Director, Women's Cancer Research Center
University of Pittsburgh Cancer Institute
The long-term goal of Dr. Lee’s studies is to improve prediction of breast cancer prognosis and response to therapy. For many years, pathologists have recognized the tremendous differences not only between breast cancers, but also within a cancer. These differences are often termed “tumor heterogeneity.” Breast cancers often contain multiple differentiated cell types, and biomarkers differ not only between patients, such as estrogen receptor-positive (ER+) and ER-negative cancers, but also within a cancer with regions of both positive and negative staining, so called intra-tumor heterogeneity (ITH). Recent DNA sequencing studies have revealed tremendous ITH in breast and other cancers. Multi-gene tests (MGTs) have furthered the definition of different subtypes of breast cancer and provided new measures of prognosis. However, these tests are all performed on whole crushed up tissue, and while they can report on differences between breast cancers, they cannot report on differences within a cancer. Finally, while there has recently been a tremendous effort to describe ITH in breast cancer, the clinical significance of ITH is poorly understood.
Dr. Lee’s group has recently examined how MGTs (OncotypeDX, PAM50, Mammaprint, BCI, EndoPredict) differ within specific regions of a tumor, and specifically for OncotypeDx, compared recurrence risk scores (RSS) from different regions of a tumor, and the effect this would have on risk stratification compared to clinical measurement. They found that, in ~20% of cases, specific regions of a breast cancer gave risk stratification that was different than that based upon the whole tumor. Dr. Lee and colleagues believe this is the first example of the direct clinical significance of ITH on MGT prediction of prognosis and therapeutic decision making. They are now ready to directly test whether breast cancers that recur show high ITH compared to those that do not recur. As the immediate future in prognostic testing likely will not allow for multiple tests on every patient biopsy (due to time, expense etc.), Dr. Lee will develop methods and tools for defining and quantifying molecular heterogeneity from whole crushed up samples, and using quantification of ITH to scale MGTs and improve risk prediction. His long-term goal is to measure biomarkers in situ using a novel hyper-plexed imaging system (MxIF) which has the potential to revolutionize prognostic biomarker measurement.
Dr. Lee’s team previously found that multi-gene tests (MGTs) for predicting patient prognosis can differ when they are performed on different regions of a tumor. To investigate this further, they are examining the underlying genomic heterogeneity in these regions to see if this accounts for the molecular diversity. They are also testing new methods to examine biomarkers heterogeneity in breast cancer. To do this they have first generated a tissue microarray (TMA) containing a spectrum of breast cancers and breast cancer cell lines. They will optimize methods to analyze biomarker expression and then examine the heterogeneity of their expression in breast cancer. Their ultimate goal is to determine whether tumor heterogeneity is a poor prognostic indicator.
Dr. Adrian Lee is Director of the Women’s Cancer Research Center at the University of Pittsburgh Cancer Institute. He obtained his doctorate in Breast Biology from the University of Surrey in Guildford, UK and trained as a post-doctoral fellow at the University of Texas Health Science Center at San Antonio.
The goal of Dr. Lee’s laboratory is translational breast cancer research. The laboratory has two main areas of focus. The first involves targeting the insulin-like growth factor pathway in breast cancer. The second area of Dr. Lee’s research is studies on tumor heterogeneity and molecular changes during progression, with a particular focus on DNA and RNA structural rearrangements. Dr. Lee’s laboratory participated in the first comprehensive report of structural rearrangements in a breast cancer cell line (MCF7) and last year reported on a novel massively parallel fosmid-based mate-pair assay for determining structural rearrangements. This work focuses on different tumor areas, or tumors from different parts of the body (obtained via rapid autopsy) to identify novel changes that may offer therapeutic insight. In addition, the University of Pittsburgh is the largest contributor of tissue to The Cancer Genome Atlas (TCGA), and many results are validated in these index cases.