertuzumab (Perjeta) and trastuzumab (Herceptin) followed by T-DM1 for most patients. And once we get past that point, there are a variety of options, including drugs that are a little bit dated at this point, like lapatinib (Tykerb), as well as combinations of trastuzumab and other chemotherapy agents. There are other, [newer] drugs…including neratinib (Nerlynx) [that have emerged].

Where are we at with the use of trastuzumab across the various treatment lines?

Have we seen any progress with immune checkpoint inhibitors in breast cancer?

With respect to early-stage disease, one of the things that we now confront is how to integrate both pertuzumab and neratinib into the adjuvant setting. Data from the APHINITY trial showed that there was a very modest incremental improvement when you combine pertuzumab with trastuzumab [in the adjuvant setting]—[it] probably will not be for every single patient, but for those with high risk. For those who have a very high risk—positive nodes—then we may consider neratinib afterwards. But, we have to take into account the side-effect profile of these drugs. We are really talking about duration of therapy that goes into years now. Certainly, in the preoperative setting we use chemotherapy with trastuzumab, now often with pertuzumab—so a combination that has dual anti-HER2 targeting along with standard chemotherapy. In the adjuvant setting, we again use trastuzumab with pertuzumab, often with chemotherapy. And in the metastatic disease setting, it’s any of a variety of agents, but the theme here is that we are starting to use dual HER2-targeting as a first step in many of these settings—preoperatively, postoperatively, as well as early in the sequence for patients with metastatic disease. Immune checkpoint inhibitors are very exciting. They have been around now for a few years, and where they have gained the most traction has been in settings other than breast cancer—lung cancer, melanoma.

We are now starting to see that there are signals in smaller trials in breast cancer. We have heard data now with monotherapy as well as combinations with chemotherapy where checkpoint inhibitors are used. And we see activity, and in some cases, in select patients you can have prolonged benefit from a checkpoint inhibitor.

Where are we with biomarker development in breast cancer?

We are also starting to see the introduction of these drugs into both the preoperative setting, as well as the adjuvant setting. But, as a bottom line, if you were to ask me today what checkpoint inhibitor we use in breast cancer, there isn’t one. Biomarkers are something that we always try to utilize, if possible, for selecting treatments for a given patient. So, if you think about the biomarkers that we've traditional had available, we have had the hormone receptors and HER2, and that allows us to determine whether or not a patient is a candidate for endocrine therapy or HER2-based therapy.

What is the most pressing unmet need in the treatment of breast cancer?

Once we get beyond that, we start getting into more research-type questions. There is a lot of work being done with molecular profiling of tumors, the hope being that we’ll be able to select patients for specific therapies based not the presence of a mutation. As an example, estrogen receptor (ER) mutations, perhaps they would be better served by getting a specific kind of antihormonal therapy. If someone has a PI3-kinase mutation, might they benefit from certain drugs that effect those pathways? At the present time, we refer to these things as “potentially actionable,” but to date, we are still lacking…prospective data that allows us to utilize these kinds of markers as standard of care in the treatment of patients every day.There are a lot of unmet needs in the treatment of breast cancer, but certainly, in metastatic disease we do not have a cure for any subset of breast cancer. Although we have a lot of options for HER2-positive disease and ER-positive disease, we still have patients who die of the disease. Similarly, in TNBC, despite all of the trials that are ongoing, the standard of care is chemotherapy. I think what we hope for and really the subject of a lot of ongoing clinical research is to try and define, based on molecular fingerprints—either by obtaining tissue or circulating tumor DNA—characteristics of the tumor that will allow us to tailor our therapies in all of our settings so we have better outcomes.