Considering the Sequence of ADCs in HR+, HER2- and HER2-Low Breast Cancer


During a Targeted Oncology™ Case-Based Roundtable™ event, Elizabeth Mittendorf, MD, discussed how antibody-drug conjugates fit into the treatment algorithm for patients with advanced breast cancers.

Mittendorf EA

Elizabeth A. Mittendorf, MD, PhD

Rob and Karen Hale Distinguished Chair in Surgical Oncology, Brigham and Women's Hospital

Director, Breast Immuno-Oncology Program

Co-Director, Breast Cancer Clinical Research Program

Dana-Farber Brigham Cancer Center

Professor of Surgery, Harvard Medical School

Boston, MA

Targeted Oncology: What trial data supported the use of trastuzumab deruxtecan (Enhertu) in patients with HER2-low breast cancer?

ELIZABETH A. MITTENDORF, MD, PHD: There is an interest in thinking about antibody-drug conjugates [ADCs], and where we're going to position them for these patients. The data from DESTINY-Breast04 [NCT03734029] were presented at ASCO [American Society of Clinical Oncology Annual Meeting] 2022 in a plenary presentation.1 This study looked at trastuzumab deruxtecan, an ADC that targets HER2 as opposed to TROP2, [which is targeted by sacituzumab govitecan (Trodelvy)], and the payload is a bit different. DESTINY-Breast04 was looking at patients with HER2-low metastatic breast cancer, so these are the HER2 1+, 2+ [by immunohistochemistry (IHC)], and then they could be hormone receptor [HR] positive or HR negative.

One thing that we note in the trial is that it was a 2:1 randomization of trastuzumab deruxtecan versus physician's choice of chemotherapy, and although patients could enroll regardless of the HR status, the majority of patients—approximately 480 of the enrolled patients—were HR positive. The primary end point was progression-free survival [PFS] by independent central review. The highlight of the baseline characteristics, once again, is that it was primarily those with HR-positive, HER2 1+ or 2+ disease who enrolled on this study.

In that HR-positive population, there was benefit with respect to PFS with an HR of 0.51 favoring patients who received trastuzumab deruxtecan. Then overall survival [OS] favored the ADC with an HR of 0.64, which was after a median follow-up of 18.4 months.… This led to approval of this agent in patients with HER2 1+ and 2+ disease.

The forest plot was more impressive than what we saw in the TROPiCS-02 trial [NCT03901339]. DESTINY-Breast04 clearly showed that there was not a subgroup that didn't benefit from the trastuzumab deruxtecan.

What impact has the introduction of the HER2-low subtype had on the field of breast cancer research?

HER2-low breast cancer has become a hot topic. It's a huge issue for our pathology colleagues. Every pathology conference now is struggling with how do we determine HER2 status? It was [previously considered] if it was there at all [or not]. The 0 or 1+ didn't really matter because we weren't going to be giving them targeted therapy, and now they need to differentiate.

There has been a lot of interest in whether or not this is a distinct disease entity versus a continuum. The work done by Paolo Tarantino, MD, who is an international fellow spending time at Dana-Farber Cancer Institute, suggests it's not a distinct entity, that the clinical outcomes of patients with HER2-low disease, 1+ 2+, is driven by their HR status, and the extent of HR expression.2,3

What is the proposed roadmap for treating patients with HR-positive, HER2-negative metastatic breast cancer?

Patients start with the first line, [which] is endocrine therapy with a CDK4/6 inhibitor. The way that I think of it is I have to cycle through endocrine therapy plus targeted therapy, and it's my responsibility to figure out if there's a target that has a therapy. We would do genetic testing because if they were a mutation carrier, there'd be consideration of PARP [inhibitor]. Then...[I would look at] single-agent chemotherapy, and then these data looking at ADCs are very exciting [but] those trials weren't first-line therapy. It would be considered first-line therapy if you went straight from your endocrine therapy to [an ADC]. So when it starts to get to multiple lines and is using 1 of the ADCs, [the proposed] preference is for the HER2-low [population] to use trastuzumab deruxtecan and for the HER2-negative [population] to use sacituzumab based on DESTINY-Breast04 and TROPiCS-02, respectively.

How do the NCCN (National Comprehensive Cancer Network) guidelines address sequencing of therapies?

The NCCN guidelines [display] first-line therapy, second-line therapies, and subsequent therapies, and there are multiple different options, which are going to be dictated by the considerations I've reviewed.4 [In terms of] where the ADCs follow with respect to line of therapy, for first-line patients without a [germline BRCA1/2 mutation, they are eligible to receive] systemic chemotherapy. If they have a mutation, [they may receive] a PARP inhibitor. In the second line, now we're starting to think about the ADCs, and then clinical trials.


1. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690

2. Tarantino P, Hamilton E, Tolaney SM, et al. HER2-low breast cancer: pathological and clinical landscape. J Clin Oncol. 2020;38(17):1951-1962. doi:10.1200/JCO.19.02488

3. Schettini F, Chic N, Brasó-Maristany F, et al. Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer. NPJ Breast Cancer. 2021;7(1):1. doi:10.1038/s41523-020-00208-2

4. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 4.2023. Accessed June 27, 2023.

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