2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Chemoprevention for Breast Cancer:
Overcoming Barriers to Treatment
By Abenaa M. Brewster, MD, MHS, Nancy E. Davidson, MD, and
Worta McCaskill-Stevens, MD, MS
Overview: Evidence from placebo-controlled, randomized
clinical trials supports the use of chemoprevention in women
at high risk for developing breast cancer, and two agents—
tamoxifen and raloxifene—are U.S. Food and Drug Administration
(FDA)-approved for the indication. Despite clinical
guidelines that recommend physicians counsel high-risk
women about the use of chemoprevention and the estimated
2.4 million women in the United States who meet eligibility
criteria for net benefit, the uptake of breast cancer chemoprevention
has been exceedingly low. Assessments of the risks
and benefits of chemoprevention are aided by the availability
of models that can be used to estimate of the risk–benefit
ratio. However, many physicians remain unaware of these
SEVERAL RANDOMIZED clinical trials have provided
evidence for the chemoprevention of invasive breast
cancer by selective estrogen receptor modulators (SERMs).
The Breast Cancer Prevention Trial (BCPT) randomly selected
13,388 women age 35 or older with a 5-year predicted
risk for breast cancer of 1.66% or higher to receive either
tamoxifen or placebo. 1 At a mean follow-up of 4 years, there
was a 49% reduction in the risk of developing invasive breast
carcinoma and a 50% reduction in the risk of noninvasive
breast cancer among women who were assigned to the
tamoxifen arm. The absolute risk reduction was 21.4 cases
per 1,000 women over 5 years. The benefit of tamoxifen was
limited to estrogen receptor–positive tumors, and the greatest
risk reduction (86%) was observed in women with a
history of atypical hyperplasia. However, tamoxifen was also
associated with a 2.5-fold increased risk of endometrial
carcinoma and an increased risk of stroke, deep venous
thrombosis, pulmonary embolus, and cataracts. 1 The results
of the Study of Tamoxifen and Raloxifene (STAR) demonstrated
that raloxifene was as effective as tamoxifen in
reducing the risk of breast cancer in postmenopausal women
at increased risk of breast cancer with less adverse events of
thromboembolic events, endometrial cancer, and cataracts. 2
Similar risks for ischemic heart disease, fractures, and
stroke were found for both drugs. There was a nonstatistically
significant higher risk of noninvasive breast cancer
from raloxifene, which diminished at longer follow-up. 2
Additional evidence for the efficacy of SERMs is derived
from the European randomized trials of tamoxifen compared
with placebo, which have demonstrated a more modest
benefit of tamoxifen for reducing the risk of invasive breast
cancer. 3
The significant reduction in contralateral breast cancer
seen in the adjuvant aromatase inhibitor treatment trials
and the potentially serious toxicities associated with SERMs
led to the investigation of aromatase inhibitors for the
primary prevention of breast cancer. Goss et al published
the first results of a randomized placebo-controlled trial
designed to investigate exemestane for the primary prevention
of invasive breast cancer. The National Cancer Institute
of Canada Clinical Trials Group MAP.3 randomly selected
4,560 postmenopausal women to receive exemestane or
resources to determine patient eligibility for chemoprevention
and lack the time to provide informed counseling to their
patients. The barriers for patients’ acceptance of chemoprevention
treatment include fear of side effects and the perception
that chemoprevention will not substantially lower their
risk of developing breast cancer. Despite these challenges,
there are substantial opportunities to increase the utilization
of chemoprevention. These strategies include education, dissemination
of user-friendly risk–benefit models, and the support
of research efforts focused on identifying biomarkers that
can more accurately select women most likely to develop
breast cancer and predict responsiveness of treatment.
placebo. The inclusion criteria were similar to the BCPT and
STAR trials and included a 5-year predicted risk for breast
cancer of 1.66% or higher, history of atypia, or lobular
carcinoma in situ (LCIS). Women with ductal cancer in situ
were also eligible but represented a small portion of the
study participants (2.5%). At a median follow-up time of 35
months, exemestane was found to significantly reduce the
annual risk of invasive breast cancer by 65% (p � 0.002). 4
Arthritis (p � 0.01) and hot flashes (p ��0.001) were more
common in the exemestane treatment group, but there was
no statistically significant difference between the groups
in rates of new diagnoses of osteoporosis or cardiovascular
disease. Another phase III trial, IBIS-II, has randomly
selected 6,640 high-risk women to receive either placebo or
anastrozole and the results are eagerly awaited.
Evaluating Risk–Benefit Indices for Chemoprevention
The FDA-approved indication to reduce the incidence of
invasive breast cancer for tamoxifen includes both premenopausal
and postmenopausal women. However, raloxifene—
which was FDA approved in 2007—is indicated for postmenopausal
women with osteoporosis or at high risk of
breast cancer based on the Gail model 5-year projected risk
of 1.66% or higher. Adverse events that are associated with
these agents raise concerns among women and physicians
about the benefits and risks, especially in women at high
risk of developing breast cancer who are otherwise healthy.
In addition to chronic diseases that accompany increasing
age, the risks of endometrial cancer, venous thromboembolic
events, bone fractures, and cataracts complicate the counseling
for tamoxifen and raloxifene.
In 1998, the National Cancer Institute convened a workshop
to determine the best ways of communicating the
results of the BCPT. The primary goal of this workshop was
From the University of Texas M. D. Anderson Cancer Center, Houston, TX; University of
Pittsburgh Cancer Institute, Pittsburgh, PA; and National Cancer Institute, Bethesda, MD.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Abenaa Brewster, MD, MHS, University of Texas M. D.
Anderson Cancer Center, 1155 Herman P. Pressler, PO Box 301439, Houston, TX 77230;
email: abrewster@mdanderson.org.
© 2012 by American Society of Clinical Oncology.
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