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
Project 1: Dr. Pusztai is studying if different regions of a single cancer or different metastatic sites in the same patient contain genetically different cancer cells. The purpose of this research is to determine whether and how these genetic differences within the same tumor would affect treatment effects and patient outcome. Previously, Dr. Pusztai’s team examined DNA sequences from matching breast cancer and metastatic sites and found that the metastatic sites often carry new mutations and differ not only from one another but also from the primary cancer in the breast. In the next phase of this research they will examine and if this genetic heterogeneity of the cancer influences treatment response and survival.
Project 2: Dr. Pusztai will collaborate with Dr. David Rimm at Yale in a project that utilizes new sequencing technologies to study if different regions of a single cancer or different metastatic sites in the same patient contain genetically different cancer cells. This project 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.
Another component of the 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.
Project 1: In the current phase of their research, Dr. Pusztai and his team are examining if biopsies obtained from the same primary breast cancer at different locations yield different biomarker results. They compare the genomic abnormalities seen in different regions of the same cancer. They are also studying if the degree of tumor heterogeneity at the genomic level correlates with response or resistance to chemotherapy. In the past six months all data acquisition has been completed and the researchers are now analyzing the results.
Project 2: 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. Lajos Pusztai is Chief of the Breast Medical Oncology Section at Yale University Cancer Center and Co-Director of the Cancer Center Genomics and Genetics Program at Yale. He previously led the breast cancer pharmacogenomics program at University of Texas MD Anderson Cancer Center (MDACC). 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 and therefore should be considered different diseases. They have shown that different biological processes are involved in determining the prognosis and treatment response in different breast cancer types. They also demonstrated that a subset of basal-like (ER- and HER2-negative) breast cancers have significantly higher chemotherapy sensitivity than ER positive cancers and demonstrated the statistical pitfalls of conducting clinical trials that include both ER-positive and ER-negative breast cancer (that contributed to the numerous contradictory results generated by older randomized adjuvant chemotherapy trials). They also showed that the epidemiological risk factors of triple negative breast cancer (e.g. lack of breast feeding and multiparity) are distinct from those of ER-positive cancers.
Dr. Pusztai has played an important role in evaluating gene expression profiling as a diagnostic technology and particularly as a potential predictive test for chemotherapy and endocrine therapy sensitivity. During this process, his team developed several new bioinformatics algorithms to identify informative genes. Through collaboration with a large number of academic and industry partners, this research ultimately has led to the recognition that drug-specific sensitivity signatures are currently not accurate enough for clinical use, however, general chemotherapy and endocrine sensitivity and prognosis can be predicted reasonably accurately for breast cancer. Dr. Pusztai and colleagues are using state-of-the-art technologies to identify novel therapeutic targets. They are also developing new bioinformatics tools that can enable them 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.