As data emerge from a surge of new therapies,
doctors combine the best of the best.
By Elizabeth Whittington
In a minute’s time, Kristine Kulowiec went from total
despair to excitement. Herceptin® (trastuzumab) and
chemotherapy had stopped working for her recurrence of
HER2-positive metastatic breast cancer, which meant the
49-year-old qualified for a clinical trial of a new targeted drug combination.
“When the physician’s assistant told me the CT (computed
tomography) scan came back showing growth, I
didn’t really hear anything else after that,” Kulowiec says.
She was barely listening to the information the assistant
was giving her about a clinical trial when her oncologist
walked in.
“Now we can really get down to business,” Kulowiec
remembers her doctor saying with a big smile.
“She was so excited about this trial and wanted to tell
me,” says Kulowiec, who lives in Wake Forest, North
Carolina. “Seeing her excited made me really excited about
it. All of a sudden, I realized this was really important.”
Because Kulowiec’s cancer had progressed on Herceptin,
she qualified for a study examining a combination of
Herceptin and Tykerb® (lapatinib)—another targeted
agent that inhibits HER2, but by a different mechanism.
She started the combination in September 2006, and by
mid-March of this year, Tykerb was approved for metastatic
disease in combination with an orally administered
chemotherapy called Xeloda® (capecitabine).
Because breast cancer treatment has become individualized
based on stage, hormone receptor sensitivity,
genetics, menopausal status, protein overexpression and
lifestyle, breast cancer is no longer “just” breast cancer.
“I think we’re entering a new era,” says Julie Gralow, MD,
associate head of the Breast Cancer Program at the Fred
Hutchinson Cancer Research Center in Seattle. “There
are multiple benefits in assessing individual tumors in
individual patients instead of lumping everything together
as breast cancer.”
Currently, two traits pathologists primarily look for
when diagnosing breast cancer are HER2 overexpression
and estrogen status, which help doctors decide the best
course of treatment—essentially eliminating therapies
that would have little or no effect. But scientists are beginning
to examine many other targets, including vascular
endothelial growth factor, or VEGF, a substance cancer
cells secrete to spur blood vessel growth to the tumor.
Scientists are taking this rapidly growing arsenal of targeted
agents, chemotherapies and anti-estrogens—even
if they showed little benefit alone or lost benefit over
time—and are finding that combining them can enhance
their effects.
The Targets
[HER 2] Herceptin ushered in the age of personalized
breast cancer therapy in the 1990s. Researchers found
cancer cells that overexpress the HER2 protein on their
surface make good targets for the monoclonal antibody,
which was first approved for metastatic breast cancer in
1998. In 2005, an analysis of two large phase III clinical
trials showed Herceptin plus chemotherapy cut the
recurrence rate in early-stage breast cancer by half compared
with chemotherapy alone, and the Food and Drug Administration consequently approved the drug for that indication
in 2006. Side effects of Herceptin include fever, nausea and, rarely,
heart damage.
Newly approved Tykerb targets both HER2 and the epidermal
growth factor receptor (EGFR), also called HER1. The Tykerb/
Xeloda combination delayed disease progression for 27.1 weeks compared
with 18.6 weeks for patients taking Xeloda alone. Researchers
are still waiting to see if an overall survival benefit results from the
combination. Because Tykerb had such positive results in advanced
cancer, experts believe the benefit in early-stage cancer will be even
more dramatic, as was the case with Herceptin.
But that’s where the comparison ends, says Neil Spector, MD,
director of the Translational Research Oncology program at Duke
Comprehensive Cancer Center, who contributed to the development
of Tykerb, which began nearly a decade ago. One of the attributes
that distinguishes Tykerb from Herceptin is its administration—oral
versus Herceptin’s intravenous delivery. But it also works differently.
"There are multiple benefits
in assessing individual tumors
in individual patients instead of
lumping everything together as
breast cancer."
—Julie Gralow , MD
“The best analogy is if you looked at the tumor cell as a
room with a bunch of wall sockets, with the sockets providing
power that promotes the growth and survival of the
room. Herceptin is the childproof cap,” Dr. Spector says,
whereas Tykerb “cuts the wire inside the wall.”
For 16 weeks, Kulowiec saw her tumors shrink on the
Tykerb and Herceptin combination, a response even her
doctors didn’t expect. At 24 weeks, her cancer has stabilized. “I feel so much better now than I did six months
ago—to me, that’s the miracle,” Kulowiec says, who no
longer has to take naps because of severe fatigue and can
drive herself to treatment. Patients taking Tykerb may
experience diarrhea, vomiting and rash.
