‘More sensitive’ HER2 test may allow for more personalized lung cancer therapy
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Researchers developed a highly sensitive, analytic, quantitative immunofluorescence assay that may enable more patients with lung cancer to benefit from an approved targeted therapy.
The test measures HER2, a commonly used biomarker for breast cancer.
Current HER2 tests show only 2% to 3% of patients with lung cancer have sufficient levels of HER2 to be eligible for fam-trastuzumab deruxtecan-nxki (Enhertu; AstraZeneca, Daiichi Sankyo), a HER2-directed antibody-drug conjugate often called T-DXd.
The new test, however, suggests a majority of patients with lung cancer may have sufficient HER2 expression to benefit from T-DXd.
David Rimm, MD, PhD — Anthony N. Brady professor of pathology and professor of medicine (medical oncology) at Yale School of Medicine and member of Yale Cancer Center — and colleagues evaluated the test on tissue specimens collected from 741 patients with lung cancer collected over several years at Yale and in Greece.
The test identified elevated levels of HER2 — sufficient to qualify for treatment with T-DXd — in 63% of the lung cancer tissue samples.
“As pathologists, we try to improve our level of agreement. One way we can do that is to switch from reading to measuring, and that’s what this assay does,” Rimm told Healio. “The way we did this measurement was by using cell line standards, which is a bit novel. That’s what enabled us to take this from a qualitative assay to an analytic assay.”
Healio spoke with Rimm about the limitations of current biomarker testing approaches and how this new assay may identify help identify more patients with lung cancer who could derive benefit from T-DXd.
Healio: What are the limitations of current biomarker testing strategies to guide lung cancer treatment?
Rimm: T-DXd has been evaluated in lung cancer but, initially, it was only given to patients who had mutations or genetic alterations in HER2, which is the target of the drug. This is the only lung cancer indication for which T-DXd is approved, and those patients have a good response to T-DXd.
In a secondary trial, results showed some patients who had high immunohistochemistry also responded, even though they didn’t have a mutation or an amplification of the gene. This suggested the drug may work for patients who have high enough levels of the target to bind to the drug. It also suggested that, in lung cancer, patients might not require an alteration of the genetic code for it to work.
Healio: How did you develop the new assay?
Rimm: The test was developed for breast cancer, and we basically leveraged quantitative fluorescence methods that we’ve been working on for many years. We then added a cell line standard so we could translate levels of signal into attomoles/mm2, or number of molecules per square millimeter. We use the denominator of square millimeter because we don’t want to try to count the cells. Cell counting is fraught with error, whereas square millimeters of tumor can be done by a molecular parameter.
Healio: How did you evaluate the assay and how did it perform?
Rimm: We built the test but had no way of evaluating the efficacy, because we couldn’t access the clinical trial. So, finding a threshold above which patients could respond to the drug was not possible for us. Then, in collaboration with breast medical oncologist and clinical researcher Paolo Tarantino, MD we looked at 51 breast cancer cases retrospectively. We received tissue from these cases, all of which had received T-DXd. We measured HER2 in those samples and found that, for every increase of 5 attomoles/mm2, there was an increase in response. When we looked at quartiles, the lowest quartile of expression did the worst, and the highest quartile of expression did the best. This work was reported at ESMO Congress and an manuscript is in preparation.
Healio: Now that you have studied the assay in lung cancer, do you plan to evaluate it in other cancer types?
Rimm: We’re in the process of evaluating this in colon, ovarian, gastric, hepatocellular and pancreatic cancers. Those tests are underway, and we’ll probably have them finished in the next month or two.
Healio: Is there anything else you’d like to mention?
Rimm: The difference in what we’ve done with this test is that it is measured and not read. This is a quantitative, analytic assay, like blood glucose. It’s not a judgement of a score where a pathologist reads it. When pathologists read things — even the best pathology readings — they don’t always agree, and lately, some of the companion diagnostic tests are impossible to read in a reproducible manner.
Also, the original assay designed to assess HER2 by the pathologist was to tell the difference between gene-amplified and nongene-amplified HER2. A nongene-amplified case might express 500,000 molecules, whereas a gene-amplified case might express 5 million molecules. That test was designed to tell the difference between 500,000 and 5 million. However, with T-DXd, there is the possibility that patients with as few as 100,000 or 50,000 molecules might respond. We changed our scale to make our test more sensitive.
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For more information:
David Rimm, MD, PhD, can be reached at david.rimm@yale.edu.
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