Titles and Affiliations
Chief Clinical Research Officer
Associate Cancer Center Director, Clinical Research
Director, Clinical Trials Office
Yale Cancer Center
Research area
Improving HER2 testing so that more patients can benefit from HER2-targeted therapy.
Impact
Twenty percent of breast cancers express a very high level of a protein called HER2. These HER2-positive cancers are treated with drugs targeting HER2, which can be highly effective. The level of HER2 is measured using a scale of 0, 1+, 2+ or 3+. Only cancers with the highest level of HER2 protein, 3+, are called HER2-positive. Cancers that are HER2 1+ or 2+ are termed HER2-low. Most current anti-HER2 drugs, such as trastuzumab (Herceptin®), are not effective in HER2-low cancers. However, the development of more specific HER2 drugs such as trastuzumab deruxtecan (T-DXd) is changing this paradigm. T-DXd (Enhertu®) recently demonstrated a high level of effectiveness in HER2-low breast cancers and is the only FDA approved targeted drug to treat HER2-low cancers. Because up to 50 percent of all breast cancers have some level of HER2, the potential clinical impact of T-DXd in breast cancer is great. However, there currently is no HER2 test to accurately distinguish HER2-low cancers from HER2-0 cancers. In fact, 30 percent of breast cancers scored as HER2-0 responded to T-DXd in clinical trials, further suggesting that the current test misses many potential T-DXd-responsive cancers.
Progress Thus Far
Dr. Krop has developed a new HER2 assay optimized for the HER2-low expression range that could more accurately distinguish patients who may benefit from T-DXd. Initial studies show the test is both highly sensitive for HER2 protein and reproducible. To definitively test this assay, his team is conducting a clinical trial of T-DXd in patients with defined HER2 0 metastatic breast cancer, the subgroup for whom the benefits of T-DXd are most uncertain. They are using breast tumor samples from trial participants to determine if the test is able to predict which tumors will respond and those that will not. The trial was launched and is now actively accruing participants. In other studies, they are utilizing sophisticated spatial RNA tests to evaluate breast tumor samples from previous patients treated with T-DXd. They hope to identify biomarkers that can determine which tumors are most sensitive and which are resistant to T-DXd. They are also seeking to identify the mechanisms used by tumors to become resistant. To date, they found that tumors that highly express genes involved in DNA repair and intracellular protein processing and degradation do not respond to T-DXd—this suggests that these pathways may be involved in T-DXd resistance.
What’s next
Over the next year, Dr. Krop and his colleagues will continue to accrue participants to the trial testing their HER2 test. They will also build on their findings using spatial RNA tests to identify biomarkers as well as delineate the mechanisms whereby tumor cells become resistant to T-DXd. Together, their results will help optimize the use of T-DXd in patients likely to benefit from this agent, spare patients unlikely to benefit from toxicity, and provide insight into mechanisms of resistance to this agent so that they can be overcome.
Biography
Ian Elliott Krop, MD, PhD, is the Chief Clinical Research Officer and
Associate Cancer Center Director for Clinical Research at Yale Cancer Center in New Haven, CT.
Dr. Krop is a translational investigator focused on the development of novel molecularly targeted therapies and immunotherapies for breast cancer, and elucidating the mechanisms of resistance to these treatments. The majority of his effort is concentrated in the area of HER2+ breast cancer. He was a leader in the development of the antibody-drug conjugate trastuzumab emtansine (T-DM1).
Dr. Krop currently serves as Chief Scientific Officer for the Translational Breast Cancer Research Consortium. He is a member of the National Cancer Institute’s Breast Cancer Steering Committee and co-chairs its Immuno-Oncology Working Group. He is also the co-vice chair for correlative science for the Alliance for Clinical Trials in Oncology. He is a member of the Eastern Cooperative Oncology Group Data Monitoring Committee.
Dr. Krop is a graduate of Johns Hopkins University and Johns Hopkins University School of Medicine. He trained at Johns Hopkins Hospital, Dana-Farber Cancer Institute, Harvard Medical School, and Brigham and Women’s Hospital. He completed a medical oncology fellowship at Dana-Farber.
