Andrea Richardson, MD, PhD, and Zhigang Charles Wang, MD, PhD
Researchers at Dana-Farber Cancer Institute have discovered a gene
activity signature that predicts a high risk of cancer recurrence in
certain breast tumors that have been treated with commonly used
Despite their resistance to drugs of the anthracycline class, the
breast cancers bearing this gene signature will probably still be
vulnerable to other types of chemotherapy agents, say scientists in a
letter to be published in Nature Medicine on its Web site and later in a print edition.
Thus, the findings could lead to a genetic test of breast cancers to
help physicians choose the best initial treatment for an individual
With this guidance, physicians could avoid the current
trial-and-error approach that in some cases exposes patients to the
toxic side effects of a cancer drug that is destined to be ineffective.
The new report underscores the potential of personalized cancer care, in
which knowing the specific molecular features of a patient's cancer
helps direct the course of care.
The investigators from the Dana-Farber Women's Cancers Program
undertook the studies to search for molecular traits in tumors that
cause some patients to suffer recurrences in the wake of breast cancer
surgery despite post-surgery, or "adjuvant," chemotherapy, while other
patients do well for many years.
Led by Andrea Richardson, MD, PhD, and Zhigang Charles Wang, MD, PhD,
the investigators identified two genes that, when abnormally active,
enabled cancer cells to resist the effects of drugs called
anthracyclines. This class of agents includes doxorubicin, daunorubicin,
and epirubicin, which are often used as adjuvant therapy in breast
The scientists probed stored breast tumor specimens from 85 patients
and found the gene signature associated with drug resistance in about 1
in 5 samples, according to the report. Clinical records on file showed
that those patients had poorer outcomes than those without the culprit
However, the overexpression of the two genes did not protect
laboratory-grown breast cancer cells against other classes of drugs,
including paclitaxel and cisplatin, reported Richardson, Wang, and the
first author, Yang Li, PhD.
"These results suggest that tumors resistant to anthracyclines may
still be sensitive to other agents," said Richardson, who is also on
faculty at Brigham and Women's Hospital and Harvard Medical School. "So
this would be very useful as a test to help pick the therapy that's
going to be most effective for these patients."
Such a tool should not be difficult to develop, she said, and could be available for clinical testing within a year or two.
It's been known that some breast tumors acquire, during the course of
treatment, altered genes or chromosomes that make them resistant to
many cancer drugs. But with one or two exceptions, "No tests are done
before treatment begins to predict who's going to be resistant or
sensitive to different compounds," says Richardson. "Most breast cancer
patients are initially given the same drugs."
Exceptions include patients whose tumors are spurred by estrogen and
are often less sensitive to any chemotherapy; hormonal treatment is
generally prescribed in that case. Also, breast cancers found to be
HER2-positive are treated with the antibody trastuzumab — another
example of "personalized" or tailored therapy.
In search of genetic alterations that might explain disease
recurrence despite treatment with adjuvant chemotherapy in some breast
cancer patients, the Dana-Farber scientists scanned the genome (all the
DNA) of stored breast cancer samples from patients who had been treated
according to modern guidelines, including the use of anthracyclines. The
samples had been taken in the operating room during breast surgery —
before any drug therapy had begun — and thus enabled the scientists to
look for DNA alterations that could be linked to the patients'
subsequent disease recurrence.
Richardson and Wang's laboratory team sifted the tumor DNA and
spotted a region on chromosome 8 that contained many redundant, or
amplified, copies in the drug-resistant tumors. They found that this
small region, labeled 8q22, was associated with a poor outcome in the
breast cancer patients. In parallel, they discovered that 12 genes in
that region were consistently "overexpressed" — making abnormal amounts
of protein — as a result of amplification. "This was the only region of
the genome that was tightly associated with poor outcomes despite the
adjuvant chemotherapy treatment," Wang noted.
Wang, Richardson, and colleagues singled out the genes in the region
that might be involved in tumors' drug resistance, based on their
structures and functions. They then experimentally narrowed the field to
two likely candidates — LAPTM4B and YWHAZ.
When the researchers knocked out the two genes' function in cancer
cells grown in the laboratory, the cells became vulnerable to
anthracycline compounds. Conversely, when the genes were overexpressed,
the cells resisted anthracycline compounds, but were killed by other
agents, cisplatin and paclitaxel.
To clinch their case, the researchers needed to carry out a blind
test in which they didn't know ahead of time which patients' tumors had
responded well to drug therapy. Fortunately, they learned of a Belgian
clinical trial in which breast cancer patients had been treated prior to
surgery with epirubicin — one of the anthracyclines — and their tumors
were studied to determine the drug's effectiveness. Among other things,
the researchers had obtained gene expression data from the tumors. The
Dana-Farber researchers used that data to predict the degree of
patients' tumors' response to the drug by measuring the LAPTM4B and YWHAZ activity in the tumors.
When their predictions were matched with the Belgian outcome data,
"it turned out that the expression level of these two genes was highly
associated with anthracycline resistance in the tumors," said
Eric Winer, MD, director of the Breast Oncology Center at
Dana-Farber, commented, "While this work remains preliminary, it may
ultimately help us use the anthracyclines in a much more thoughtful
manner and allow us greater ability to personalize our breast cancer
treatments to the tumor and the patient."
The research was supported by the Breast Cancer Research Foundation of New York and the US Department of Defense.