Treatment of HER2-Low Triple-Negative Breast Cancer


Breast cancer experts talk through their approaches to treating HER2-low triple-negative breast cancer.


Hope S. Rugo, MD, FASCO: It’s interesting to think about how we made these advances. I’m excited about the antibody-drug conjugates [ADCs]. I totally agree with you that this is a better way to deliver chemotherapy, and it will eventually take over what we do in the early stage setting. There are more ADCs in development, which I hope will offer us sequential therapy. I don’t know if we’re going to be smart enough in the next few years to know which ADC is right for which patient, but sequential use will be important for our patients as well.

The new agents coming out are exciting. They offer new treatment options for our patients. We saw the approval of sacituzumab for hormone receptor–positive disease as well as triple-negative breast cancer, so we have 2 ADCs for a relatively broad group of patients. We don’t know how to manage the IHC [immunohistochemistry]: 1+ or 2+? I have a patient who had 1 fine-needle aspiration that was 1+. Every other test that she had was 0. What are we going to do with HER2 [human epidermal growth factor receptor 2] low? How are we going to define this going forward?

Paolo Tarantino, MD: This is extremely important because we’ve seen several retrospective studies, even prospective studies, showing how HER2 IHC scores can change depending on the timing of the biopsy. Even a primary tumor that’s HER2 low can become HER2 0 in a metastatic setting, and the opposite. Or 2 different biopsies in a metastatic setting can have different IHC scores. We’ve also seen an interesting…study presented at San Antonio [Breast Cancer Symposium], showing that in the same liver, a patient can have lesions that are HER2 0 or HER2 low. There’s wide discordance. We’re not sure if this is predictive of T-DXd [trastuzumab deruxtecan]. In DB04 [DESTINY-Breast04 trial], patients had the same benefit with T-DXd [trastuzumab deruxtecan], whether they were IHC 1+ or 2+. In the BEGONIA trial, we saw the same thing with T-DXd [trastuzumab deruxtecan] plus immunotherapy. There was also a high response rate in both IHC 1+ and 2+.

One thing that helped was a presentation at San Antonio by Aleix Prat. The biomarker data from DB04 showed that the benefit of T-DXd [trastuzumab deruxtecan] over physician choices and chemotherapy were seen regardless of the HER2-low status detected in the last biopsy or a fresh biopsy, in an archival tissue, or even on the primary tumor. About one-third of the patients in DB04 were enrolled based on HER2 low in the primary tumor, and they benefited from T-DXd [trastuzumab deruxtecan] compared with chemotherapy, similar to the overall population. The takeaway is that you need 1 biopsy that tests HER2 low to offer this opportunity to the patients.

In the future, we need to explore the HER2 0 realm. We know that even this tumor that we call HER2 0 has some expression over HER2, but the IHC wasn’t developed for this. It was developed to understand which patients are HER2 driven and have amplification of the HER2 oncogene. We also need to become also smarter with the assays. But for the moment, we have approval of T-DXd [trastuzumab deruxtecan] for patients with HER2-low disease—IHC 1+ or 2+—so it’s important to test all the samples of the patient. If at least 1 sample is HER2 low, it’s reasonable to offer this treatment to the patient.

Hope S. Rugo, MD, FASCO: I think so too. We have to take the data about the samples from DESTINY-Breast04 with a little caution, but it’s interesting because of when the trial started. About 30% to 40% of patients—in enrolled patients, it was about 31%—had their samples obtained from 2014 to 2018, and about 56% were obtained in 2019 or later. Even if it was the primary tumor, in the primary site—the breast—in one-third of the patients, it could have been breast cancer at a the time of metastatic diagnosis. We don’t know that from that data, so we have to be a little cautious and think about which treatment we’re giving patients based on what we know and the strength of the evidence. It’s a little easier in hormone receptor–positive disease, where patients are more responsive to chemotherapy. I tend to use the phase 3 data to drive primary decisions, particularly in patients who have more resistant metastatic cancers. I don’t know what you think about that or how you decide on sequencing.

Paolo Tarantino, MD: In the hormone receptor–positive setting, it’s a little easier, depending on the enrollment criteria of the trials, like DB04 and TROPiCS-02. In DB04, patients received a median of 1 prior chemotherapy. In TROPiCS-02, patients were slightly more pretreated. One could anticipate using T-DXd [trastuzumab deruxtecan] first and then sacituzumab progression. Triple negative is harder, but sacituzumab was tested in a large phase 3 trial powered to predict an outcome improvement in triple-negative disease, so sacituzumab should be prioritized in triple-negative disease.

At the same time, it’s about not only the enrollment criteria but also the patient in front of you and their comorbidities and preferences. We know that sacituzumab causes more alopecia compared with T-DXd [trastuzumab deruxtecan]. This can make a difference. A patient may have lung comorbidities, so you might prefer something that doesn’t have the risk of ILD [interstitial lung disease], like T-DXd [trastuzumab deruxtecan].

Transcript edited for clarity.

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