Tarantino Talks Limitations in HER2-Low Breast Cancer Management, Key Advancements in HER2+/TNBC

Paolo Tarantino, MD

In an interview with OncLive®, Paolo Tarantino, MD, discussed the challenges of defining and managing HER2-low breast cancer, emphasizing the need for better quantitative assays in this space; outlined the emergence of new treatment options, including immunotherapy and antibody-drug conjugates (ADCs); and emphasized the need for improved education on managing toxicities associated with new and emerging therapies across breast cancer subtypes.

Tarantino also highlighted key points from his colleagues’ presentations during a recent OncLive® State of the Science Summit™ on breast cancer, which he chaired, including advancements in biomarker identification and targeted therapy development that enable personalized treatment in HER2-positive early breast cancer, and evolving attitudes towards the management of triple-negative breast cancer (TNBC).

“[Overall,] there is a lot going on, but I think we are on the right track and soon we will tailor treatments even better for patients,” Tarantino stated.

In a concurrent interview, Tarantino discussed the evolution of therapies beyond traditional chemotherapy in hormone receptor-positive, endocrine-refractory metastatic breast cancer.

Tarantino is a researcher at the European Institute of Oncology in Milan, Italy, and a clinical research fellow at Dana-Farber Cancer Institute in Boston, Massachusetts.

OncLive: What are some of the current limitations regarding the current methods of defining HER2-low breast cancer?

HER2-low is a very controversial definition. It basically [came about] with the results of [the phase 3] DESTINY-Breast04 trial [NCT03734029] 2 years ago, which showed that patients with HER2-low metastatic breast cancer derived significant benefits from fam-trastuzumab deruxtecan-nxki [Enhertu; T-DXd]. We knew back then that even patients with HER2-zero disease still have some expression of HER2 in the tumor; [these patients] can have up to 10% of their tumor cells showing faint HER2 staining. Now we’re calling this low expression HER2-ultralow expression. We found that patients with HER2-ultralow metastatic breast cancer can benefit from T-DXd over chemotherapy.

What are the next steps for better defining the distinction between HER2-ultralow and -zero disease?

This is a moving target, and immunohistochemistry [IHC], which is what we use to categorize HER2-low, -ultralow, or -zero [disease], was not made for this purpose. IHC was developed to dissect patients with HER2-positive breast cancer from those with non-HER2-positive disease, who do not have the amplification of HER2 and do not benefit from [T-DXd]. However, it is very likely that we will need better quantitative assays to dissect these low HER2 expression [categories]. For the moment, it’s still important to utilize IHC to detect HER2-low expression, because the current approval for T-DXd is for HER2-positive or -low [disease]; we still do not have an approval for HER2-zero or -ultralow [breast cancer]. However, it’s important to remember that this will change over time, and we need to remain open minded and keep track of every evolution in this field.

Regarding the presentation given by your colleague, Adrienne G. Waks, MD, what advancements have made the tailoring of treatment possible in early-stage HER2-positive breast cancer?

HER2-positive early-stage breast cancer is one of the fields where we are achieving this tailoring of treatment. That is something we hope to do in every setting, but we do not always have enough drugs, biomarkers, and knowledge to understand how to tailor treatments. In early-stage HER2-positive disease, we are achieving this because we have good data with anthracycline-based treatments, non-anthracyclines, carboplatin and taxane-based treatments, treatments with trastuzumab [Herceptin] and pertuzumab [Perjeta], and even data with TKIs and the escalation of trastuzumab emtansine [Kadcyla; T-DM1].

We’re [also] starting to understand more in terms of biomarkers, both in terms of biologic biomarkers [with the] HER2DX [assay, which] looks at the genomic signature of HER2 addition, proliferation, and luminal signature; but also imaging biomarkers, such as PET scans and MRI scans. All [these data are] maturing, and we are learning how to utilize all these biomarkers and drugs to treat our patients with the least amount of treatment required to prevent recurrence.

Another important thing we learned is that if we utilize neoadjuvant treatment, we can select patients who do not have a pathologic complete response and identify where we can escalate post-neoadjuvant treatment.

What ongoing trials are expected to further inform personalized approaches to treatment in early-stage HER2-positive breast cancer?

We have many tools that have emerged in the past few years that already allow us to tailor treatment for patients with early-stage HER2-positive disease, but many trials are also ongoing. A big one we’re waiting for is [the phase 2] CompassHER2-pCR trial [NCT04266249], which is [evaluating] if neoadjuvant docetaxel, trastuzumab, and pertuzumab can be [an adequate regimen] for many patients. This is a very well tolerated regimen, and we hope the trial will be positive. We’re also waiting for [data from] 2 other [phase 3] trials: DESTINY-Breast05 [NCT04622319] and CompassHER2 RD (NCT04457596). [These will help us] understand whether we can further escalate treatment for high-risk patients.

How has the TNBC treatment arsenal expanded in recent years, and what emerging therapies or targets offer new hope for improving outcomes in this aggressive disease, as per the presentation by Sara M. Tolaney, MD, MPH?

Dr Tolaney was tasked with talking about TNBC, which lacks important targets like the estrogen receptor and HER2 overexpression. [However,] we’ve learned over time that there are many actionable targets that we can utilize either with targeted drugs, with immunotherapy, or with antibody-drug conjugates. In the last few years, we saw an emergence of so many new treatment options in TNBC, which is probably the most aggressive subtype of breast cancer. [This includes] immunotherapy in the first line with pembrolizumab [Keytruda] added to chemotherapy, and PARP inhibitors for patients with germline BRCA mutations. We also learned [about] germline PALB2 mutations and somatic BRCA mutations that were validated in a Translational Breast Cancer Research Consortium trial. We also have ADCs targeting TROP2 and HER2, and we will [hopefully] have many more in the future.

I do feel that this [treatment landscape] is changing rapidly. [For patients with] this very aggressive disease who once had very poor survival, we are improving [outcomes]. It’s still not enough, and we need a lot more clinical development in this field. However, all these new targeted drugs, ADCs and immunotherapy have brought hope in a field where, for a long time, there was not enough of it. I feel that we can build on that hope to further improve outcomes for patients with TNBC.

What strategies could help improve oncologists’ understanding and proactive management of adverse effects in the context of new breast cancer treatments?

Irrespective of the setting and the type of drug, it is becoming more and more important to be aware of and to manage adverse effects [AEs]. Many of the new treatments we’re developing do come with AEs that are not completely benign. They can [be associated] with diarrhea, nausea, fatigue, interstitial lung disease [ILD] or neutropenia. We need to build up everything that we learned about managing AEs with chemotherapy and learn how to manage new AEs that are emerging, [such as] ocular toxicities. Stomatitis [is another AE that was] uncommon with prior drugs that is [now] happening more and more. Establishing guidelines, discussing strategies to best to proactively manage AEs [associated] with ADCs and other novel drugs, and learning how to [potentially] prevent these AEs [are important].

We need to understand which patients are more vulnerable for [certain] AEs and possibly exclude them from certain treatments. We can get there, but for the moment, education is extremely important. The risk of ILD, nausea, vomiting, and any new AEs needs to be discussed to improve not only survival for patients, but also quality of life, which is just as important.