Breast cancers are as diverse as the women who have them. Now
experts are using gene-based information to tailor
In the 1950s, breast cancer was treated as though it were a
single disease, with a "gold standard" therapy — radical
mastectomy, followed by radiation. Even that harsh regimen didn't
always prevent recurrence of the cancer, and by the 1970s,
cytotoxic chemotherapy had been added to the mix — powerful drugs
that kill rapidly dividing cells, both cancerous and normal.
That, too, had a price: nausea, hair loss, numbness, and "chemo
The one-size-fits-all approach wasn't due to medical ignorance.
Researchers had long suspected that breast cancers aren't all the
same. Some, they believed, could safely be eliminated by surgery
alone; others might respond to hormone treatments; and a few
might need chemotherapy. But no one knew which tumors would
respond to which treatments, so all breast cancer patients were
treated the same way — aggressively.
Now, thanks to advances in molecular biology, clinicians are
better able to make those distinctions. Breast cancer research
today is focused on identifying the specific genes and protein
receptors that can distinguish resistant forms of breast cancer
from those that are easier to eradicate. In the process, it's
become clear that breast cancer isn't a single disease, but
rather a collection of disorders that respond to widely varying
Discovering the role of receptors
It's been known since the 19th century that estrogen can fuel
breast cancer growth. But it wasn't until the 1960s that
scientists learned how: it locks onto a receptor molecule in the
cell nucleus and turns on genes that spur cell growth. The
discovery of estrogen receptors in breast cancer tissue led to
the development of estrogen-blocking drugs like tamoxifen
(Nolvadex). Tamoxifen not only cut the risk of recurrence in
women with estrogen receptor (ER)–positive breast cancer but also
became the first medical option for preventing breast cancer in
A decade later, researchers identified another receptor, called
HER2, which is the docking station for epidermal growth factor
beta, another hormone that can spur breast cancer growth. HER2 is
present in normal breast cells, but in about one-fifth of breast
cancers, it's present in abnormally high numbers — an indication
that these tumors are powered, in part, by high doses of growth
factor. Like ER-positive tumors, HER2-positive tumors can be
treated with a targeted drug. In this case, it's trastuzumab
(Herceptin), which blocks the receptors and inhibits cell
division. The addition of trastuzumab to standard chemotherapy
has dramatically reduced recurrence rates and improved survival
in women with HER2-positive tumors.
The BRCA breakthrough
All cancers are genetic diseases — that is, they're caused by
mutations in DNA, the molecule that carries the instructions
needed for the development and growth of cells, including cancer
cells. Individual sections of DNA, known as genes, encode
specific parts of the instructions, such as the code for
synthesizing a certain protein. In recent years, scientists have
discovered the genes responsible for at least some breast
cancers. In 1994, for example, they identified BRCA1 and BRCA2.
The normal versions of these genes produce proteins that repair
DNA, but the aberrant forms (mutations), which were identified in
women with inherited breast cancer, do not function normally,
making DNA vulnerable to many kinds of damage. We have two copies
of most genes, so women with an abnormal version of the BRCA gene
also have a normal one that can take over the job of DNA repair.
But 60% to 85% of these women eventually lose the function of the
normal gene in breast tissue, and they develop breast cancer
before age 70.
The discovery of the BRCA genes has transformed medical
approaches to prevention in women at high risk of the disease.
Because the mutant BRCA genes are present in every body cell,
they can be identified by a simple blood test. Women found to
carry one of the harmful gene mutations have several options:
screening via frequent mammograms and breast MRI, taking
tamoxifen to reduce the risk of breast cancer, or undergoing a
double mastectomy. Most women carrying a BRCA mutation opt to
have their ovaries removed, because the harmful BRCA genes also
raise the risk of ovarian cancer, for which there is no effective
early detection option and for which surgery reduces risk by more
More recent research has linked breast cancer to several other
mutated genes, including ATM, CDH1, CHEK2, p53, PTEN, and STK11.
However, the degree to which these mutations contribute to breast
cancer risk in the general population is unknown.
Acquired gene defects
Unlike breast cancer linked to the BRCA1 and BRCA2 genes, most
breast cancer isn't hereditary. Gene mutations are involved, but
they aren't passed down from generation to generation. Rather,
they crop up when errors occur in the process of DNA duplication
during cell division. Unlike inherited gene mutations, these
errors don't appear in all of the body's cells: they're found
only in breast tissue. A variety of environmental factors
increase the risk. Some, like radiation, damage DNA directly;
others, like aging, increase the number of cell divisions,
thereby providing more opportunities for the cell's copying
machinery to go awry. In breast cancer, two of the most common
sites for genetic mutations are HER2 — the gene for the epidermal
growth factor beta receptor — and microRNAs, which are tiny
regulatory molecules that stimulate or suppress growth genes.
In June 2009, researchers announced the discovery that another
receptor, AGTR1, is overexpressed — that is, present in unusually
large numbers — in as many as 20% of breast cancers. In normal
cells, AGTR1 links to angiotensin II, a hormone that raises blood
pressure and is believed to promote cell growth. The receptor is
overexpressed only in tumors that are ER-positive and
A new tumor classification system
Traditionally, breast cancers have been classified on the basis
of tumor size, the presence of cancer cells in the lymph nodes,
and the rapidity of cell division. Advances in understanding the
molecular basis of cancer have led to a new system, in which
early-stage breast cancers are classified as one of these four
Luminal A. These tumors are estrogen
and progesterone receptor–positive and HER2-negative.
