ASCOGenomic resequencing of DNA in blood samples from
the Breast Cancer Prevention Trial (BCPT) conducted during the 1990s shows that
tamoxifen (Nolvadex) reduced the incidence of breast cancer by 62% in women
with BRCA2 mutations, but had no effect in women with BRCA1 mutations.
Mary-Claire King, PhD, American Cancer Society Professor,
University of Washington, Seattle, presented the preliminary data in a special
report at the 37th Annual Meeting of the American Society for Clinical Oncology
(ASCO) without prior announcement or abstract. She described the new results as
consistent with studies that show tamoxifen to be effective against
estrogen-receptor (ER)-positive tumors, but not ER-negative tumors.
"None of this bears in any way on the usefulness of
tamoxifen for treating breast cancer," Dr. King cautioned. "Our data
bear on incidence, not on treatment."
Conducted by the National Surgical Adjuvant Breast and Bowel
Project (NSABP), the BCPT established that daily doses of tamoxifen could
reduce the breast cancer risk in high-risk women by 49%. The NSABP halted the
trial in 1998, so that all 13,000 participants could have access to tamoxifen.
In 1999, it began the comparative Study of Tamoxifen and Raloxifene (STAR)
Dr. King’s laboratory did the resequencing study in
collaboration with the National Cancer Institute and the NSABP. The new results
focus on 288 of 315 women who developed invasive breast cancer during the
When these women entered the trial, BRCA1 had been mapped but
not cloned, and BRCA2 had not yet been mapped, Dr. King said. Blood samples
were taken at the outset, however, and stored. The researchers extracted DNA
from these samples for genotyping.
For about 10% of the women who developed invasive breast
cancer, Dr. King said, no sample could be found, or the sample did not yield
sufficient DNA, or the woman declined to have her sample used for the study.
In all, about 24,000 base pairs in each sample8,000 in BRCA1
genes and 16,000 in BRCA2 geneswere sequenced, Dr. King said. Counting
forward and reverse sequencing and overlaps in the sequences, she estimated the
total number of base pairs reviewed at more than 40 million. "This is
certainly the largest genomic resequencing project that has been undertaken to
address a clinical question," she said.
The data she presented show that about 7% of the women who
developed invasive breast cancer during the trial and were sequenced had a
BRCA1 or BRCA2 mutation. Eight of the women who developed breast cancer were
found to have a BRCA1 mutation: 5 had been randomized to tamoxifen and 3 to
placebo. A BRCA2 mutation was found in 11 of the women who developed breast
cancer: 3 had been randomized to tamoxifen and 8 to placebo.
Based on these data, Dr. King calculated the risk ratio for
women given tamoxifen vs women given placebo as 1.67 for women with BRCA1
mutations, 0.38 for women with BRCA2 mutations, and 0.48 for women with wild
type versions of the two genes. "And as one would expect, 0.48 is very
close to the overall value for the prevention trial as a whole of 0.51 for all
women," she said.
Dr. King said that the data are only suggestive because the
number of women who had a BRCA1 or BRCA2 mutation was small. Nonetheless, she
maintained that the results could be interpreted in the context of biology.
To that end, Dr. King cited studies indicating that about 80%
of invasive breast cancers are ER negative in women with inherited BRCA1
mutations and 80% are ER positive in women with inherited BRCA2 mutations.
"This same fraction (80%) obtains for the women in the trial," she
The risk ratios for tamoxifen vs placebo for breast cancer
incidence were also similar: 1.23 for ER-negative tumors and 1.67 for
participants with BRCA1 mutations, and 0.32 for ER-positive tumors and 0.38 for
participants with BRCA2 mutations.
In an interview after the talk, Dr. King said that she thinks
the data may be understated. The number of women in the study with BRCA1 and
BRCA2 mutations was probably lower than in the real world, she said, because
the mutations often lead to cancers in women younger than the minimum age of 35
years for participation in the trial.
In addition, she suspects some women from families with severe
histories of breast cancer chose to have double mastectomies rather than enter
a trial that might place them on placebo.
Dr. King’s talk was tagged on to an ASCO special session at
which Nobel Laureates J. Michael Bishop, MD, and Harold Varmus, MD, and other
speakers discussed the growing influence of molecular biology on oncology.
ASCO president-elect Larry Norton, MD, hailed the study as
"provocative and extraordinary." He described the prospect of
molecular diagnosis, molecular classification, and molecularly targeted
therapies as a "holy grail" for which oncologists have been waiting a
long time. "To see it start to happen now in real time is profoundly
exciting," he said.