Goal: Developing methods to identify which patients would benefit from immunotherapy.

Impact: Immunotherapy helps a patient’s own immune system fight cancer and can be very effective, but only in about 15 percent of patients with triple-negative breast cancer (TNBC). The use of immunotherapy drugs is complicated by their potentially life-long side effects including those similar to autoimmune disorders. Dr. Balko and his team have identified a test that may help identifywhich patients do or do not need immunotherapy so that these side-effects could be avoided.

What’s next: Dr. Balko's team will analyze tumor tissuefrom patients enrolled in an ongoing clinical trial to determine the efficacy of their test and optimize its use. This may provide anew way to identify patients that will benefit from immunotherapy and lead to its testing in larger clinical trials. The data his team collects could alsopotentially reveal new effective treatments or biomarkers to improve outcomes for patients with aggressive TNBC.

Goal: Identifying social and biological determinants of breast cancer outcomes in Black women.

Impact: Black women are 41 percent more likely to die from their breast cancer than white women. This is due, in part, to a lack of diversity in genomics research that propagates a paucity of equitable therapeutic/diagnostic options to serve a diverse population ofbreast cancer patients. Dr.Davis’team will study the relationshipsbetween ancestry, the tumor microenvironment, socialdeterminants of health, and breast cancer survival to address this disparity.

What’s next: Her team will utilizepatient samples from a cohort of 100 patients with breast cancer from the African diaspora. They will focus on the immune cells within the tumor microenvironment and assess how they influence tumor response. Her team will also examine how social determinants of health such as obesity, diet, and psychosocial health may influence the tumor microenvironment to alter immune responses. These analyses in concert with patient outcomes data will help identify how multiple factors can influence breast cancer disparities.

Goal: Developing a new strategy to improve the efficacy of immunotherapy in metastatic breast cancer (MBC).

Impact: Researchers are focused on harnessing the power of the immune system to eliminate breast cancer. Dr. Welm has found a promising novel target for immunotherapy and key mediator of breast cancer metastasis--sfRON. This target influences the host immune system not the tumor itself and allows the tumor cells to escape immune surveillance and metastasize. Dr. Welm found that blocking sfRON prevented metastasis and is now deciphering the mechanism of action.

What’s next: Dr. Welm showed that sfRONincreases specific immune cells around tumors and is testingexisting RON inhibitors in combination with immunotherapy to block the process. Her team will leverage laboratory models they created to mimic the metastatic tumor environment to study the effects of RON inhibitors. She hopes the results will warrant moving this combination strategy into the clinic to treat MBC.

Goal: Identifying genetic determinants of treatment-related comorbidities in Black patients with early-stage breast cancer

Impact: Non-Hispanic Black (NHB) women are two times more likely to die after a breast cancer diagnosis than non-Hispanic white (NHW) women in metropolitan Atlanta. Following treatment, other illnesses are observed more frequently in NHB than NHW women and contribute to poor survival. These illnesses are classified as treatment-emergent comorbidities. Polygenic risk scores (PRS) are a composite of genetic variants within an individual’s DNA that may indicate a level of risk for developing a disease.

What’s next: The team will conduct a study of NHB and NHW women with early stage, HR-positive/HER2-negative breast cancer. Patients will undergo testing to assess genetic differences that might be associated with treatment-related comorbidities. Identifying genetic predictors of these comorbidities will enable physicians to personalize care, support proactive preventative interventions, and select treatments that are more effective, less toxic, and improve overall survival.

Goal: To understand the origins of breast cancer.

Impact: The underlying cause of most breast cancers is unknown. Continuous funding from BCRF enabled Dr. Rennert and his team to develop one of the largest breast cancer studies in the world, incorporating 30,000-plus individuals—of Israeli and Arab descent—with and without breast cancer. This study now has20 years worth of data that inform health habits and risk factors and trends in breast cancer incidence and mortality. Biological samples from this study, collected and analyzed over time, now benefit from new analytical technologies such as artificial intelligence and are subjected to retroactive tests to develop new insights.

What’s next: In the coming year, the team will continue to study women who developed cancer early (before age 45). They will continue to build a comprehensive dataset with individualized information on genetic mutations and biological drivers that may increase breast cancer risk.

Goal: To improve response to immunotherapy in triple-negative breast cancer (TNBC).

Impact: A clinical trial tested the combination of immunotherapy with chemotherapy in TNBC and was recently extended to high- risk HER2-positive breast cancer. Dr. Gianni’s team analyzes samples from these trials to understand the mechanism of immune resistance and sensitivity to develop better immunotherapy strategies. They have discovered that unique interactions between specific types of immune and tumor cells in these patients might inform who benefits most from immunotherapy.

What’s next: The team will continue to analyze the complex molecular and genetic data gleaned from these important trials to discover relevant and predictive biological indicators that indicate which patients would benefit from these types of immunotherapies.

Goal: To identify new strategies for the prevention and treatment of aggressive breast cancers.

Impact: Dr. Merajver studies inflammatory (IBC) and triple-negative breast cancers (TNBC), breast cancers that often spread to other vital organs. She and her team are studying the networks these cancer cells form when they spread and are developing new avenues to attack these cells as they are spreading by interfering with their mobility throughout the body and the energy they need to survive.

What’s next: Dr. Merajver’s team is aiming to identify and exploit metabolic vulnerabilities of cancer cells and develop unique laboratory models and devices, which closely mimic environments where cancer cells spread. These novel systems and devices will allow the team to develop better drug screening methods, model the activity of drugs in a more realistic environment, and allow for better therapeutic options for patients with aggressive breast cancer.

