Professor of Medicine
Chief, Breast Medical Oncology
Co-Director, Yale Cancer Center Genetics and Genomics Program
Yale School of Medicine
New Haven, Connecticut Member, BCRF Scientific Advisory Board
Seeking strategies to improve response to immunotherapy in triple negative breast cancer (TNBC)
Clinical and laboratory studies are conducted to assess gene expression profiles of tumor cells and infiltrating immune cells to devise strategies to improve response to these therapies.
These studies will inform the design of rational combinations of immunotherapy drugs for early stage and metastatic breast cancer.
New immune therapies called checkpoint inhibitors have shown some success in triple negative breast cancers (TNBC), but most patients do not respond. In the past several years, Dr. Pusztai's team have been conducting studies to examine the interaction between the breast cancer gene mutation profile and the immune microenvironment of the tumor to devise strategies to improve response to these therapies.
He and his colleagues discovered that triple negative breast tumors that contained a high concentration of immune cells had fewer genomic abnormalities. Comparing immune cells in cancer tissues obtained before and after preoperative chemotherapy, they found that the number of immune cells, but not PD-L1 levels (the target of immune checkpoint therapy), decreased significantly after chemotherapy. This suggests that immune-rich cancers may benefit from immune therapy and led to the initiation of a preoperative immunotherapy trial (NCT02489448).
The continued presence of PD-L1 expression in cancers, however suggests that adjuvant immune checkpoint inhibitor therapy could improve survival. These findings led the team to initiate a large adjuvant clinical trial to test immune checkpoint therapy as adjuvant therapy for TNBC (NCT02954874).
Planned studies for the next year include: 1) Immune gene expression analysis of matching pre- and post-chemotherapy cancer tissues to better understand how chemotherapy affects the immune cells in breast cancer. 2) Count tumor-infiltrating lymphocytes (cancer fighting immune cells), assess PD-L1 protein levels, and immune genes in paired primary and metastatic cancer samples to study changes in the immune microenvironment during breast cancer disease. 3) Analysis of the genetic similarities of tumor-infiltrating T cells in breast cancer tissues.
Information obtained from this research will allow the design of rational combinations of immunotherapy drugs to treat early stage and metastatic breast cancer more effectively.
Dr Pusztai is Professor of Medicine at Yale University and Chief of the Breast Medical Oncology Section at the Yale Cancer Center. He is also Co-Director of the Cancer Center Genomics and Genetics Program. Dr. Pusztai received his medical degree from the Semmelweis University of Medicine in Budapest, and his D.Phil. degree from the University of Oxford in England. His research group has made important contributions to establish that estrogen receptor-positive and-negative breast cancers have fundamentally different molecular, clinical and epidemiological risk characteristics. He has been a pioneer in evaluating gene expression profiling as a diagnostic technology to predict chemotherapy and endocrine therapy sensitivity and have shown that different biological processes are involved in determining the prognosis and treatment response in different breast cancer subtypes. His group has also developed new bioinformatics tools to integrate information from across different data platforms in order to define the molecular pathways that are significantly disturbed in individual cancers and could provide the bases for future individualized treatment strategies. He made important contributions to clarify the clinical value of neoadjuvant chemotherapy in different breast cancer subtypes.
Dr Pusztai is also principal investigator of several clinical trials investigating new drugs and potential response markers. He has published over 200 manuscripts in high impact medical journals and is the Clinical Editor of the British Journal of Cancer, Member of the Scientific Advisory Board of the Breast Cancer Research Foundation, Member of the Breast Cancer Steering Committee of the NCI and Co-Chair of the Trans-ALTTO Committee that oversees the translational research projects of tissues collected during two larger randomized clinical trials (ALTTO and NeoALTTO). He is also Chair of the Data Safety Monitoring Committee of the OPTIMA trial.