Tolaney Details IHC Testing Considerations for HER2-Low TNBC and Data on ADCs

Sara M. Tolaney, MD, MPH

Using immunohistochemistry (IHC) scores to determine HER2-low status is challenging as HER2-low triple-negative breast cancer (TNBC) is dynamic, but HER2-low expression is key in determining which patients should receive fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd), according to Sara M. Tolaney, MD, MPH.

In an interview with OncLive®, Tolaney highlighted data on T-DXd and sacituzumab govitecan-hziy (Trodelvy) in TNBC as well as how she uses IHC scores to determine HER2-low status of patients. Tolaney is chief of the Division of Breast Oncology and associate director of the Susan F. Smith Center for Women’s Cancers in Boston, Massachusetts. She is also a senior physician at Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School.

Tolaney also shared key perspectives on the treatment of TNBC, expanding on checkpoint inhibitor combinations, in another interview with OncLive.

OncLive: What are biopsy considerations when determining HER2-low status in patients with TNBC?

Tolaney: One of the challenges that we face with HER2-low disease is that it is dynamic. A patient could have a [tumor that has an IHC score of] HER2 0 at one point in time, and then you could biopsy it later and see that it’s HER2-low. The other problem is its expression is heterogeneous—one spot in the body could [have a HER2 score of] 0 and another spot could be HER2-low. Therefore, where you stick your needle [may affect] what you’re going to get as a result. 

Additionally, [results are] not so reproducible between pathologists. If one pathologist looks at [a tumor and does an IHC test], that pathologist may read [the score as HER2] 0 and another pathologist [may] read that same slide as 1+. That is a big difference because that’s what is determining whether the patient is a candidate for T-DXd. Most of us have defined HER2-low as having a biopsy at some point in time that was read as HER2-low–meaning 1+ or 2+ and not FISH amplified—in someone who has triple-negative disease. If someone has always [had a score of] HER2 0 on repeated biopsies, we often consider biopsy again to see if they have HER2-low status. Usually, we will recommend repeat biopsy if they’ve never had any tissue at any point in time read as HER2-low.

What key data have emerged within the TNBC treatment landscape?

We’re really excited to have antibody-drug conjugates [ADCs] available for patients with metastatic TNBC. The first ADC approved for patients with metastatic triple-negative disease was sacituzumab govitecan, based on data from the phase 3 ASCENT trial [NCT02574455]. This was a confirmatory phase 3 trial that compared sacituzumab govitecan with physician’s choice of chemotherapy in patients who were receiving treatment as their third-line therapy or later. 

However, the trial didn’t count patients who had early relapse, so they counted that as a line of treatment. There were patients on the ASCENT trial receiving treatment in the second line setting or later. [Findings] showed that sacituzumab govitecan did much better than chemotherapy head-to-head. It [almost] tripled progression-free survival [PFS] and doubled overall survival [OS], which is very impressive. It clearly established sacituzumab govitecan in my mind as our second-line standard of care option for patients with metastatic TNBC.

We have since seen approval for T-DXd, an ADC that targets HER2 and has a topoisomerase I payload—it was studied in the phase 3 DESTINY-Breast04 trial [NCT03734029] for patients who had HER2-low breast cancer. In this study, when T-DXd was compared with chemotherapy, T-DXd improved both PFS and OS. However, the primary end point was in patients with hormone receptor-positive disease. There were only 58 patients with TNBC in the study, so an exploratory subgroup analysis [was conducted]. In that subgroup of patients with TNBC, you can see the clear improvement in PFS and OS, even if it wasn’t statistically designed to look at that.

Therefore, the FDA granted approval for T-DXd, not just for patients with hormone-receptor–positive disease, but also for those with TNBC if [they had] HER2-low expression. If a patient has HER2-low TNBC, I personally would think about using sacituzumab govitecan in the second line and then T-DXd often in the third line setting.