Goal: Improving immunotherapy in breast cancer.

Impact: Cellular immunotherapies, which cultivate a patient’s own immune cells so that they recognize and target tumors, are highly effective in blood cancers but less effective in "solid” cancers like breast cancer. The primary challenge in breast cancer is that cellular immunotherapies fail to penetrate the tumor, which prevents them from working effectively.

What’s next: Dr. Emelianov and his team successfully devised a novel strategy to safely deliver immune cells directly to tumors. In the coming year, the team will continue to improve immune cell delivery and infiltration to tumor tissue and test their method for its efficacy in eliciting a robust immune response. Their results may provide a way to customize and improve immunotherapy, predict outcomes, and plan a better treatment.

Goal: Predicting breast cancer risk and enhancing our understanding of preventive therapy.

Impact: Analysis of biobanked samples—blood, tissue, and clinical data from consenting patients—is critical for cancer research. Mountains of data can be gleaned from biobanks, and Drs. Francis, Cuzick, and their teams are pioneers in leveragingthe biobanked data to expand our understanding of breast cancer prevention. Their studies may assist with the development of personalized treatments.

What’s next: Prevention research is a long-term game as it takes many years of follow-up to ensure that preventive measures are effective. In the coming year, the team will continue to add digitized data from ongoing, imminent clinical trials to their databank to further explore correlative factors including patient hormone levels and prognostic biological indicators using new artificial intelligence-based technologies.

Goal: Predicting breast cancer risk and enhancing our understanding of preventive therapy.

Impact: Analysis of biobanked samples—blood, tissue, and clinical data from consenting patients—is critical for cancer research. Mountains of data can be gleaned from biobanks, and Drs. Francis, Cuzick, and their teams are pioneers in leveragingthe biobanked data to expand our understanding of breast cancer prevention. Their studies may assist with the development of personalized treatments.

What’s next: Prevention research is a long-term game as it takes many years of follow-up to ensure that preventive measures are effective. In the coming year, the team will continue to add digitized data from ongoing, imminent clinical trials to their databank to further explore correlative factors including patient hormone levels and prognostic biological indicators using new artificial intelligence-based technologies.

Goal: Developing a new, blood-based screening tool for detecting breast cancer.

Impact: Dr. Brewster and her team developed a new technology to detect exosomes, which are small particles secreted by cancer cells. This technique could provide a sensitive, easily accessible, and noninvasive method for the early detection of breast cancer and provide guidance on the frequency of other types of screening.

What’s next: The team will conduct a study to rigorously evaluate the performance and reliability of this technology by detecting exosomes in the blood of women one to two years before their breast cancer diagnosis. The team will also assess perceptions and preferences for this form of screening from a cohort of women at high risk of developing breast cancer. The findings could translate into increased rates of screening, earlier detection, and decreased mortality associated with breast cancer.

Goal: Identifying genetic markers that can help select the optimal endocrine therapy for individual patients with hormone receptor- positive breast cancer.

Impact:While endocrine therapy has proven effective in many patients with estrogen receptor-positive breast cancers (affecting ~1M per year globally), some do not respond as well or experience such intolerable side effects that they suspend therapy. The research team is studying the mechanisms by which a patient’s individual genetic makeup can affect tolerance and response to endocrine therapy.

What’s next: The team is extending its approaches to include state of the art techniques to identify genes and their functions associated with disease progression and response to endocrine therapy, such as aromatase inhibitors (AIs).They will build on the biomarkers they have already identified to further understand the mechanism of AI-resistant estrogen receptor positive breast cancer.

Goal:Identifying genetic markers that can help select the optimal endocrine therapy for individual patients with hormone receptor- positive breast cancer.

Impact: While endocrine therapy has proven effective in many patients with estrogen receptor-positive breast cancers (affecting ~1M per year globally), some do not respond as well or experience such intolerable side effects that they suspend therapy. The research team is studying the mechanisms by which a patient’s individual genetic makeup can affect tolerance and response to endocrine therapy.

What’s next: The team is extending its approaches to include state of the art techniques to identify genes and their functions associated with disease progression and response to endocrine therapy, such as aromatase inhibitors (AIs).They will build on the biomarkers they have already identified to further understand the mechanism of AI-resistant estrogen receptor positive breast cancer.

Goal: Developing vaccines to lower the risk of developing breast cancer.

Impact: Metastatic triple-negative breast cancer (mTNBC)-cancer that has spread beyond the breast to other organs of the body-has few treatment options and is therefore very difficult to cure. Dr. Disis and her team are addressing this challenge by developing combination approaches utilizing immunotherapy and chemotherapy. They developed a vaccine called STEMVAC which can recognize multiple breast cancer antigens, tested it in a Phase I clinical trial, and optimized the vaccine and dosing schedule. They are now examining the efficacy of using the STEMVAC alone and in combination with chemotherapy in laboratory models of NBC. The team has also created a novel vaccine called ADVac (adipocyte-directed vaccine) for further development.

What’s next: The team will conduct a study in laboratory models to determine the extent ADVac immunization can reverse metabolic dysfunction at the tumor and prevent cancer development. They will also collect data that will help quickly identify where ADVac-specific T- cells go in the body after vaccination and if beneficial changes in inflammation patterns are observed in other organs. The addition ofthe drug metformin will also be tested for improved vaccine efficacy and prevention of tumor development.