A new DNA-based sequencing technique-Sequence Based Diagnosis (SBD)-that determines p53 gene status in primary breast cancers, yields better prognostic information than standard immunohistochemistry, according to a study in the February 20, 1996, issue of the Journal of the National Cancer Institute. The findings may have important implications for some of the over 180,000 US women diagnosed annually with breast cancer.
"These are important findings for women and their physicians who, every day, must make decisions about therapy," said Jonas Bergh, MD, associate professor of oncology at University of Uppsala, and a director of the study. "The goal of clinical research must be that we will be able to treat these women more intelligently and efficiently."
Since cancer develops in stages through a step-by-step breakdown of the mechanisms that control normal cellular growth, an accumulation of genetic changes has been identified as a key event in the progression of the disease. p53, a tumor-suppressor gene, is located on the short arm of chromosome 17; mutations of the p53 gene are considered to be a critical step in the development of certain tumors.
Study Results
The JNCI study compared the effectiveness of a cDNA-based sequencing method developed by Pharmacia Biotech AB, Sequence Based Diagnosis (SBD), with the standard method, immunohistochemistry (IHC), in detecting p53 mutations in breast cancer specimens and in determining the prognostic value of the information obtained using these methods.
The study showed that the SBD technique is superior to IHC in detecting p53 status and determining prognosis in breast cancer. Specifically, 23 breast cancers with p53 mutations detected by SBD did not generate a positive IHC reaction, suggesting that IHC failed to detect 33% of the mutations. Also, 19 of the IHC-positive tumors sequenced negative, indicating a 30% false-positive rate with IHC.
"The importance of Sequence Based Diagnosis cannot be overstated," said Margaret Bywater, MedPhL. "For years, we've been aware of the relevance that emerging molecular techniques can have in evaluating tumor development, determining prognosis, and ultimately, guiding choice in therapy. It is gratifying to see confirmation of this work." Dr. Bywater, a pioneer of the SBD technique and former director, molecular medicine, market development, Molecular Systems Division, at Pharmacia Biotech, is currently a consultant to the industry.
The current article is the final installment in a landmark three-part study of 316 Swedish women operated on for breast cancer from January 1987 through December 1989. The study represents the first complete sequencing of the p53 gene in a large retrospective study of a population-based cohort. Earlier published articles on this study have shown that complete sequencing of the p53 gene will potentially lead to more tailored regimens and, ultimately, improve patient survival.
The study was supported by grants from Pharmacia Biotech, Uppsala, Sweden and the Swedish Cancer Society, and was conducted at the Uppsala Akademisk University Hospital, Sweden.
To further establish the clinical utility of p53 mutation status as a potential marker to better predict response to therapy in breast cancer disease management, Pharmacia Biotech will begin work in 1996 on a joint project with Pharmacia & Upjohn (Milano), the company's headquarters for the oncology treatment product portfolio.
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