HER2+ Breast Cancer Outlook Improved, But More Work Remains

Kelly McCann, MD, PhD

The outlook of HER2-positive breast cancer has vastly improved in recent years, in large part due to the emergence of targeted therapies that have had a significant impact on patient outcomes, says Kelly McCann, MD, PhD.

The combination of pertuzumab (Perjeta) and trastuzumab (Herceptin) has been a staple in HER2-positive breast cancer treatment since June 2012. The regimen was initially approved by the FDA in combination with docetaxel for the treatment of patients who had not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

In September 2013, the FDA approved pertuzumab for neoadjuvant use in combination with trastuzumab and docetaxel for patients with HER2-positive, locally advanced, inflammatory, or early breast cancer. The agency next approved pertuzumab/trastuzumab plus chemotherapy in December 2017 as an adjuvant treatment for patients with HER2-positive early breast cancer at high risk for recurrence.

Meanwhile, small molecule inhibitors, such as neratinib (Nerlynx) and lapatinib (Tykerb), have been therapeutic additions to the landscape for select patients. Ado-trastuzumab emtansine (T-DM1; Kadcyla), an antibody-drug conjugate, is FDA approved for patients with metastatic HER2-positive disease.

“HER2-positive breast cancer used to have the worst prognosis—now it has one of the best prognoses in terms of breast cancer,” said McCann, a medical oncologist in the Breast Cancer Research Group at the University of California, Los Angeles.

Even with these available regimens, McCann says more work is in progress, specifically with de-escalation trials for smaller HER2-positive breast tumors.

OncLive: Please provide an overview of your lecture on HER2-positive breast cancer in the curative setting.

Are there subtypes within HER2 that could predict better response to therapy?

In terms of therapies, are there standard sequencing strategies? How are these agents typically tolerated?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Breast Cancer, McCann discussed the therapies available for patients with HER2-positive breast cancer and the potential benefit with additional subtyping in the field.McCann: The way the field is currently divided is that there are 3 major types of breast cancers: hormone receptor (HR)-positive/HER2-negative, HER2-positive, and triple-negative disease. Although, that is going to be subdivided later on. A large part of the success in the HER2-positive breast cancer field has been developing targeted therapies to the HER2 receptor. These included trastuzumab, pertuzumab, as well as 2 tyrosine kinase inhibitors (TKIs), which act intercellularly, called neratinib and lapatinib. We subdivide HR-positive/HER2-positive cancers out from the HR-negative breast cancers. We see that these are actually very different biologies and, in many trials, this has been recognized. We are starting to realize that the HR-positive/HER2-positive cancers—even though they don’t have a high rate of pathologic complete response (pCR), they still do have better overall outcomes than the HR-negative/HER2-positive breast cancer subtype. Eventually, they will be treated as different diseases in more ways than just adding endocrine therapy [to one over the other]. A lot of work in the HER2-positive breast cancer field has been done in the neoadjuvant setting in looking at pCR rates as a measure of outcomes.

Could there eventually be an immunotherapy breakthrough in this landscape?

Moving forward, where would you like to see research on HER2-positive breast cancer focused?

Trastuzumab is generally very well tolerated; there is a low risk of cardiotoxicity, which requires monitoring by echocardiogram every 3 months. Pertuzumab can be associated with diarrhea and some skin toxicity, but in general, both of these antibodies are very well tolerated. The 2 TKIs, neratinib and lapatinib, are associated with diarrhea, so there are clinical trials examining the amelioration of the diarrhea in addition to giving these therapies. Technically, you could consider trastuzumab and pertuzumab to be immunotherapies because they are antibodies that bind to HER2 and they highlight the HER2-positive breast cancer cells for the immune system. However, they are not immunotherapies in the same way that ipilimumab (Yervoy) or nivolumab (Opdivo) are. In addition to a lot of the escalation therapies, in which we're adding pertuzumab to trastuzumab in the adjuvant setting, and adding neratinib to long-term chemotherapy plus 1 year of trastuzumab, we are also looking at de-escalation therapies for tumors that are much smaller. These include trials with just a taxane plus trastuzumab with or without pertuzumab. Those have been promising, but we haven’t seen very long-term overall survival or disease-free survival yet. Therefore, we can’t make too many conclusions about that.

Overall, what are your thoughts on the way breast cancer treatment is evolving?

For very small tumors—less than 1 cm—some people are starting to use a taxane plus trastuzumab for these node-negative patients. However, we certainly know that these tumors still have a chance to recur, so not doing any therapy at all wouldn’t be advised. We also know that trastuzumab alone is not as potent and efficacious as trastuzumab plus chemotherapy. HER2-positive breast cancer used to be the worst prognosis, and now it’s one of the best because we have targeted therapies. We are still not there with triple-negative breast cancer (TNBC), but we're learning more about the biology. Eventually, we are hoping to get to the point where we'll be able to treat patients with TNBC and improve the prognosis like we have with HER2-positive breast cancer.