Professor, Department of Pathology
Director, Pathology Tissue Services
Director,Translational Science in Pathology
Yale University School of Medicine
New Haven, Connecticut
Co-Investigator: Lajos Pusztai, MD, D. Phil, Yale University School of Medicine
This project led by Drs. Pusztai and Rimm is the continuation of two studies related to targeted therapy in breast cancer. The first study analyzes DNA from HER2-positive (HER2+) breast cancers that were obtained from cancer biopsies from patients who participated in the randomized clinical trial NeoALTTO. This clinical trial tested the anticancer activity of lapatinib and trastuzumab or the combination of both of these drugs as preoperative treatment given together with paclitaxel chemotherapy for early stage (stage I to III) breast cancers. Biopsies of the cancer were taken before any therapy and at the time of the surgery to sample cancer cells that were not eliminated by the therapy. The purpose this study is to identify mutations in genes that could predict who will benefit from these drugs and to identify what mechanisms lead to resistance to these therapies.
A second study, running in parallel, is related to immunological targets. Recently, therapies have been described for lung cancer and melanoma that use the body's own defense mechanisms to attack the tumor. Some tumors develop a "cloaking device" which makes the tumor invisible to the normal immune system. The new therapy blocks the cloaking signals on the tumor cells which result in T-cells attacking the tumors. When the T-cells are turned on, they are a formidable therapy and about a third of the patients that have received this therapy have experienced long term benefit or possibly cure. These therapies are now being testing in breast cancer. The goal of this project is the molecular characterization of breast cancer tumors with respect to their immune status to predict and ultimately test response to these next generation immune therapies.
Drs. Rimm and Pusztai are analyzing genomic material (DNA) from HER2-positive breast cancers that were obtained from cancer biopsies from patients who participated in the randomized clinical trial NeoALTTO. This clinical trial tested the anticancer activity of lapatinib and trastuzumab or the combination of both of these drugs as preoperative treatment given together with paclitaxel chemotherapy for early stage (Stage I-III) breast cancers. The initial results of the trial were published two years ago and the first survival endpoint was reported in December 2013. DNA has been extracted from the initial biopsy from each patient and the researchers have received the DNA and completed the technical part of whole exome sequencing on 225 patients. In an effort led by expert bioinformatician, Christos Hatzis, they are beginning the quality analysis and ultimately the detailed genomic analysis to determine which genetic alterations are associated with response to resistance to lapatinib, trastuzumab or both.
The second half of this project is related to immune therapy. In Melanoma and Lung Cancer, great strides have been made in treatment of high stage disease with a therapy that interrupts the mechanism that tumors use to hide from the host immune system. This molecular axis, called the PD1 axis, when interrupted by a number of targeted therapies, causes the patients’ immune system to attack the cancer. In a subset of patients this has led to complete response and long term survival. The researchers proposed to study this axis in breast cancer. They have measured both PD-L1 and immune cells in three different breast cancer cohorts and are now completing the data analysis. Over the next 6-9 months, they will determine the relationships between these molecules and others in the PD1 pathway with each subtype of breast cancer.
Dr. David Rimm is a Professor in the Department of Pathology at the Yale University School of Medicine. He completed an MD-PhD at Johns Hopkins University Medical School followed by a Pathology Residency at Yale and a Cytopathology Fellowship at the Medical College of Virginia. Dr. Rimm is the Director of Yale Pathology Tissue Services and the Executive Director of Translational Science in Pathology. His lab group (15 researchers) focuses on quantitative pathology using the AQUA® technology invented in his lab with projects related to predicting response to therapy in breast cancer and predicting recurrence or metastasis in melanoma and lung cancer. The technology has also been used in a series of efforts related to biospecimen science. He is an author of over 250 peer-reviewed papers and holds eight patents and was a scientific co-founder of HistoRx, a digital pathology company (sold to Genoptix in 2012) and Metamark Genetics, a prognostic determinant company.