W. Fraser Symmans, MD

2009-2010 BCRF Project:
The quality and preservation of a clinical sample is critical for the reliability and accuracy of any laboratory test result. Indeed, concerns about the reliability of current standard breast cancer tests have been raised in both professional and public discourse, and have led to recent guidelines to improve standardization of sample preparation and interpretation. It would be advantageous to anticipate the implications of breast cancer sample quality on emerging molecular diagnostic technologies. For these new tests, the improved quality of information from precise quantification of many molecules is offset by even greater reliance on a representative sample with acceptable molecular integrity for accurate measurement.

Focused studies in this area should establish evidence-based standards to interpret whether a sample and assay quality are appropriate for reporting test results. Dr. Symmans leads a multi-center study to evaluate inter-laboratory, inter-sample, and inter-technology reproducibility of microarray-based tests which is now active at five sites around the country and high quality samples have been collected from 120 consenting patients to date. A minimum of 125 and up to 245 samples can be collected, so the prospective accrual is proceeding very well. Pilot analyses have so far illustrated high reproducibility (without bias) between laboratories and between different types of sample (cytologic versus tissue samples), but there appears to have been a bias introduced to the results of a multi-gene test when they were compared in different generations of microarray technology. Dr. Symmans recently was awarded a contract from the National Cancer Institute to complete the Affymetrix microarray profiling for this study, thanks in large part to early support from BCRF that led to the demonstration that a multi-center collaboration can actually conduct this type of research.

Separately, Dr. Symmans and colleagues have developed a microarray-based predictive signature that can be measured from a routine biopsy of breast cancer at the time of diagnosis or surgery in order to predict whether a person with newly diagnosed breast cancer would benefit from chemotherapy containing a sequence of paclitaxel (Taxol) and anthracycline-containing chemotherapy. This test is currently undergoing formal validation studies to independently evaluate its accuracy in samples from other patients with breast cancer who received chemotherapy containing paclitaxel. The researchers are also interested to learn whether this test is limited in its application to paclitaxel, or whether it is also predictive when the related treatment of docetaxel (Taxotere) is used instead of paclitaxel. Preliminary data from 57 patients who received pre-operative chemotherapy containing docetaxel suggests that the test has predictive potential for docetaxel.

Since this is another standard chemotherapy treatment option for people with newly diagnosed breast cancer, the researchers believe it is important to proceed to a formal analysis of samples from patients with known follow up, to understand whether predictions from this test could be applied to docetaxel containing treatment. This study will compare the predicted response to chemotherapy with actual survival (distant relapse free survival) in 227 patients who received post-operative chemotherapy with a regimen of fluorouracil, epirubicin and cyclophosphamide, then followed by docetaxel (FEC/T). The predictive testing will be performed in Dr. Symmans' laboratory using gene expression microarrays to measure the expression of specific breast cancer genes in each patient's original breast cancer sample (without any knowledge of outcomes), and those test results will then be forwarded to the patients' treating institution for an independent comparison with their known outcomes from at least three years after their surgery. Specifically, this study has been designed to have 90% power to identify a reduced risk for distant relapse of more than two-thirds for the patients whose breast cancer gene expression signature predicted responsiveness to chemotherapy, compared those who are predicted to be non-responsive.

Bio:
Dr. Symmans is Professor of Pathology at The University of Texas MD Anderson Cancer Center where he practices Breast Surgical Pathology and Cytopathology and co-directs the Breast Cancer Pharmacogenomics Program.

Dr. Symmans received his medical degree from the University of Auckland, New Zealand in 1987. He completed his residency training in Anatomical Pathology at Columbia University College of Physicians and Surgeons, New York City and fellowship training in Cytopathology at MD Anderson Cancer Center, Houston. Dr. Symmans joined the faculty of New York University Medical Center in 1993 and moved to MD Anderson Cancer Center in 2000.

Dr. Symmans' research is focused on breast cancer, with specific emphasis on neoadjuvant (pre-operative) treatment trials for evaluation of chemosensitivity and development of diagnostic tests to select the most effective treatments for individuals with breast cancer. Dr Symmans has adapted genomic technologies to clinical needle biopsies of breast cancer in order to use gene expression profiling to identify important genes for response to chemotherapy and, independently, to endocrine therapy; to validate gene expression tests with clinical potential; and to establish their performance in the context of clinical testing.