A new, highly sensitive test for a cancer biomarker could allow more lung cancer patients to benefit from a recently FDA-approved chemotherapy.
The key to this promising news is the HER2 protein (human epidermal growth factor receptor 2), which is frequently used as a biomarker for breast cancer but is also found in a few other malignancies, including lung cancer. However, current tests for HER2 suggest that only 2% of lung cancer patients have enough of the protein to qualify for trastuzumab deruxtecan (T-DXd), a cancer drug that targets the biomarker, compared to around 70% of breast cancer patients.
Now, in a study published July 2 in Modern Pathology, a more sensitive test suggests that over 60% of lung cancer patients may have adequate HER2 to also benefit from the T-DXd. This test, developed by David Rimm, MD, PhD, Anthony N. Brady Professor of Pathology, professor of medicine (medical oncology) at Yale School of Medicine, and member of Yale Cancer Center, and colleagues, could one day help clinicians determine which patients are best suited to receive certain cancer drugs, says Rimm.
“The original test is kind of like a scale for weighing elephants, and we were trying to weigh mice on it,” says Rimm. Knowing that the test may have been missing eligible candidates, “we made a scale for mice.”
Minimizing chemotherapy’s hazards
Chemotherapy is the most widely used method for treating cancer. But its toxicity—which stunts the growth of cancer cells—can also increase the risk for infection and make people feel sick, among other side effects.
Some drugs, called antibody-drug conjugates, aim to circumvent common side effects of chemotherapy by directly targeting cancer cells. These drugs work by using antibodies against cancer biomarkers—such as HER2—to directly deliver highly toxic chemotherapy doses to cancer cells while largely ignoring other parts of the body. But there are some practical considerations to these therapies. Patients must have sufficient levels of the target biomarker in their cancer cells for the drug to work. And drugs such as T-DXd, which target HER2, can also be dangerous, with some percentage of patients developing a life-threatening lung disease.
Therefore, biomarker tests are a step that doctors must take to help ensure a possible benefit from the treatment before exposing a patient to the risk of side effects from the drug. Currently available tests for HER2 levels are designed for breast cancer, where the protein is massively overexpressed. In one lung cancer study, researchers looked for mutations in the ERBB2 gene, which encodes HER2, to determine eligibility for T-DXd—which led that study to conclude that only a small fraction of lung cancer patients would qualify.
This low number seemed off to Rimm. Given that HER2 was so prevalent in breast cancer cells, “why would it only be 2% in lung cancer?” he recalls. Based on his previous research, Rimm suspected that HER2 was expressed in lung cancers even without a mutation to increase its production. Current tests “seemed like they were going to get a lot fewer patients on the drug than could benefit from the therapy,” he says.
A far more sensitive HER2 test
Lung cancers without a mutation in and around ERBB2 still produce lower, but clinically relevant, levels of HER2 protein. To search for these lower levels, Rimm and his colleagues developed a much more sensitive test than those that are now available.
The team then tested its assay on a collection of tissues from 741 lung cancer patients collected over several years at Yale and in Greece. The study detected elevated levels of HER2 in 63% of these lung cancers—enough that those patients could have qualified to receive T-DXd.
This number, far higher than the 2% reported in other studies, means that more lung cancer patients could be eligible for T-DXd in the future. The test can be ordered now as a lab-developed test, but it is not yet FDA approved. The team is also working on developing similar tests for other cancer types.
This test is the first step in developing more sensitive ways to predict how patients will respond to cancer drugs. Personalized medicine, where treatments are tailored around the unique biology of each patient, is on the rise in cancer treatments. Around 700 drugs, such as T-DXd, are currently in clinical trials. In a few years, clinicians might be able to test not just HER2 but a range of targets to see which cancer drug to use, says Rimm.
Assays that look at levels of HER2 and other cancer biomarkers “will be an important test,” in up-and-coming cancer treatment, he says. “Come back to me in three to five years and I think it’ll be a common thing to determine which tag is the highest level, so you can pick that drug first.”