Expert Highlights Expanding Options for HER2+ Breast Cancer

Lajos Pusztai, MD

Additional treatment options are emerging for patients with HER2-positive breast cancer, according to Lajos Pusztai, MD.

For example, the ongoing phase III KATHERINE study is investigating the efficacy and safety of trastuzumab emtansine (T-DM1) versus trastuzumab (Herceptin) as an adjuvant therapy in patients with HER2-positive breast cancer who have a residual tumor present in the breast or axillary lymph nodes following neoadjuvant treatment (NCT01772472). Patients were randomized to receive T-DM1 at 3.6 mg/kg or trastuzumab at 6 mg/kg intravenously every 3 weeks for 14 cycles.

The primary objective of this trial is to determine the invasive disease-free survival, with secondary outcomes including disease-free survival, overall survival (OS), and incidence of adverse events. The data collected from this study is estimated to be completed by 2023.

OncLive: What data do we have supporting neoadjuvant therapy for patients with HER2-positive breast cancer?

In an interview with OncLive, Pusztai, a professor of medicine, chief of Breast Medical Oncology, Yale Cancer Center and Yale School of Medicine, discussed neoadjuvant and adjuvant treatment decisions for patients with HER2-positive breast cancer, as well as the potential of immunotherapy in the metastatic setting.Pusztai: HER2-positive disease has become rich in treatment options, which sometimes creates confusion with how to best select treatments for patients. In the neoadjuvant setting, combining trastuzumab, pertuzumab (Perjeta), and a third-generation chemotherapy of paclitaxel followed by doxorubicin hydrochloride (Adriamycin) and cyclophosphamide (AC) or AC followed by paclitaxel and either of the targeted therapies, produces pathologic complete response (pCR) rates of 75% to 80% in the estrogen receptor (ER)-negative subset and 50% to 60% in the ER-positive subset. Current therapies can accomplish high pCR rates.

It is also provides an important reason to scale back treatments for some patients because less complex combinations can still produce pCR rates that are quite high—30% to 50% response rates. In fact, pertuzumab and trastuzumab alone can produce pCR rates around 25% to 30%.

We also learn that including 1 year of pertuzumab in the adjuvant setting with trastuzumab improves disease-free survival. Neratinib (Nerlynx) added on after 1 year of trastuzumab can also improve invasive recurrence-free survival. This creates many choices.

There is one large study whose results have not been announced yet. The KATHERINE study followed a similar design as the post-neoadjuvant capecitabine study for triple-negative breast cancer (TNBC). This study randomized patients with HER2-positive disease who had residual cancer after the neoadjuvant chemotherapy. That included HER2-targeted therapy with either 1 year of T-DM1 or the standard of care of 1-year of trastuzumab. If that study is positive, it establishes that additional therapy can improve survival if a patient has HER2-positive breast cancer and has residual disease.

Until this study’s results are announced, one speculative but reasonable approach is to give neoadjuvant chemotherapy and, if patients have extensive residual disease, then choose one of the more aggressive adjuvant options. For a patient with ER-positive disease, that would be trastuzumab and pertuzumab, followed by neratinib. In patients with ER-negative disease, it could be trastuzumab and pertuzumab.

We are seeing early signals of PD-1 in TNBC. Do you think there is potential for immunotherapy for patients with HER2-positive breast cancer?

This is based on the idea that those with residual disease have a higher risk, and these regimens are better than the simpler and much less expensive single-agent trastuzumab approach. The high-risk patients might benefit from costly and more toxic regimens than standard adjuvant therapy with trastuzumab.In the early-stage disease setting, I-SPY randomized patients with ER-positive breast cancer to receive standard-of-care chemotherapy or chemotherapy combined with pembrolizumab. This also showed an improvement in pCR rates. In the I-SPY study, this combination graduated for most of these subsets. I am not aware of any major studies currently ongoing in the neoadjuvant space for ER-positive disease.

What are the biggest challenges in neoadjuvant therapy for patients with HER2-positive disease?

Is there anything else you would like to add?

The metastatic setting is where most of the immuno-oncology drugs are being studied in breast cancer. Patients with TNBC appear to have higher objective response rates than the patients with ER-positive disease, at least with single-agent therapy and with a combination of endocrine therapy. One of the biggest challenges is understanding who needs which treatment with pertuzumab, trastuzumab, and chemotherapy. There are other patients who could achieve a good response with fewer treatments. We need to determine whether to start with fewer treatments. Additionally, those who do not accomplish a pCR could be salvaged with additional treatment after surgery. The KATHERINE study addresses this, but we will have to wait for the results.I would like to convey that it is a smarter option to start with chemotherapy for TNBC and HER2-positive breast cancer. If a patient has residual disease, this provides them with a backup option to receive additional treatment after surgery. That additional treatment is usually capecitabine for TNBC, since it is shown by a randomized trial to improve OS by 70% to 79% at 3 years. For the patients with HER2-positive disease, this provides the option to receive one of the more aggressive treatments, including pertuzumab or neratinib.