DDIR/HRD Status Predicts Response to Chemoimmunotherapy in TNBC
Abstract
About 15% of breast cancers diagnosed in American women are triple-negative breast cancers (TNBCs). Unlike the more common hormone-driven breast cancers and breast cancers caused by abnormal activity of a gene called HER2, we do not have targeted treatments for TNBC. Treatment for TNBC usually consists of multiple types of chemotherapy, surgery, and usually radiation therapy. Despite this course of treatment, 30%-40% of TNBC patients will die of their breast cancer. A very recent clinical trial showed that the addition of a new type of treatment called immunotherapy could improve outcomes for TNBC patients. Immunotherapy works by activating the body’s immune system to fight their cancer. Sometimes this causes a patient’s immune system to attack their own tissues, and this can lead to severe, permanent, and rarely even deadly side effects. The study that tested immunotherapy in TNBC showed that only about 15% of patients benefit from this treatment. If we could identify markers in TNBC that predict who will have good outcomes with chemotherapy alone and who will benefit from immunotherapy, we would be able to personalize treatment for each individual TNBC patient. Rather than treating all TNBC patients the same, we would be able to give the most effective treatment with the least side effects and treatment cost. Some of our recent research has shown that two molecular markers, called DDIR and HRD, can predict prognosis in TNBC patients. DDIR is a marker of immune system activation and HRD is a marker that indicates tumor cells are sensitive to chemotherapy drugs that damage DNA. Each of these markers can predict how a patient will respond to treatment, but they do so in different ways. By using DDIR and HRD together, we believe that we can predict which TNBC patients can be treated with chemotherapy alone and which patients will benefit from adding immunotherapy to chemotherapy. We recently conducted two clinical trials testing new treatments for TNBC. The first trial, called NeoSTOP, showed that a much less intense course of chemotherapy using only two drugs leads to equivalent outcomes compared a more standard four chemotherapy drug regimen. This suggests that we may be able to treat many TNBC patients with fewer drugs, which will lead to less side effects and less treatment cost for patients. The second study, called NeoPACT, tested this less intense chemotherapy regimen plus immunotherapy. We have already measured the DDIR marker in all the tumor samples from patients who were treated on these two clinical trials. In this grant, we are proposing to measure the HRD marker in all the tumor samples so that we can classify patients into three groups based on their DDIR and HRD status (those patients who are positive for both markers, those patients who are positive for one but not both markers, and those who are negative for both markers). We suspect that patients who have both markers will do extremely well without immunotherapy and can be treated with chemotherapy alone. For patients who have one but not both markers, we suspect that they will benefit from combination chemotherapy and immunotherapy. Our previous research has shown that patients who do not have either of these markers do much worse than the other groups. We do not yet currently know the best treatment for them, and more research is needed. Once we show that classifying TNBC patients by the DDIR and HRD markers can predict the best treatment from the NeoSTOP and NeoPACT patient samples, we will confirm this in another group of TNBC patients who are treated with chemotherapy plus immunotherapy on our ongoing TNBC registry trial, which is already funded. Our research is important because it may allow us to personalize treatment for each individual TNBC patient. This will help us maximize cure rates, eliminate unnecessary side effects, and reduce the burden and cost of treatment for patients. Because we have many patient samples already available an
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210323
Entities
People
- Priyanka Sharma
Organizations
- United States Army
- University of Kansas Medical Center