August 04, 2025
4 min read
Key takeaways:
- A novel assay may help direct antibody-drug conjugate therapy through measurements of HER2 and TROP2.
- Most patients have either higher HER2 or TROP2, or neither.
Antibody-drug conjugates are currently being investigated in more than 260 clinical trials.
“It’s going to be the next novel therapy wave in oncology,” David Rimm, MD, PhD, Anthony N. Brady Professor of Pathology and professor of medical oncology at Yale School of Medicine, told Healio.
Yet, many antibody-drug conjugates (ADCs) are prescribed without knowing the specific biology of a patient’s tumor.
That prompted Rimm and colleagues to develop a novel assay to measure HER2 and TROP2 levels in patients with breast cancer. These data could help physicians decide which ADCs should be used in each individual case.
“We’re the first one of these,” Rimm said. “As more and more ADCs are approved, it’s going to be more and more important to look at the tags (or surface antigens) that the patients have. This is truly precision medicine. You look at the tumor from the patient. You look at what color tag they have, and then you give them the drug that has the antibody for that color.”
“It has huge potential,” he added.
ADCs have ‘changed outcomes’
Healio previously reported on the efficacy of ADCs on metastatic breast cancer.
One study found trastuzumab deruxtecan-nxki (T-DXd; Enhertu; AstraZeneca, Daiichi Sankyo) plus pertuzumab (Perjeta, Genentech) reduced disease progression or death 44% compared with standard of care.
Another showed T-DXd alone extended PFS for patients with HER2-positive disease, including HER2-low and HER2-ultralow.
A different trial found patients with metastatic triple-negative PD-L1-positive breast cancer had nearly a 4-month improvement in PFS with sacituzumab govitecan (Trodelvy, Gilead Sciences) plus pembrolizumab (Keytruda, Merck) compared with chemotherapy plus pembrolizumab.
“They have really changed outcomes in patients with metastatic breast cancer and probably will change outcomes in earlier stage cancers, as well,” Rimm said.
HER2 and TROP2 are common targets for breast cancer.
Between 15% and 20% of breast cancer malignancies can be treated with HER2-attacking regimens, according to study background.
TROP2 also is found on multiple breast cancer types, notably triple-negative disease.
ADCs use those targets to kill the tumor, but determining which ADC is best is an inexact science.
“What struck me is here is the absence of a selection method for this targeted therapy. We know how it works from a molecular perspective, and yet we aren’t measuring the molecular tag,” Rimm said. “We are just kind of guessing on the tag. For some of the drugs, we don’t even look at the tag. For other drugs, we have a test that was built for something else that we’re repurposing. It’s like we have a scale made for weighing elephants, and we decided to use it to weigh mice. Well, it doesn’t work so well for weighing mice because it’s made for weighing elephants. It’s in the wrong dynamic range.”
Rimm and colleagues developed a novel assay called Troplex to change that.
‘Mandatory’ in the future
Troplex can be used to calculate the exact number of HER2 and TROP2 targets a patient’s tumor has.
“Comparing that to previous ways of doing this test, which is having pathologists estimate intensity using a test that’s in the wrong dynamic range, we do much better,” Rimm said. “We’re much more accurate.”
The researchers validated Troplex on 323 breast cancer samples and found most tumors either had an abundance of HER2 or TROP2, or neither (inverse correlation = –0.17; P = .001).
“That further illustrates the importance of this,” Rimm said. “Tumors, just by their nature, don’t have a lot of both. They usually choose one or the other, and although there is a handful of tumors that have both, that may explain why the drugs don’t work so well. Most of the tumors depend on one or the other. That’s why I think with the appropriate tags and identification of the biology of the tumor using those tags, we can then give the right drug to the right patient.”
Rimm and colleagues plan to further evaluate the assay in the TRADE-DXd trial, which is investigating the sequence of T-DXd and datopotamab deruxtecan (AstraZeneca/Daiichi Sankyo) in individuals with metastatic HER2-negative (HER2-low or HER2-0) breast cancer following disease progression.
“We’re going to try to measure the amount of each tag before they even get the first drug and then see if we can predict which drug they’re going to respond to,” Rimm said.
The researchers still do not know how many tags a patient must have for a treatment to be successful, but that is the next step in research.
“We expect that there will be a minimum number of tags required on the cancer cell in order for a patient to benefit,” Rimm said.
Troplex is already in use at Yale pathology labs and has been approved by the New York State Department of Health.
Rimm is currently speaking with other institutions trying to get them to adopt the test, as well.
Though Troplex only evaluated HER2 and TROP2, there are “probably at least a hundred other tags” for future ADCs across cancer types, Rimm said.
He expects assays such as these to become “mandatory” for treatment in the future.
“ADCs are just making their way into earlier settings,” Rimm said. “Over the next 5 to 10 years, as ADCs become more important, so will this type of assay.”
For more information:
David Rimm, MD, PhD, can be reached at david.rimm@yale.edu.
Sources/Disclosures
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Disclosures:
Rimm reports consulting or advisory roles with AstraZeneca, Cell Signaling Technology, Cepheid, Daiichi Sankyo/AstraZeneca, Danaher, Halda Therapeutics, Incendia, NextCure, Nucleai, Paige AI, Regeneron and Sanofi; and research funding from AbbVie, Cepheid, Lunit, Navigate Biopharma, NextCure and Regeneron. Please see the study for all other authors’ relevant financial disclosures.
