2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

TREATMENT FOR OLDER WOMEN WITH BREAST CANCER
should reinforce the importance of adherence to maximize
treatment benefit.
The adjuvant use of aromatase inhibitors (anastrozole,
letrozole, exemestane) for postmenopausal women with
early breast cancer has been evaluated in several studies.
These studies have involved the use of aromatase inhibitors
either as initial adjuvant therapy, 19 as sequential therapy
after 2 to 3 years of tamoxifen, 20 or as extended therapy
after 4.5 to 6 years of tamoxifen. 21 The findings of these
studies are consistent in demonstrating that the use of a
third-generation aromatase inhibitor for postmenopausal
women with hormone receptor–positive breast cancer, regardless
of patient age, is superior in decreasing the risk of
disease recurrence, including ipsilateral and contralateral
breast cancer, and distant metastatic disease compared with
tamoxifen. Additionally, sequential use of aromatase inhibitors
20 or extended therapy 21 has been shown to provide an
overall survival advantage compared with tamoxifen use for
5 years. No survival advantage has been demonstrated with
the upfront use of aromatase inhibitors for 5 years compared
with tamoxifen.
There are differences in the toxicity profiles of aromatase
inhibitors and tamoxifen. The incidence of venous thromboembolic
disease, cerebrovascular events, endometrial cancer,
vaginal bleeding, and hot flashes are less likely to be
associated with aromatase inhibitors than tamoxifen,
whereas the incidence of musculoskeletal pain, osteoporosis,
and bone fractures have been found to be higher with
aromatase inhibitors. 19 Emerging data also suggest that
aromatase inhibitors may be associated with a small but
higher risk of cardiovascular events compared with tamoxifen,
22,23 but not compared with placebo. 24 In a metaanalysis
of seven trials in which aromatase inhibitors were
compared with tamoxifen, longer duration of aromatase
inhibitor use or aromatase inhibitor use alone for 5 years
was associated with a higher likelihood of cardiovascular
events compared with tamoxifen alone (odds ratio [OR] �
1.26, 95% CI 1.10–1.43). 25 Because studies of aromatase
inhibitors have not included extensive follow-up, the full
effect of aromatase inhibitors on cardiovascular disease and
coronary heart risk remains to be determined.
Although there is little evidence of age-related differences
in the benefits of aromatase inhibitors for postmenopausal
women, results of studies designed to examine age-related
differences in the pattern of toxicity have been mixed. In
general, the incidence of grade 3–5 nonfracture-related adverse
events is higher among women 75 and older than
among women less than 75 years. 26 However, a comparison
of the quality of life and the side effect profile for women who
participated in MA-17, a study in which 5 years of letrozole
was compared with placebo, showed no age-related differences
in side effects. 24 The long-term consequences and
implications of these side effects and any-age-related differences
remain to be well characterized.
Based on the results from recent studies that favor aromatase
inhibitors over tamoxifen, current guidelines recommend
that aromatase inhibitors should be offered to all
postmenopausal women with hormone receptor-positive
early stage breast cancer, either alone, as sequential therapy
after 2–3 years of tamoxifen. Given the lack of overall
survival advantage associated with aromatase inhibitor use
for 5 years, for women with pre-existing heart disease or
bone loss, use of tamoxifen for 5 years or a switching
strategy is a reasonable approach. For women with low
grade, node-negative tumors 1 cm or smaller, endocrine
therapy may be optional and observation acceptable, although
the risks and benefits should be discussed with the
patient.
Adjuvant Chemotherapy
Cytotoxic chemotherapy can be considered for older
women with either node-positive or high-risk node-negative
disease, particularly, triple-negative breast cancer. An
abundance of literature has demonstrated the benefit of
adjuvant chemotherapy for younger women, with benefit
decreasing as age increases. The EBCTCG overview analysis,
13 which has 15 years of follow-up data, demonstrated
that adjuvant chemotherapy reduced the annual risk of
recurrence by 37% and 19%, for women younger than 50 and
50 to 69, respectively. The annual risk of death was reduced
by 30% and 12%, for women younger than 50 and 50 to 69,
respectively. The benefit of adjuvant chemotherapy for
women with early stage breast cancer over age 70 was
difficult to assess in the EBCTCG overview analysis
because of the paucity of randomized trials that incorporated
this age group. Of 29,000 women included in 60
adjuvant polychemotherapy trials, 4% were 70 and older.
This paucity of data has prevented definitive estimates
regarding the magnitude of benefit of chemotherapy for
women age 70 and older. In addition, with advancing age,
organ function and performance status decline, and comorbidities
increase, making the risks associated with chemotherapy
even greater. Moreover, the risk reductions for
chemotherapy are lower for postmenopausal women than for
premenopausal women, although the reasons are unclear.
Coupled with the apparent decline in the efficacy of chemotherapy
with age is the increased risk of death from competing
illnesses (comorbidity), leading to additional decline in
the benefit from chemotherapy. As a result of all these
factors, older women with early stage breast cancer receive
adjuvant chemotherapy considerably less frequently than do
younger women.
However, a growing body of evidence suggests that adjuvant
chemotherapy leads to improved survival outcomes
for older women with breast cancer, particularly older
women with hormone receptor-negative and node-positive
breast cancer. A retrospective analysis of four Cancer and
Leukemia Group B (CALGB) randomized clinical trials
showed superior disease-free and overall survival benefits
with the use of more aggressive chemotherapy (compared
with less aggressive chemotherapy), among 6,487 women
with node-positive breast cancer in all age groups, including
70 and older. 27 This benefit, however, came at the cost of
increased risk of toxicity in older women, with older women
more likely to discontinue treatment and to have an increased
risk of treatment-related mortality. Additionally,
data from large population studies have demonstrated a
survival benefit from adjuvant chemotherapy for older
women with hormone-negative or node-positive early stage
breast cancer. 28,29
Results from randomized controlled clinical trials that
have specifically focused on older women with breast cancer,
though scant, have helped to fill the gap on chemotherapy
benefit for older women with early stage breast cancer.
In the largest study in this population to date, a CALGB and
Breast Cancer Intergroup study, 33 patients 65 and older
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