Navigating HER2+ Early Breast Cancer: Insights Into the Current Treatment Landscape

In this Precision Medicine Perspectives series Navigating HER2+ Early Breast Cancer: Insights, Innovations, and Future Horizons, Sandra M. Swain, MD, associate dean for research development and professor of medicine at the Georgetown University Medical Cancer, outlines the treatment landscape of early-stage HER2-positive (HER2+) breast cancer and discusses how recent data will impact treatment paradigms.

Targeted Oncology™: Please briefly provide an overview of the treatment landscape and the factors you consider for treatment selection.

Dr Swain: For the treatment of HER2+ early-stage breast cancer, the landscape has changed so dramatically in the last 20 years with the use of HER2-targeted therapies like trastuzumab, pertuzumab, T-DM1 [trastuzumab emtansine], and tyrosine kinase inhibitors (TKIs).

First, when we look at the patient, we decide what the size of the tumor is. That’s the most important initial thing that we look at to decide whether the patient should have neoadjuvant treatment [along with whether they have] tumors [measuring] greater than 2 cm or clinically node-positive [disease]. For patients in that setting, we would recommend treating with neoadjuvant chemotherapies such as [the] TCHP [regimen] (docetaxel, carboplatin, trastuzumab, and pertuzumab). Now, there have been studies looking at the comparison of an anthracycline [regimen] with [one that does not contain an anthracycline]—for example, the TRAIN-2 study (NCT01996267). The results of this study did not show any difference in the pathologic CR [complete response] (pCR) rate. Currently, most patients are transitioned to a [regimen that does not contain an anthracycline] in that setting. Once treatment is given, the patient proceeds to surgery. If they present with a pCR in their tumor, we recommend that they continue HER2-targeted therapy with trastuzumab and pertuzumab, even if they have clinically node-negative [disease]. For patients with residual invasive disease, we recommend T-DM1 followed by neratinib if they express high-risk hormone-receptor positivity.

[For patients who] present with tumors less than 2 cm [in size], we usually will take those patients to surgery first and try to determine whether they have positive or negative nodes. If the nodes are negative, then we would treat them with an optimized HER2-targeted regimen with just trastuzumab and paclitaxel. If they end up having positive nodes, we would treat with chemotherapy and pertuzumab in the neoadjuvant setting. That’s basically a general outline of how we approach these patients. And it really doesn’t matter, for the most part, whether the tumors are ER [estrogen-receptor]–positive or ER-negative, except in the situation of potentially considering neratinib [therapy].

The other point to remember is [that] recently approved were subcutaneous injections for trastuzumab and pertuzumab, and those are also treatments that can be incorporated into the regimen. And patients, in many studies that have been done, [have preferred] the subcutaneous regimen.

Targeted Oncology: Please review the study design and rationale of the APHINITY study (NCT01358877). What were the key data and how do they translate to clinical practice?

Dr Swain: The APHINITY trial was a large study. This trial consisted of almost 5000 patients,…[and] patients had surgery first. Keep in mind that this trial was started many years ago, before we transitioned to treating most patients with neoadjuvant therapy. Patients were [randomly assigned] to chemotherapy [and] trastuzumab [plus either] pertuzumab or placebo. The interesting part about the APHINITY trial is that about 40% of the patients who were enrolled had no negative nodes. Specifically, patients had to have tumors greater than 1 cm if the nodes were negative. If they weren’t greater than 1 cm, they had to have several high-risk factors. Almost half of the patients had negative nodes, and they would do very well with trastuzumab alone, which is what showed in the data.

Looking at the recent 8-year data, for invasive disease-free survival (IDFS), [results] showed that the study was positive. For IDFS, [results] showed a 2.6% absolute benefit overall for patients who got the addition of pertuzumab. And [for] those patients who had positive nodes, it was almost a 5% improvement. However, in those patients who had negative nodes, there was no improvement at all. It didn't matter if the receptors were positive or negative; the benefit was shown for both groups, especially, as I said, if the nodes were positive. When you look at the overall survival analysis, which is the third interim analysis presented last year, there was no significant overall survival benefit. Overall, there was a difference of 0.7%. But when you looked at those patients who had positive nodes, those patients had the IDFS benefit with a 1.9% improvement. For [overall] survival, though, it wasn't significant. There will be another definitive survival analysis conducted in the future.

Targeted Oncology: Regarding dual anti-HER2 blockade, how do you monitor potential adverse events (AEs) from baseline and throughout therapy?

Dr Swain: With the use of pertuzumab, [results of] the APHINITY trial demonstrated an increase in toxicities. For example, diarrhea was increased. If you look at all-grade, it was about 71% [for] patients who got the pertuzumab and 45% for those patients who got placebo. And if you look at specifically grade 3, I think it was about a 9% increase, which can be a significant problem. Some people have to stop pertuzumab while on HER2-targeted therapy, especially in the maintenance setting, if they do have significant diarrhea. There’s also a slight increase in rash and mucosal inflammation, but the other [toxicities] are pretty much the same. If you look at the cardiac toxicity, there really wasn't an increase…with pertuzumab when added to trastuzumab. Enrolled patients were allowed to either have an anthracycline-containing regimen, of which 77 [patients] did, or a regimen with [that does not contain an anthracycline]. It was in [the] anthracycline [arm] that the cardiac toxicity mostly occurred, which we know from previous experience also. Most of the cardiac events…were reversible.

In practice, patients usually get a baseline echocardiogram before starting any treatment, and then every 3 months [they] receive a repeat echocardiogram. If the patient does well after completing a year with HER2-targeted therapy, I would decrease that to probably once a year and then maybe stop. At that point, very few patients will have a problem with cardiac toxicity. When you look at the data from APHINITY, it seems that the patients who are [older] than 65 [years] had a high body mass index or had a baseline low ejection fraction between 55[%] and 60[%] are the ones who more commonly would have a decrease in their ejection fraction and [would] not usually [be] symptomatic. This was also shown, as I mentioned, in those who had the anthracycline-containing regimen.