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New Hope for Young Breast Cancer Patients
By Judy Peres
A
dding a hormone-suppressing
drug to chemotherapy helps avert
premature menopause—one of
the most distressing side effects of treatment—in
hormone-insensitive
breast
cancer patients, according to a recent
clinical trial that some oncologists called
practice-changing.
“Preserving fertility is a common and
important concern among younger women
diagnosed with cancer, and these findings
offer a simple, new option for women with
breast cancer, or possibly other cancers,”
said lead study author Halle Moore, M.D.,
of the Cleveland Clinic in Cleveland, Ohio,
who presented the findings at the 2014
annual meeting of the American Society of
Clinical Oncology.
In the phase III intergroup trial known as
SWOG S0230, or POEMS (Prevention of
Early Menopause Study), women with early
breast cancer who received the luteinizing
hormone-releasing hormone (LHRH) goserelin in addition to chemotherapy were
64% less likely to develop premature ovarian failure than women who received chemotherapy alone, and they were more likely
to get pregnant. Unexpectedly, women who
received goserelin were also 50% more
likely to be alive and well 4 years later.
In the study, 257 premenopausal women
with stage I–IIIA estrogen receptor (ER)–
negative and progesterone receptor (PR)–
negative breast cancer were randomized to
treatment with cyclophosphamide-containing chemotherapy alone or chemotherapy
plus goserelin. Goserelin (Zoladex) was
given as monthly injections starting 1 week
before the first chemotherapy treatment.
Two years after starting treatment, 8%
of women in the goserelin arm had ovarian
failure (defined as cessation of menstrual
periods and postmenopausal levels of folliclestimulating hormone), compared with 22%
of women in the control arm. Twenty-two
women assigned to goserelin plus chemotherapy became pregnant, whereas only 12
assigned to chemotherapy alone became
jnci.oxfordjournals.org
pregnant. Sixteen patients in the goserelin arm delivered at least one healthy baby,
compared with eight in the control arm.
Goserelin was not associated with increased
risk of miscarriage or pregnancy termination.
“Premenopausal women beginning
chemotherapy for early breast cancer sho­
uld consider this new option to prevent
premature ovarian failure,” said Kathy
Albain, M.D., of Loyola University Medical
Center in suburban Chicago, the study’s
senior author. “I think it will be practicechanging, not just to preserve fertility but
to prevent premature menopause, which
can be debilitating.”
Chemotherapy-induced menopause tends
to come on suddenly, so symptoms—including vaginal dryness, hot flashes, sleep disturbance, and mood changes—may be more
intense.
“Preserving fertility is a
common and important
concern among younger
women diagnosed with cancer,
and these findings offer a
simple, new option for women
with breast cancer, or possibly
other cancers.”
Since most women survive breast cancer, “survivorship issues have become
paramount,” said Claudine Isaacs, M.D.,
codirector of the breast cancer program at
Georgetown Lombardi Comprehensive
Cancer Center in Washington, D.C. For
younger patients, “preservation of fertility is key. Anything we can do to allow
these women to live a normal life is the
goal.”
Patricia Ganz, M.D., director of cancer prevention and control research at the
Jonsson Comprehensive Cancer Center at
the University of California, Los Angeles,
said, “Preserving fertility is an important
component of quality survivorship care.
This study provides strong evidence for
a safe and effective strategy for younger
women with breast cancer to preserve
ovarian function and the possibility of
pregnancy.”
George Sledge, M.D., chief of oncology at
Stanford University, agreed: “If I had a young
ER-negative patient who wanted to have
children, I’d offer it to her, sure.”
Sledge noted that the trial’s primary endpoint had a wide confidence interval, because
the study was statistically underpowered.
(Its original accrual
target was 416.) But
“it’s as good as we’re
going to get,” Sledge
said. “It’s hard to
randomize patients
in this setting. This
was an international
Halle Moore, M.D. effort, and it still
didn’t get all the
patients it wanted. But even so, they showed a
significantly reduced likelihood of premature
menopause.”
Albain stressed that the impact of the
trial goes beyond fertility preservation.
“We have not yet had a trial of anything to prevent a major toxicity” caused
by chemotherapy intended to cure cancer,
she said. “In this case, the toxicity is that of
sudden menopause and all the symptoms
that come with it that often make women
miserable. To prevent that in a substantial
number of women is an advance that will
improve quality of life for thousands of premenopausal women with ER-negative disease embarking on adjuvant or neoadjuvant
chemotherapy.”
About 25% of breast cancers—approximately 58,000 per year in the U.S. (68,000,
if one includes in situ cases)—occur in
women younger than 50 years. Overall,
about one-quarter of all breast cancer cases
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are hormone receptor negative, but the
proportion is greater in younger women.
