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.
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
"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
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