Later-line treatment options such as ADCs continue to evolve for patients with HR+/HER2- metastatic breast cancer (MBC). In this discussion, leading experts examine how biomarker interpretation, HER2 status, and sequencing strategies are shaping later-line treatment decisions for MBC.

The drug that has generated a lot of excitement in the MBC world is trastuzumab deruxtecan (T-DXd). In the past, only tumors classified as HER2+ by immunohistochemistry (IHC 3+) would be treated with T-DXd; patients who were not considered to have HER2+ disease were not eligible. However, what was formerly considered HER2- (ie, IHC 1+ or IHC 2+ unamplified) is now considered HER2-low. These patients are now eligible for T-DXd treatment in the metastatic setting, and studies have shown that T-DXd works quite well in such individuals. It has also shown great efficacy in HER2-amplified patients.

The problem is that the HER2-low designation depends on the pathologist, not on the patient’s tumor. We are working on trying to make that determination more quantitative and based less on a subjective score. Currently, we are developing a quantitative immunofluorescence assay that can accurately measure HER2 and TROP2 in breast cancer tissue, which may be important in determining which patients would most likely benefit from T-DXd as opposed to the TROP2 ADCs sacituzumab govitecan and datopotamab deruxtecan. By building an analytic assay, we can be much more accurate in matching the right patient to the right drug.

One question that remains is: Does a category between HER2-null (ie, IHC 0) and HER2-low, IHC 1+, exist? The College of American Pathologists (CAP) and the American Society of Clinical Oncology (ASCO) have designated an HER2-ultralow, IHC 0+ category, but it is not widely condoned and, arguably, it is not possible for pathologists to identify it consistently. Nevertheless, T-DXd has been approved by the US Food and Drug Administration (FDA) based on results from the pivotal DESTINY-Breast06 clinical trial showing a clear benefit of T-DXd treatment for all patients, regardless of IHC status. I personally am hesitant to recommend treatment for patients with tumors designated as IHC 0+ or HER2-ultralow with T-DXd, since the scoring is unreliable. However, it is in the guidelines.

We start thinking about ADCs, which are now FDA approved for second-line therapy and beyond, for patients with HR+/HER2- MBC once they have exhausted endocrine therapy–based options (ie, CDK4/6, PIK3CA, and AKT inhibitors). This is based on their superior overall response rate (ORR), progression-free survival, and overall survival (OS). For example, the DESTINY-Breast04 and DESTINY-Breast06 trials both demonstrated the clinical benefit of T-DXd vs physicians’ choice of chemotherapy in previously treated patients with MBC/advanced breast cancer. DESTINY-Breast04 included patients with HER2-low (IHC 1+/IHC 2+ unamplified) tumors, while DESTINY-Breast06 included patients with HER2-low and HER2-ultralow (IHC 0+) tumors.

In my opinion, capecitabine remains a reasonable option for many patients after endocrine therapy (eg, those with bone disease or indolent slow-growing disease). However, when an urgent clinical response is needed, I tend to choose T-DXd because the ORR with T-DXd is far superior compared with the ORR with single-agent chemotherapy. Similarly, for patients with visceral disease, including central nervous system (CNS) disease, I tend to choose T-DXd over single-agent chemotherapy. Moreover, for patients with HER2-low tumors who have already received 1 line of chemotherapy, we have seen tremendous benefit with T-DXd in terms of progression-free survival and OS.

Two agents targeting TROP2 have also been FDA approved: sacituzumab govitecan and datopotamab deruxtecan. These medications have different schedules and associated toxicities, so patient preference and previously experienced toxicities help guide treatment selection. One advantage of the TROP2 ADCs is that HER2 expression is largely irrelevant; like T-DXd, they have also been FDA approved for patients with HER2 IHC 1+/IHC 2+ unamplified, and even IHC 0+, tumors.

Overall, determining how best to sequence ADCs remains a major challenge in clinical practice. We need better ways of assessing biomarkers. As Dr Rimm mentioned, we may eventually be able to select patients for TROP2-directed ADCs, but right now, based on results from HR+ studies, we cannot do this—it does not seem like TROP2 expression is predicting which patients would benefit most from which ADC.

Compared with sacituzumab govitecan and datopotamab deruxtecan, the efficacy of T-DXd is so impressive, particularly in terms of its meaningful OS advantage for patients with HR+/HER2- MBC. But like Dr Sardesai, I do not usually start an ADC in patients with HR+/HER2- MBC once they have exhausted endocrine therapy–based options or are not deemed to be candidates for continued endocrine therapy unless they have CNS metastases.

This is because, if they have an indolent natural history, some of these patients do incredibly well on capecitabine for many months and even years, and they can avoid having to be tied to an infusion center for treatment as well as having any significant alopecia. So, in the absence of CNS disease, I think that a trial of capecitabine is appropriate in this setting before reaching for an ADC.