[Estrogen] Even before the approval of the anti-estrogen
therapy tamoxifen 30 years ago, scientists knew not all
breast cancers behaved the same way. Tamoxifen was the
first drug approved for the type of breast cancer fueled by
hormones—namely estrogen. It works in about half of all
women with estrogen receptor-positive breast cancer by
mimicking the hormone and binding to its receptor to
shut down cancer growth. At the time, it was considered a
huge success and is still the standard treatment for breast
cancer in premenopausal women. The drug may cause
hot flashes and increased risk of blood clots and uterine
cancer, though this is rare.
Another type of anti-estrogen therapy called aromatase
inhibitors (AIs), which include Aromasin® (exemestane),
Arimidex® (anastrozole) and Femara® (letrozole), work by
reducing estrogen production, primarily from the adrenal
glands and fat issue since the ovaries in postmenopausal women no longer produce estrogen. AIs, which can cause
significant bone loss, have been found to be effective in
early-stage and advanced breast cancers, but are only used
in postmenopausal women.
"We found that if we treated [cancer cells] upfront with Tykerb and an antiestrogen,
you could essentially prevent development of resistance in cell
culture (laboratory tests)."
—Neil Spector , MD
Although estrogen receptor-positive breast cancers have
been studied for decades, evidence shows these cancer cells
may be “smarter” than previously thought. Cancers sometimes
develop resistance to drugs like tamoxifen, especially
in advanced-stage disease. “One of the frustrating aspects
is you often see very dramatic clinical responses where the
tumor just melts away, but unfortunately the tumor comes
roaring back,” says Dr. Spector. “The question is what is in
the tumor that enables it to develop resistance?”
Scientists suspect some hardy tumor cells that use
estrogen to fuel growth change their growth pathway
from estrogen to HER2 when flooded with anti-estrogens.
Likewise, while HER2-positive breast cancer cells
may respond tremendously to Tykerb or Herceptin at
first, after a while some cells become resistant. Therefore,
researchers are pounding the cancer with multiple drugs
that target estrogen receptors and HER2 at the same
time to destroy cancer cells before they begin to alter their
growth pathway (download illustration as PDF).
“We found that if we treated [cancer cells] upfront with
Tykerb and an anti-estrogen—the most effective being
fulvestrant (Faslodex®),” says Dr. Spector, “you could
essentially prevent the development of resistance in cell
culture (laboratory tests).”
In a human study published in the journal Cancer in
2005, 240 patients with no previous therapy for their
estrogen-sensitive, HER2-negative cancer were treated with either tamoxifen or Femara. At the time of disease
progression, 26 percent of patients were found to have
cancers that converted from HER2-negative to HER2-
positive disease.
“Does this mean we have the possibility of preventing all
acquired resistance in patients receiving these [therapies]?
We certainly hope so,” Dr. Spector says. “Clinical trials
that are ongoing—combining aromatase inhibitors and
Tykerb, Faslodex and Tykerb, tamoxifen with Tykerb—will
hopefully validate the lab findings.”
"You don't waste money, you don’t waste time and you don’t waste women’s lives.
People won’t have to wait a long time to see if a drug works or not. It’s very innovative
and it’s really going to revolutionize the way we test drugs."
—Ingrid Mayer , MD
[VEGF] A target scientists have utilized to create several
new drugs is the VEGF protein. Avastin® (bevacizumab)
neutralizes VEGF, thus inhibiting a process known as
angiogenesis in which the tumor secretes proteins to
attract the growth of new blood vessels to deliver oxygen
and nutrients to the tumor. Approved for lung and
colorectal cancers, Avastin has been studied in breast cancer
for a number of years in different combinations and
sequences. The drug showed benefit for metastatic disease
primarily when combined with chemotherapy, and current
trials are studying the antiangiogenic drug in early stage
breast cancer. Patients taking Avastin experienced
high blood pressure and increased risk of blood clots.
Investigators hope to find successful breast cancer
therapy regimens using different combinations of targeted
agents, including Avastin, Herceptin, Tykerb, Xeloda and
Sutent® (sunitinib), another antiangiogenic drug recently
approved for kidney cancer.
In a phase III study published in the Journal of Clinical
Oncology in 2005, Kathy Miller, MD, associate professor
in the division of hematology/oncology at the Indiana
University School of Medicine, and colleagues reported
that adding Avastin to Xeloda in previously treated metastatic
breast cancer patients increased the response rate
from 9 percent to nearly 20 percent, but the combination
didn’t significantly improve overall survival. (A response
was defined as tumor shrinkage of 30 percent or greater.)
Preliminary results from another Avastin/Xeloda study,
a phase II trial known as XCALIBr, were presented
at the San Antonio Breast Cancer Symposium late last
year. Unlike the JCO study, the metastatic breast cancer
patients enrolled in XCALIBr are all HER2-negative
and have received no prior treatment. Early data show 34
percent of patients taking the combination have at least
30 percent tumor shrinkage and another 38 percent have
stable disease.
