News Article

Powering a new paradigm for pathology

November 1, 2024
Conceptual artwork of diagnostic pathology

Antibody-drug conjugates are a powerful new modality, but doctors need new diagnostics to determine which patients should receive them. Danaher collaborator David Rimm of Yale School of Medicine lays out the challenges and a potential solution for breast cancer patients. 

Pathology is arguably one of the oldest specialties in medicine. Today, thanks to technological advances, it is facing a very modern challenge: “pathologists are now in the awkward situation of being asked to do something that humans aren’t capable of,” says David Rimm, MD, PhD, Professor of Pathology and Medicine at Yale School of Medicine. The problem he is describing is that of the increasing demand for pathologists to be able to distinguish between fleetingly small differences in signal levels using nothing but their powers of observation and eyesight.

To understand the challenge, consider the way pathologists measure HER2 – an oncogenic protein – in breast cancer patients. Current companion diagnostic technologies were developed to identify patients with high levels of HER2, as the first generation of antibody drugs worked best in these patients. However, a new generation of antibody-drug conjugates (ADCs) has shown significant success with patients expressing lower levels of HER2. The question is now, how low can the levels go before the drugs cease to work?

Differentiating between low levels and very low levels of HER2 is like “weighing mice on a scale made to weigh elephants. The dynamic range is wrong,” says Dr. Rimm. As a result, it is very challenging for pathologists to know which patients are most likely to benefit from the new ADCs – and “I think it's as likely that you'll be able to train pathologists to differentiate these levels as you'll be able to train them to fly when they jump out a window.”

 

A new paradigm in pathology is needed.

The solution is to move “from reading to measuring,” as Dr. Rimm says. “Reading is the current standard of care, and that's when pathologists look at slides and give their opinion in the form of a score. Measuring, on the other hand, is quantitative and objective.”

Many diagnostics are based on direct measurements, such as blood glucose levels. The challenge comes when the sample type is not a blood draw, but a thin slice of tissue on a microscope slide, as is common in cancer diagnostics. These samples come from biopsies and are made up of both tumor tissue and normal tissue. This structural information is important, allowing for pathologists to define the location and extent of the tumor. Immunohistochemistry tests provide additional information on the presence or absence of specific biomarkers within the tumor. Yet these tests currently rely on pathologists to “eyeball” scores rather than providing objective, quantitative measurements for the biomarkers.

Metastatic breast cancer on a lymph node
Metastatic breast cancer on a lymph node, Leica Biosystems

To address this issue, Dr. Rimm and his lab developed a new, high sensitivity HER2 assay in 2022. “Our solution doesn’t force the pathologist to judge the level, but instead utilizes their ability to differentiate what's cancer and what's not.” With the new assay, the pathologist indicates the boundaries between tumor and healthy tissue, then HER2 antibody binding is measured with immunofluorescence and compared to a standard curve. In Dr. Rimm’s experience, this approach dramatically increases the accuracy, reproducibility, and sensitivity of the assay. “We're about 10 times more sensitive than the average HER2 test,” Dr. Rimm says.

Unfortunately, getting the test certified for use in patients was a process that took the Rimm lab nearly two years. “We can now offer this test our CLIA lab at Yale, but we can only do about fifty a month, which is a drop in the bucket compared to the 240,000 breast cancer patients a year in the US,” says Dr. Rimm. “That’s where Leica Biosystems, Cepheid, and the Danaher Beacons program come in.” The Danaher Beacons program funds product-driven scientific research with globally recognized academic investigators to solve some of the most pressing challenges facing human health.

“We see huge potential in the assay created by Dr. Rimm and his colleagues,” says Rob Monroe, Chief Scientific Officer, Oncology for Danaher Diagnostics. “With the rise of ADCs, we need assays that are quantitative and more sensitive to identifying the patients most likely to benefit from these therapies. This ability to perform direct measurements of biomarkers such as HER2 on pathology slides can help breast cancer patients get the care that they need and has broad applicability for the assessment of ADC targets across many tumors.”
 

The Rimm lab’s work with Danaher and its two operating companies – Leica Biosystems, a global leader in anatomic pathology, and Cepheid, a leading molecular diagnostics company – is two-fold. First, Dr. Rimm is working with Leica Biosystems to turn the lab’s “academic hodgepodge” assay into a standardized product that could be distributed and run in clinical labs around the world. The second is in supporting a clinical trial to test the efficacy of the assay and to determine the quantitative threshold of HER2 that distinguishes the patients most likely to respond to a relevant ADC. The clinical trial is in collaboration with Angela DeMichele, MD, of the Perelman School of Medicine, Eleanor Taranto, MD at the University of Pennsylvania, and the Translational Breast Cancer Research Consortium (TBCRC).

"One of the exciting things about the clinical trial is that we are testing two complementary technologies in it: the assay we developed in my lab, and the STRAT4 assay developed by Cepheid, which measures HER2 RNA levels instead of protein,” says Dr. Rimm. “This could never be done with two independent companies and really highlights the value of Danaher.”

When asked if he thinks one technology will prove better than the other in the trial, Dr. Rimm replied, “Frankly, I don't care – the winner is the patient.”

Companion diagnostics, like the one being developed for HER2-targeting ADCs in this collaboration, help determine if a patient is a good candidate for a particular therapy. They are the key to ensuring the promise of precision medicine – the ability to treat the right patient with the right medicine in the right dose at the right time – is realized. 

Danaher recently opened two new Centers of Innovation to pioneer a new, holistic approach to developing companion diagnostics.

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