GAITHERSBURG, MarylandResearchers have identified 18 genes that behave similarly to estrogen-receptor-alpha (ESR1) in patients with estrogen-receptor-positive (ER-positive) breast cancer. The cluster includes seven genes not previously associated with estrogen regulation or with breast cancer, Mihael H. Polymeropoulos, MD, head of pharmacogenetics, Novartis Pharmaceuticals Corporation, told ONI in an interview.
Dr. Polymeropoulos and his colleagues described the cluster in an article in The Pharmacogenomics Journal (1:135-141, 2001). He said that some activity in the cluster might be coincidental to breast cancer, but all 18 genes should be investigated as potential biomarkers for predicting how individual patients will respond to endocrine therapies such as tamoxifen(Drug information on tamoxifen) (Taxol) and letrozole(Drug information on letrozole) (Femara). "This is the beginning of customizing the treatment of breast cancer," he told ONI.
ER-positive breast cancers are less likely to relapse and have better overall survival rates, he said, but about half do not respond to antiestrogens or estrogen-deprivation therapy. The hope is that supplementing ESR1 with additional markers will help physicians differentiate tumors by their genetic fingerprints and choose treatments accordingly.
The following seven genes had not previously been linked to estrogen stimulation or breast cancer: SCNNIA, SERPINA3, ASAH, LCN1, TGFBR3, GRIA2, and CYP2B. The other genes in the cluster are: CEACAM5, MGB1, LIV-1, PIP, MGP, TFF1, TFF3, HNF3A, HPN, XBP1, and AZGP1.
Dr. Polymeropoulos’ group found the genes via a DNA microarray, which can analyze gene expression at the level of RNA. In this process, he said, small glass slides containing minute amounts of thousands of known genes are matched against each biopsy sample. The gene "chips" on each slide can rapidly detect which of the thousands of genes are expressed in a human tissue sample.
In this study, the investigators examined gene expression for 7,000 genes in RNA taken from 53 breast tumors and from six other samples, including pooled normal breast tissue. That was as many genes as could be studied at the time, but Dr. Polymerop-oulos predicts that all 30,000 or more genes in the human genome will eventually be screened for overexpression in ER-positive breast cancer.
Twenty-one RNA samples in the study came from a randomized phase III clinical trial of letrozole vs tamoxifen that led to the FDA’s approval in January 2001 of letrozole tablets as a first-line hormonal treatment for advanced breast cancer in postmenopausal women.