Genetically, they resemble normal breast tissue more closely than
other tumors, and they're associated with a low risk of
recurrence. More early breast cancers are luminal A than any
Luminal B. These tumors have estrogen
or progesterone receptors (or both) but in smaller numbers than
luminal A tumors. Their genetic profiles are more abnormal than
luminal A. They account for 8% to 15% of early breast cancers and
are considered intermediate to high risk.
HER2-positive. These tumors often have
several other gene mutations that are associated with epidermal
growth factor. They make up about 20% of early breast cancer
tumors and are considered high risk.
Basal-like breast cancers. These tumors
are estrogen-, progesterone-, and HER2-negative —
"triple-negative." They constitute about 15% of early tumors.
Because they grow and metastasize rapidly, they are classified as
high risk. Women with a BRCA1 mutation are more likely
to develop these tumors than another type. They're often detected
before they've spread to the lymph nodes and thus aren't flagged
as high risk by the traditional classification system.
Some cancer specialists are also using two new gene tests
(MammaPrint and Oncotype DX) to further assess the risk of
recurrence in women with breast cancer, to gauge how aggressively
a tumor should be treated. Both display the activity of breast
cancer–related genes in a tissue sample. MammaPrint surveys 70
genes (see box); Oncotype DX, 21. The tumor is assigned a score
based on the number of abnormal genes found, and this information
is used to help calculate the risk of a recurrence within 10
years. MammaPrint may be used for women under age 61 whose tumors
are confined to the breast; it requires fresh tissue from the
operating room. Oncotype DX is useful for women with an
ER-positive, lymph node–negative tumor; it uses "fixed" tissue
kept after the tumor is analyzed in the lab.
Gene expression patterns and breast cancer prognosis
Above, each row is a breast cancer tumor; each column, a
gene. The patterns of gene activity, or gene expression,
shown above the horizontal threshold line indicate a
relatively low risk of recurrence. In the rightmost
column, white indicates tumors that metastasized within 5
years of diagnosis.
Source: Based on MammaPrint microarray data; courtesy
Individualizing targeted treatment
Cancer specialists are now using gene-based diagnostic tests in
various ways to plan more effective treatments for women with
early breast cancer:
to determine which women with ER-positive tumors are at high
risk of recurrence and therefore likely to benefit from
chemotherapy in addition to tamoxifen.
to identify women with HER2-positive tumors who might benefit
from chemotherapy and trastuzumab therapy given
before surgery. (Treatment given before surgery is
called neoadjuvant therapy.)
to identify women with ER-positive tumors who carry certain
forms of the gene for CYP2D6, a liver enzyme that helps
metabolize specific drugs, including tamoxifen. These women
do not metabolize tamoxifen as actively, and might do better
with aromatase inhibitors, which effectively treat
ER-positive breast cancers in postmenopausal women but don't
rely on CYP2D6.
On the horizon
A number of other approaches are being developed to target
different types of breast cancer. Among the most promising are
PARP inhibitors for triple-negative breast
cancer. These molecules interfere with an enzyme
called poly (ADP-ribose) polymerase, or PARP, which repairs DNA
damage. Although healthy breast cells have a number of ways to
correct the errors that occur during normal cell division, cancer
cells with BRCA mutations have lost one important DNA repair
pathway and must rely more on a different pathway in which PARP
is a key element. Drugs that block PARP allow DNA damage to pile
up until cancer cells die, while leaving normal cells relatively
unscathed. In two early studies, two different PARP inhibitors —
olaparib and BSI-201 — significantly reduced tumors in women with
advanced BRCA-related breast cancer (olaparib) and
triple-negative metastatic disease (BSI-201).
MicroRNA replacement therapy. MicroRNAs
are small regulatory molecules that work by preventing the
production of proteins that stimulate growth in certain body
tissues. In essence, they act as brakes on cell growth. MicroRNA
levels are low in breast cancer cells, compared with normal
cells. In June 2009, researchers reported that inserting microRNA
into cancer cells shrank tumors in mice. This approach hasn't
been tested yet in humans.
Losartan. This drug is an angiotensin
II inhibitor, currently prescribed for lowering blood pressure.
It has been found to shrink breast tumors with high levels of
AGTR1 receptors that were transplanted into mice. The treatment
hasn't been tested yet in humans.
What to do
If you've recently been diagnosed with breast cancer, you may
want to ask your oncologist about the following:
MammaPrint or Oncotype DX analysis. In
women with ER-positive tumors, these tests can help determine
whether to add chemotherapy to tamoxifen therapy.
CYP2D6 testing. This test is only for
postmenopausal women with ER-positive tumors. Women with a defect
in the CYP2D6 gene have a fourfold greater risk of recurrence
after tamoxifen treatment. This test can determine whether
aromatase inhibitors should be substituted for tamoxifen.
Multi-gene classification for women with
triple-negative tumors. Several tests can help
determine the most effective drug treatment by providing a
tumor's genetic profile. For example, if the tumor contains a
high number of epidermal growth factor receptor (EGFR) genes, it
might be helpful to prescribe cetuximab (Erbitux), which blocks
For women with early breast cancer, the reassuring message is
that targeted therapies are now state-of-the-art, and advances in
gene-based treatments are accelerating. Each improvement brings
us closer to the day when targeted therapies can score a
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