2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

ecurrence. This remains an important and unresolved
question. It was also clear that ovarian ablation and/or
suppression was effective but not significantly so when
added to chemotherapy, perhaps because of chemotherapyinduced
amenorrhea.
In 2005, structural changes were required in the Overview
process. The Trialists formed a new steering committee and
organized subcommittees, many of which continue today to
work very effectively. Many new trials were added and there
were many additional years of follow-up for all major questions.
However, data from many major trials, particularly
those of taxanes, were missing in 2005.
In 2006, the Trialists and their subcommittees met and
a series of priorities were set. These included investigations
of the type of anthracycline-based regimen; all taxane trials;
aromatase inhibitors; trastuzumab; and chemoendocrine
therapy, particularly in relation to the ER-positive compared
with ER-negative issue in pre- and postmenopausal
women. These meetings led five important publications on
tamoxifen, chemotherapy, and loco-regional therapy. 1-5
Nearly 30 years since its inception, the Overview remains
highly relevant and informative. In comparison to individual
trials—even huge trials tallying thousands of patients as
has become common in early-stage breast cancer—the Overview
has several methodologic virtues that make it a unique
data resource. In particular, the Overview is important for
(1) having all the worldwide data; (2) avoiding publication
72
KEY POINTS
● The Oxford Overview suggests benefits for adjuvant
endocrine therapy for all patients with ER positive
breast cancer.
● The Oxford Overview suggests benefits for anthracycline-
and taxane-based adjuvant chemotherapy
regardless of nodal, ER, or PR status.
● Molecular diagnostic assays may identify ER-positive
tumors that may not warrant chemotherapy.
● Reconciling the historic “overview” and newer “personalized”
approaches to early breast cancer is a
compelling clinical challenge.
PRITCHARD, BERGH, AND BURSTEIN
Fig. 1. Effects of approximately 5 years
of tamoxifen on the 15-year probabilities
of recurrence and of breast cancer mortality
for ER-positive disease.
Abbreviations; ER, estrogen receptor;
RR, recurrence rate; SE, standard error;
(O-E)/V, (observed-expected)/variance.
Reprinted from The Lancet, 378, Early
Breast Cancer Trialists’ Collaborative
Group, Davies C, Godwin J, et al. Relevance
of breast cancer hormone receptors and
other factors to the efficacy of adjuvant
tamoxifen: Patient-level meta-analysis of
randomised trials, 771–784, 2011, with
permission from Elsevier.
bias; (3) giving average effect sizes; and (4) clarifying the
timeframes of effects through large sample size and longterm
follow-up.
Recent Notable Findings from the Overview
Endocrine Therapy
In the main tamoxifen Overview, more than 54,500
women were studied in trials of tamoxifen compared with
no tamoxifen and more than 45,000 in trials of longer
compared with shorter tamoxifen. The effects of 5 years of
tamoxifen on breast cancer recurrence and mortality are
shown in Fig. 1.
Fundamentally, tamoxifen has long and strong sustained
effects on local recurrence, contralateral breast cancer, and
distant and multiple recurrences. Tamoxifen benefits as
measured by proportional risk reduction are similar regardless
of age, stage, grade, or tumor size and with and without
background chemotherapy.
Figure 2 examines the effect of ER and progesterone
receptor (PgR) expression on the benefits with tamoxifen.
Tamoxifen is similarly effective in patients with ER-positive
disease regardless of PgR expression. Patients with ERnegative
but PgR-positive tumors do not get benefit from
tamoxifen, nor do patients with ER- and PgR-negative
tumors.
Figure 3 explores the relationship of quantitative levels of
ER with the benefits of tamoxifen. It demonstrates that
higher ER levels are associated with stronger effects of
tamoxifen.
Figure 4 shows the effects of tamoxifen over time. They
are large in years 0 to 1, 2 to 4 and 5 to 10 in terms of
recurrence, but by year 10 and beyond, the effects no longer
increase although the previous gains are not lost. In mortality
however, the benefits come out a little later in years 2 to
4 and then years 5 to 9 and they persist into the 10 to
15–year follow-up. Thus, there is a carryover effect on
recurrence of 5 years of tamoxifen that goes on to at least 10
years and in mortality that goes on to at least 15 years.
The Overview has been pivotal in demonstrating the
benefits of endocrine therapy for ER-positive breast cancer.
Five years of tamoxifen in ER-positive disease reduces
recurrences by a relative risk of 38%, breast cancer deaths
by approximately 30%, and all deaths by approximately