Dr. Miller has also combined Avastin with Taxol®
(paclitaxel) in patients without prior chemotherapy for
metastatic breast cancer, resulting in a nearly doubled
progression-free survival over Taxol alone (11 months
compared with 6.1 months). She’s now excited about a
new trial comparing that combination to Sutent/Taxol.
The Avastin/Taxol combination proved very effective
for Terry Farrer, 54, of Royal Center, Indiana. After a mastectomy,
chemotherapy and tamoxifen to treat her initial
diagnosis in 1993, breast cancer was the last thing on
Farrer’s mind when doctors found a mass on her ovary in
2002. After removing her ovary and testing the molecular
make-up of the tumor, doctors confirmed it was breast
cancer that had probably spread from her first cancer (no
cancer was ever detected in her remaining breast).
“I know now that once you have cancer, there’s always
the possibility of it returning, but I had gone on with my
life and thought it was behind me,” Farrer says.
After Femara and then Faslodex failed to prevent the
cancer from spreading, she enrolled in the Avastin/Taxol
trial. The tumor responded so well that she continued
with Avastin for another nine months after the trial ended.
When the cancer began growing again, her doctor switched
her to another combination—Herceptin/Taxol—because
her tumor tested positive for HER2 overexpression. For
nearly a year, Farrer has had no signs of cancer, but she
remains on Herceptin to keep the cancer at bay.
“I feel really good about the future and the prognosis,
and I just heard that Tykerb was approved for HER2-positive cancer and women can take it if the Herceptin stops working,” Farrer says. “But I intend for the Herceptin to work
for a very long time.”
Breast Cancer’s Future
About 30 clinical trials examining breast cancer vaccines are in
the works. Based on the notion that vaccines can spur the body’s
immune system to prevent recurrence or destroy existing cancer,
scientists have developed several different types of experimental
breast cancer vaccines, including those based on HER2 or MUC1,
another protein target.
By isolating and purifying a piece of the HER2 protein found
on cancer cells and giving it to patients along with immune-boosting
factors once a month for six months, breast cancer recurrence
dropped by 50 percent, according to a study presented at last year’s
San Antonio Breast Cancer Symposium. Indeed, after two years of
follow-up, fewer than 6 percent of vaccinated patients had a recurrence
compared with nearly 15 percent of patients who did not
receive the vaccine. Although numerous vaccines with HER2 have
been unsuccessful in treating breast cancer, this study has given
scientists the idea that perhaps these vaccines would work best as a
preventive measure.
“We’ve been working for decades on how to use our own immune
system, but for breast cancer we haven’t had anything close to a
home run,” says Dr. Gralow, who is hopeful researchers will find
the right target for a breast cancer vaccine, including MUC1. Dr.
Gralow’s team is in talks with a number of companies to make
antibodies for the protein, which is found on a large percentage of
breast cancer cells. MUC1 can also be a useful marker of circulating
tumor cells in the bloodstream.
Scientists are even looking at old drugs to use in new ways, such
as MPA (medroxyprogesterone acetate), a dated steroid initially
used as contraception and then as anti-estrogen therapy, but fell
out of favor once tamoxifen became widely used. Scientists found
MPA decreases the ability of cancer cells to metastasize and may
affect angiogenesis, and ironically “it’s able to do that in cells that
are completely insensitive to estrogen,” says Dr. Miller, who will
soon collaborate on a study involving MPA in hormone receptornegative
breast cancer. “It’s a fascinating story.”
The biggest advancement may not be one single drug at all, but
how we test certain therapies for effectiveness in breast cancer. “There is a shift in the way we’re designing and looking at clinical
trials,” says Ingrid Mayer, MD, an oncologist at Vanderbilt-Ingram
Cancer Center in Nashville.
Taking the tumor’s molecular make-up one step further, scientists
are now exploring how best to gauge the effectiveness of
treatments on the cellular level. Researchers would examine the
tumor at the initial biopsy, give the patient neoadjuvant therapy
(treatment before surgery) and then examine a follow-up biopsy
sample before the tumor is removed. The process may help investigators
see if a new drug has any effect on the tumor at the molecular
level—essentially speeding up the process because you’re looking
for molecular changes, not survival or time to progression, which
can take several years and require hundreds or even thousands of
patients to be enrolled in a trial.
“You don’t waste money, you don’t waste time and you don’t
waste women’s lives,” Dr. Mayer says. “People won’t have to wait a
long time to see if a drug works or not. It’s very innovative and it’s
really going to revolutionize the way we test drugs.” |