Almost all women taking chemotherapy
stop menstruating, at least temporarily.
The risk of permanent premature menopause varies widely depending on age and
treatment regimen, among other variables.
LHRH analogues temporarily shut down
ovarian function, which is believed to protect follicles from chemotherapy damage,
but the mechanism of action is unknown.
Breast cancer researcher Peter Ravdin,
M.D., Ph.D., noted that other researchers
have looked at the same question, and some
have reported strikingly similar results.
An Italian group led by Lucia Del Mastro,
M.D., of the National Institute for Cancer
Research in Genoa, randomized 281 early
breast cancer patients to receive standard chemotherapy or chemotherapy plus
triptorelin, an LHRH analogue similar to
goserelin. They reported in JAMA (July 20,
2011) that 12 months after the last cycle
of chemotherapy, the rate of early menopause was 25.9% in the control arm and
8.9% in the triptorelin arm. In that trial,
which included hormone-sensitive patients,
only about 20% were hormone receptor
negative.
Two years later, Del Mastro and colleagues published a meta-analysis of similar trials of LHRH analogues (also called
gonadotropin-releasing hormone agonists).
They included nine randomized trials evaluating the efficacy of ovarian suppression
to prevent premature ovarian failure in cancer patients undergoing chemotherapy. Six
were in breast cancer, one in ovarian cancer,
and two in lymphoma. Although several trials were negative, the overview still found a
statistically significant reduction in risk of
premature menopause (odds ratio = 0.43) in
patients receiving LHRH analogues.
“So I would expect the LHRH to help
prevent early menopause,” Ravdin said.
“The unexpected result in the POEMS trial
was that goserelin seemed to have a powerful adjuvant effect in hormone receptor–
negative patients. And the effect is so large
that I think it is unlikely to be a statistical
fluke.”
After 4 years, 12 patients who received
goserelin had relapsed or died, compared with 24 of those receiving standard
chemotherapy. Overall survival at 4 years
was 92% (97/105) in the goserelin group,
compared with 82% (96/113) in the
control group.
“There may very well be a direct anticancer effect of the LHRH analogue in
combination with chemotherapy,” Albain
said. “LHRH receptors are present in most
triple-negative breast cancers.”
Forthcoming results could clarify this
question. The British OPTION trial, which
began enrolling hormone-insensitive breast
cancer patients 10 years ago, is due to report
its results. And Del Mastro’s group should
update their results soon. Another researcher
eager to see what new information these
results can provide is Mitchell Rosen, M.D.,
director of the fertility preservation program at the University of California, San
Francisco. Rosen called the survival advantage reported by the POEMS investigators
awesome.
“Mechanistically, I don’t understand
it,” he said. “But it’s provocative. We need
to do further studies to determine whether
it’s true. It will be interesting to see what it
looks like with hormone receptor–positive
patients and with longer-term results.”
The POEMS trial gives more confidence that using an LHRH analogue can
increase a woman’s odds of resuming menstruation after chemotherapy, Rosen said.
“But we still have only preliminary data
that these women can get pregnant. We
know people can have [menstrual] cycles
and still have trouble getting pregnant.
So I wouldn’t use an LHRH analogue to
replace fertility preservation [i.e., harvesting and freezing the patient’s eggs
or embryos before chemotherapy]. You
can say it’s an adjunct treatment, to be
used in addition to fertility preservation
treatment.”
One unanswered question, Rosen said,
is how long restored menstruation will last.
“A 28-year-old breast cancer patient
who takes goserelin during chemotherapy
may be able to get pregnant when she’s 30,”
he said, “but can she still get pregnant at
age 35? The reproductive window may not
be the same.”
Another question is whether a woman
with fewer eggs will get the same protection as one who has more eggs.
Rosen stressed that treatment needs to
be individualized, and a multidisciplinary
team including both oncologists and reproductive endocrinologists can best do that.
“Each patient of reproductive age needs
to be evaluated,” he said. “She needs to
understand her risk, and we need a better
understanding of what she wants. Then we
can lay out the options.”
© Oxford University Press 2014. DOI:10.1093/jnci/dju308
First published online September 11, 2014
Alleviating the Crisis in Cancer Care
By Cathryn M. Delude
A
2013 Institute of Medicine (IOM)
report warned that U.S. cancer care is
in a state of crisis, for reasons that will
worsen in coming decades. The population is
aging and, since cancer is primarily a disease of
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aging, so is the population of cancer patients,
whose age-associated health conditions complicate treatment. Cancer care is becoming
more complex, making it harder for patients
to make informed decisions about treatment
options, while oncologists often have little
incentive or time to discuss an individual’s
values and preferences. The cancer workforce
is shrinking at all levels—and among potential partners in primary care and geriatrics.
Vol. 106, Issue 9 | September 10, 2014