With multiple ADCs now available for HR+/HER2- metastatic breast cancer (MBC), treatment sequencing remains uncertain. This article explores the emerging role of quantitative biomarker assessment, particularly HER2 and TROP2 expression, in predicting response and resistance to ADC therapy. Advances in quantitative pathology may enable a more precise matching of tumor biology to targeted treatments, moving beyond traditional categorical scoring toward a more individualized therapeutic approach.

As we think about ADCs in HR+/HER2- MBC, questions remain. How do we select the right drug? How should we sequence these therapies appropriately? There are now several ADCs available—trastuzumab deruxtecan, sacituzumab govitecan, and datopotamab deruxtecan—but there is very little direct evidence to guide which treatment should be given first. With the lack of head-to-head trials, we just rely on comparisons between trials, which is certainly not advisable.

In conventional cases of HR+/HER2- MBC, mutations in the PI3K pathway can often help guide treatment selection (ie, TKIs). Personally, I am not a big fan of TKIs because they are difficult to administer and less likely to have a long-term benefit compared with targeted therapies such as ADCs. However, with ADCs, you have to know which one to give, and that has been a challenge. We are truly operating in what many oncologists call an “evidence-free zone.”

I think that pathology could help improve this situation by being more quantitative in its assessments of ADC-guided biomarkers (eg, HER2 and TROP2). Currently, the VENTANA anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody assay (Roche Diagnostics) is one of the most widely used US Food and Drug Administration (FDA)–approved platforms and is often used as a reference comparator for scoring. The coefficient of variation for this assay is shockingly high (approximately 50%) because, once you have lower and lower levels of target protein, it becomes harder to detect with nonquantitative assays performed without standardization. Our laboratory and others have been working on quantitative assays that measure the exact level of HER2 and/or TROP2 in both primary and metastatic tumor specimens. For our HER2 assay, instead of using the 0 through 3 scoring, we measure units in amol/mm² where the coefficient of variation is between 1% and 10%.

Detecting TROP2 has proven more challenging. The problem is that TROP2 is measured using an H-score, and we have recently shown that the variance in this scoring system is quite high, which means that assessment results are highly dependent on the pathologist making the assessment and the laboratory in which the test is performed. I think that this is why there is not a companion diagnostic test for this biomarker.

Overall, the important thing to emphasize is that we need to move forward with more advanced technology assays. Given the computing power we now have, we should not be relying on an assay that was developed in the 1980s; we really need to catch up to become more accurate in matching patients’ tumor biology to the appropriate therapies.