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CATHERINE H. VAN POZNAK
(tamoxifen, 0.8% increase in BMD; placebo, 0.7% decrease in
BMD; p 0.06). 20 The bone data for 10-year treatment with
tamoxifen are limited. The ATLAS trial enrolled both premenopausal
and postmenopausal women and randomly assigned
them to either stopping tamoxifen at 5 years or
continuing tamoxifen for 10 years. There were 62 fractures in
the 10-year tamoxifen group and 70 fractures in the 5-year
tamoxifen group. This difference did not reach statistical signifıcance
(event rate ratio 0.86; 95% CI, 0.61 to 1.21, p 0.39)
and was not analyzed based on menopausal status. 21
In premenopausal women, tamoxifen is associated with
loss of BMD. A prospective study serially monitored BMD in
premenopausal women with breast cancer who were treated
with chemotherapy. Women with HR tumors received tamoxifen
and women with HR cancers were observed as
controls. At 3 years, women in the tamoxifen-treated group
who retained menstrual function lost 4.6% of lumbar spine
BMD whereas the controls who similarly retained menstrual
function after chemotherapy had a modest gain of 0.6% in
lumbar spine BMD. 22 A similar trend in BMD was seen in a
randomized controlled study of healthy women treated with
a chemoprevention regimen of 20 mg tamoxifen daily or placebo.
In this trial the premenopausal women lost 1.44% in
lumbar spine BMD per year over 3 years whereas those on
placebo gained 0.24% of BMD (p 0.001). 23
The aromatase inhibitors (AIs) anastrozole, exemestane,
and letrozole prevent the conversion of androgens to estrogens
by reversibly or irreversibly inhibiting the aromatase enzyme.
They are indicated for use in HR breast cancer in
postmenopausal women and may be considered an option in
women undergoing chemical ovarian ablation. 18,19 The AIinduced
decrease in serum estrogen is associated with a decrease
in risk of breast cancer recurrence and occurrence of
new breast cancer, but is also associated with accelerated loss
of BMD and an increased risk for fracture. These bone toxicities
have been seen irrespective of the particular AI
studied. 19,24-26 The effect of AIs on BMD contrasts with that
of tamoxifen, which may have a stabilizing or positive effect
on postmenopausal BMD. In a systematic review and metaanalysis,
5 years of AI therapy was associated with a 47% increase
in the odds of bone fracture compared to tamoxifen
(odds ratio [OR] 1.47; 95% CI, 1.34 to 1.61, p 0.001). The
absolute fracture risk was 7.5% in the AI group and 5.2% in
the tamoxifen group. 27
There has been interest in whether exemestane may not
have the same magnitude of bone toxicity as the nonsteroidal
AIs. The bone substudy within the phase III MA.27 study investigated
whether exemestane has a superior bone sparing
affect compared with anastrozole. At 2 years of follow-up, the
changes in BMD did not differ between treatment arms, regardless
of baseline BMD. In addition, the rates of fractures
were similarly low in both arms. 28 BMD was assessed in a
substudy of MAP.3, a randomized placebo-controlled study
of exemestane versus placebo for the prevention of breast
cancer in which 351 postmenopausal women (176 on exemestane,
175 on placebo) underwent serial BMD measurements.
At 2 years of treatment, exemestane was associated
with statistically greater bone loss in lumbar spine, hip, radius,
and tibia. 29
Ovarian ablation by chemical, radiation, or surgical means
results in lower circulating levels of serum estrogens in
premenopausal women with breast cancer and may be considered
an adjuvant endocrine therapy. 18,30 Surgery and radiation
create a permanent menopausal state whereas use of
GnRH agonists (goserelin or leuprolide) provides a temporary
chemically-induced menopausal state. The use of ovarian
suppression in the adjuvant setting has recently been
informed by the reports of two large phase III studies 31,32 and
the role for ovarian ablation in adjuvant breast cancer care is
still being defıned.
Acute cessation of ovarian function with its sudden drop in
circulating estrogen levels correlates with rapid acceleration
of bone resorption and ultimately a decrease in BMD. The
rate of loss is greatest initially and decreases over time. In a
small study of serial BMD measurements after oophorectomy,
the women had lost 18% to 19% of spine BMD at 2
years. 33 In premenopausal women participating in a randomized
clinical trial comparing goserelin, goserelin/tamoxifen,
tamoxifen alone or no endocrine therapy, women
treated with goserelin alone experienced a 5% decrease in total
body BMD at 2 years. Those treated with goserelin/tamoxifen
experienced 1.4% loss, tamoxifen alone resulted in a
1.5% loss, and the control group showed a 0.3% loss. 34 These
fındings from small older studies are consistent with BMD
changes noted in the phase III study ABCSG-12, in which
premenopausal women with breast cancer were randomly
assigned to goserelin/tamoxifen versus goserelin/anastrozole.
There was a second randomization to zoledronic acid or
not, and, as expected, treatment with 4 mg zoledronic acid
every 6 months preserved BMD. At 3 years the women who
were not treated with zoledronic acid but received goserelin/
tamoxifen lost 9.0% of lumbar spine BMD whereas those who
were treated with goserelin/anastrozole without zoledronic
acid lost 13.6% of lumbar spine BMD. 35
Chemotherapy-induced ovarian dysfunction may be temporary
or permanent and is influenced by the chemotherapeutic
regimen and the age of the patient. Because of the
inherent diffıculties in assessing residual ovarian function,
chemotherapy-induced ovarian dysfunction should not be
mistaken for menopause. A reference for the defınition of
menopause in the setting of breast cancer therapy can be
found within the National Comprehensive Cancer Network
breast cancer guidelines. Chemotherapy-induced ovarian
dysfunction is associated with loss of BMD. The rate and duration
of bone loss has not been thoroughly categorized because
of differences in the defınition of ovarian dysfunction,
duration of study, and frequent inclusions of interventions
such as bisphosphonates. The most comprehensive analysis
of chemotherapy-induced ovarian dysfunction BMD studies
was performed in the Cancer and Leukemia Group B
(CALGB) trial 79809, which enrolled 439 premenopausal
women over the age of 40 who were receiving adjuvant breast
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