DNA sequence analysis of the complete p53 tumor-suppressor gene
provides predictive information about breast cancer patients'
response to therapy, according to a study published in the October
1995 issue of Nature Medicine. The study analyzes the associations
between tumor mutations and patient outcome--especially in relation
to therapy--using Sequence-Based Diagnosis, (SBD), a new concept
for complete DNA sequencing. Although previous studies have examined
p53 using various molecular biologic methods, this study represents
the first complete sequencing of the p53 gene in a large retrospective
study of a population-based cohort. The study also confirms that
since mutations are found over the entire coding sequence, some
could be missed using traditional DNA analysis protocols.
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 progression
of the disease. p53 is a tumor-suppressor gene located on the
short arm of chromosome 17. In breast cancer, mutations of the
p53 gene have been considered to be a critical step in the development
of certain tumors. These alterations can be determined using immunohistochemistry
or DNA analysis, which reveals prognostic information.
"We hope that the results from this study will, in the future,
lead to the development of more tailored treatments for breast
cancer patients," said Jonas Bergh, MD, associate professor
of oncology and director of the study. "If we can more accurately
determine the effects of therapy, we may be able to reduce the
costs of treatment in patients with less aggressive tumors, and
at the same time, develop more aggressive regimens for those with
Commenting on the findings, Barbara Lynn Weber, MD, associate
professor of medicine and genetics and director of the Breast
Cancer Program, University of Pennsylvania School of Medicine,
said, "Increasing numbers of breast cancers are being diagnosed
at the early stages, when the tumors are small and have not spread
to distant parts of the body. Traditional prognostic factors,
including tumor size and lymph node involvement, are limited and,
as tumors are detected earlier, new, more precise methods are
needed to select individualized treatment regimens."
Study Results Differ for Lymph Node-Positive vs Node-Negative
Conducted at the Uppsala Akademiska University Hospital in Sweden
in cooperation with Pharmacia Biotech and the Swedish Cancer Society,
the study analyzed frozen tumor material from a total of 316 consecutive
Scandinavian women who underwent surgery for breast cancer from
January 1987 through December 1989. The complete coding region
of the p53 gene was sequenced and 69 mutations were discovered
using the automated laser fluorescence ALF DNA sequencer, developed
by Pharmacia Biotech.
A total of 97 patients had primary lymph node metastases and 206
were node-negative. In 13 cases, the node status of the patient
was unknown, since axillary exploration was not performed. The
median follow-up time was 57 months.
Lymph node-positive patients with p53 mutations had a significantly
shorter survival rate, compared with those without these mutations.
Therapy, especially adjuvant tamoxifen, seemed to be of less value
in lymph node-positive patients with p53 mutations than in patients
without these mutation. For node-negative patients with p53 mutations,
tamoxifen and/or locoregional radiotherapy resulted in improved
relapse-free survival; however, adjuvant tamoxifen and/or locoregional
therapy seemed to be of less value in node-negative patients with
In addition, the location of the mutations in the p53 gene differed
between the lymph-node-positive and lymph-node-negative groups,
which may explain the discriminative power of p53 alterations
to predict response to adjuvant therapy.
"For more than a decade it has been apparent that molecular
techniques can provide the answers for improved understanding
of tumor development," said Margaret Bywater, an initial
pioneer of the SBD technique and director, molecular medicine,
market development, Molecular Systems Division, at Pharmacia Biotech.
"With the automation of these techniques, the true relevance
of each mutation can be evaluated and genetic information obtained
from tumor biopsy will, in the future, be used for prognosis and
guiding the choice of therapies."