Targeted Therapies Deliver Hope in HER2-Positive Breast Cancer

Yara Abdou, MD

Historically, HER2-positive breast cancer exhibited poor prognosis and high mortality rates, according to Yara Abdou, MD. However, the emergence of targeted therapies within the past decade has revolutionized the treatment landscape.

These treatments, including trastuzumab (Herceptin), pertuzumab (Perjeta), sacituzumab govitecan-hziy (Trodelvy), trastuzumab emtansine (T-DM1; Kadcyla), trastuzumab deruxtecan (T-DXd; Enhertu), and more have offered promising avenues for previously limited patient populations.

“In the last 5 to 10 years, there has been a surge in the number of HER2-targeted agents that are approved for HER2-positive disease, in addition to developments that are powerful like antibody-drug conjugates [ADCs] targeting HER2, such as trastuzumab deruxtecan, that changed the treatment paradigm,” said Abdou, medical oncologist at the University of North Carolina (UNC) in Chapel Hill, in an interview with Targeted Oncology^TM.

In the interview, Abdou discussed the most significant challenges and transformative advancements in the treatment of HER2-positive breast cancer.

Targeted Oncology: Looking back on the past 5-10 years, what have been the biggest challenges in treating HER2-positive breast cancer?

Abdou: For decades, HER2-positive breast cancer was associated with poor outcomes and high mortality rates until Herceptin, or trastuzumab, was first approved in 1998 as the first anti-HER2 targeted therapy in metastatic HER2-positive breast cancer. Prior to that, patients were historically treated with traditional chemotherapy regimens and were not doing well. In the last 5-10 years, there has been a surge in the number of HER2-targeted agents that are approved for HER2-positive disease, in addition to developments that are powerful like ADCs targeting HER2 such as trastuzumab deruxtecan that changed the treatment paradigm.

3d rendered medically accurate illustration of a breast cancer: © SciePro - stock.adobe.com

I think 1 of the biggest challenges we face is in HER2 brain metastases because with improved systemic control, the incidence of brain metastases has increased, and it is estimated that about 60% of patients with HER2-positive metastatic breast cancer develop brain metastases. These patients continue to do poorly. Historically, patients with brain metastases were excluded from clinical trials. While we knew that some agents could cross the blood-brain barrier, we did not have great data in this setting. More recently, we are allowing our [patients with] brain metastases to enroll in clinical trials. HER2CLIMB [NCT02614794] is an excellent example. That was the first randomized trial to study [patients with] HER2-positive metastatic breast cancer with active brain metastases, which is important to accurately study the efficacy of these agents in patients with brain metastases and improve their outcomes.

What do you consider to be the most transformative advancements in the field over the past decade?

One of the most transformative advancements is how we define HER2. Until recently, HER2 status has been defined as a positive or negative result. This has evolved and now we have a newly defined cohort called HER2-low with low levels of HER2 expression. This HER2-low population accounts for approximately 55% of all breast cancers. Previously, these patients were considered negative in clinical practice because HER2 targeted therapies have not been effective in this setting. These patients had limited targeted options after they progressed on their treatments. Now with the development of potent targeting ADCs, we have opened the door to effective treatment options for this cohort of patients. T-DXd is now the first targeted therapy option approved for patients with HER2-low breast cancer based on the DESTINY-Breast04 study [NCT03734029], reclassifying this cohort as a new targetable subset in breast cancer in general, and expanding the population of patients who can benefit from HER2 targeted agents.

How has the understanding of HER2 subtypes impacted treatment personalization?

HER2 status should no longer be provided as a binary result of HER2-positive or HER2-negative. It is important for us to start routinely testing the level of HER2 expression in the tumor to identify the targetable patient population with HER2-low breast cancer classified as IDH-1 plus or -2 plus with FSH-negative. HER2-low breast cancer is a heterogeneous group of breast cancers consisting mostly of hormone-positive tumors with about 20% of hormone-negative tumors.

These tumors have distinct molecular profiles leading to different clinical pathological characteristics and prognostic differences between these groups where, for example, hormone-positive tumors more likely represent luminal subtype or hormone-negative tumors can be predominantly basal-like subtype. Heterogeneity does not necessarily affect their eligibility for targeted therapy, so the benefit of trastuzumab deruxtecan was seen in both subgroups, although the hormone-positive population was much more well represented in the DESTINY-Breast04 study. The fact that the drug works in both populations is important for that population to be identified in clinical practice. Importantly, as we start using therapies more widely moving forward, I would like to see more accurate and sensitive ways of assessing the HER2 expression status. I think we need more sensitive assays to be able to adapt.

How has the role of neoadjuvant therapy significantly changed in recent years?

We routinely choose neoadjuvant therapy for larger HER2-positive tumors that are 2 cm or more or patients with node-positive disease. We do that really for several reasons. One common reason is, for a more successful surgery, such as breast conservation, therapies are more feasible as neoadjuvant therapies, but more importantly, for lower rates of accurately axillary lymph node dissection and morbidity associated with that surgery. Another important reason why we use the neoadjuvant approach is for prognostic and predictive purposes. We know if a tumor has a pathological complete response or residual disease at the time of surgery, that determines their risk of recurrence and helps us tailor their adjuvant therapies according to how they respond. An example of that is the KATHERINE study [NCT01772472], which showed that giving adjuvant TDM-1 for patients who had residual disease at the time of surgery improved outcomes compared with just giving them or continuing the anti-HER2 therapy that they have been given neoadjuvantly. It is a way to tailor systemic therapies for patients.

How have antibody drug conjugates changed the landscape?

Antibody drug conjugates are exciting and effective drug delivery systems for the treatment of multiple subtypes of breast cancer. They showed remarkable efficacy, particularly in HER2-positive disease, and has also proven efficacy of sequential HER2-targeted ADCs with different payloads in HER2-positive disease. ADCs have also an established role now in triple-negative breast cancer and hormone-positive breast cancer where sacituzumab govitecan will be taken as an our standard-of-care for patients with metastatic disease. More recently, they have an established role in HER2-low disease where trastuzumab deruxtecan is the new standard-of-care for patients with HER2-low breast cancer.

Now, there are several ongoing trials with ADCs in earlier lines. T-DXd is being studied as a first-line treatment option for HER2-positive breast cancer in DESTINY-Breast09 [NCT04784715]. They are also being studied in early-stage, nonmetastatic disease in both HER2-positive and triple-negative breast cancer. There are also novel ADCs being developed that are now in phase 3 trials.

There are many questions that remain about ADCs that we are still trying to answer with more research. We still have to understand how we define HER2-low disease. We need to understand how we sequence these antibody-drug conjugates and understand their mechanism of resistance, and toxicity management is important. We know that ADCs have a unique set of toxicities, so it is important for us to be mindful of those and learn how to manage them appropriately.