2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

ADJUVANT ENDOCRINE THERAPY
which randomized 9,779 postmenopausal women with ERpositive
early-stage breast cancer to either exemestane for
5 years, or tamoxifen for 2.5–3 years followed by exemestane.
22 At median follow-up of 5.1 years, there was no
difference in either disease-free or overall survival, a result
very similar to that observed in the BIG 1–98 study.
Who Benefits from Which Strategy—Up-Front or Switch?
So what are we to conclude from these large, wellconducted
studies as to which strategy is the best? From the
meta-analysis of all these studies the addition of an AI in
either strategy (up-front or switch) clearly improves diseasefree
survival compared with 5 years of tamoxifen, although
delaying relapse does not appear to translate into a substantial
survival advantage, apart a modest benefit that was
seen in the analysis of all the switching studies, which
yielded an absolute gain in overall survival of 1.7% at 8
years. 8 Biomarker studies in many of these trials have
attempted to see whether conventional indicators of hormone
responsiveness, such as absolute ER and PgR
levels, 23-25 coexpression of HER2, 23 proliferation as assessed
by Ki-67 labeling index, 26 or the 21-gene recurrence score, 27
can identify those who benefit more from an AI than tamoxifen.
Although confirming the prognostic role of all these
different biomarkers in each individual study, none have
been shown to identify patients with a differential response
between tamoxifen and AI therapy. At the present time, the
two direct comparisons between up-front AI or switch strategy
(BIG 1–98 and TEAM) have shown no significant differences
between these approaches; although in the letrozole
study, for higher-risk node-positive patients, fewer recurrences
were seen with AI up-front compared with switching.
16 As such, tumor burden in addition to other inherent
risk factors related to the biology of the disease (higher
grade or proliferation score, lower levels of ER or PgR,
coexpression of HER2) might be reasonable factors to use in
clinical practice to favor an up-front use of AIs as opposed to
a switch strategy.
In addition, patient-related factors and toxicity concerns
should always be considered when making a decision with a
patient between either up-front AI use or a switch strategy.
In general, the third generation AIs are well tolerated, and
in the clinical trial setting, the different side effect profiles of
tamoxifen and aromatase inhibitors do not appear to affect
patient’s quality of life. 28 Assessing an individual’s risk or
history of venous thrombosis may influence whether tamoxifen
is indicated, and assessing joint arthropathies or the
risk of osteoporosis may determine the optimal timing of
starting an AI. Current ASCO guidelines recommend that
postmenopausal women who receive an AI should have their
bone mineral density evaluated, with calcium and vitamin D
supplementation or bisphosphonate use dependent on the
result. 29 As such, clinicians and patients have a choice on
when and how to use an AI, dependent on the level of risk
for the cancer and the general health issues for each individual
woman–with often only marginal differences in efficacy
outcomes (in particular survival), consideration of all
these issues is important.
Which AI Is Best?
The only reported comparison to date is the MA.17 study,
where 5 years of adjuvant exemestane yielded similar results
to 5 years of adjuvant anastrozole. 30 A trial compar-
Table 3. Comparative Efficacy of Extended Adjuvant Therapy of
5 Years Tamoxifen Followed by 3–5 Years Aromatase Inhibitor
Versus 5 Years Tamoxifen Alone
Study (reference) MA-17 32
NSABP B-33 36
ing the two nonsteroidal aromatase inhibitors letrozole and
anastrozole (FACE) has completed recruitment, and results
are awaited. Tolerability profiles between the different AIs
are very similar, so, to date, there is no evidence to suggest
that one agent is substantially better than another.
Adjuvant Endocrine Therapy—Is There an
Optimal Duration?
ABCSG-6a 35
Number of patients 5,170 1,562 852
Median follow up 64 mo 30 mo 62 mo
Disease-free survival HR 0.68 HR 0.68 HR 0.62
p � .0001 p � .07 p � .031
Overall survival HR 0.98 NR HR 0.89
p � .853 p � .57
Abbreviations: HR, hazard ratio; NR, not recorded.
ER-positive breast cancer has a chronic relapsing nature,
with the risk of recurrence continuing indefinitely. In the
tamoxifen overview, approximately half of all recurrences
occurred between 5 and 15 years after surgery despite 5
years of adjuvant tamoxifen treatment. 1,3 There is, therefore,
a clear rationale for considering extended adjuvant
endocrine therapy beyond 5 years in an attempt to reduce
long-term risk of recurrence further. The MA.27 study 31 was
a double-blind, placebo-controlled trial designed to test
whether 5 years of letrozole therapy in more than 5,000
postmenopausal women who had completed 5 years of adjuvant
tamoxifen could lead to a further improvement in
disease-free survival between years 5 and 10 from diagnosis.
The trial demonstrated a significant improvement in
disease-free survival in all patients who continued onto
letrozole after completion of 5 years of tamoxifen, with a
4-year disease-free survival rate (i.e., year 9 since initial
diagnosis) of 93% compared with 87%. 31 Furthermore, after
a median follow-up of 30 months among higher risk lymph
node-positive patients, overall survival was statistically significantly
improved with letrozole (HR � 0.61, 95% CI,
0.38–0.98; p � 0.04). 32 Subsequent analyses of this trial
have suggested that this benefit was greatest in those with
ER-positive PgR-positive tumors, 33 and that benefit may
also have occurred if the switch to extended adjuvant letrozole
occurred late following a period of a few years since
completion of tamoxifen. 34 Two additional, smaller separate
studies with either anastrozole 35 or exemestane 36 as extended
adjuvant therapy after completion of 5 years of
tamoxifen have shown similar quantitative results in terms
of reducing risk of recurrence, with hazard ratios of 0.62 and
0.68, respectively (Table 3).
These data confirm that risk of recurrence in hormonesensitive
breast cancer does indeed persist on an ongoing
basis well beyond completion of 5 years of adjuvant tamoxifen.
As such, careful consideration should be given to
offering longer durations of adjuvant therapy with AIs for
those deemed to be at greatest risk. Although all of these
studies looked at treatment following 5 years of tamoxifen,
increasingly, clinical practice is to either use AI therapy
up-front in higher risk node-positive patients, or a switch
approach of AIs following an initial 2–3 years of tamoxifen.
23