2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Update of the Oxford Overview: New
Insight and Perspectives in the Era of
Personalized Medicine
By Kathleen I. Pritchard, MD, Jonas Bergh, MD, PhD, and Harold J. Burstein MD, PhD
Overview: There is great appreciation for the heterogeneity
of breast cancers, particularly of hormone-receptor positive
breast cancers. A goal of modern oncology managing such
heterogeneity is to determine how to individualize therapy
based on the specific pathological and biological features of a
given tumor. Two distinctive clinical literatures exist to guide
treatment of hormone-receptor-positive breast cancer. The
Oxford Overview, a seminal meta-analysis effort, has recently
been updated, and suggests that nearly all patients with
ER-positive tumors benefit from adjuvant endocrine therapy.
THE OXFORD Overview of the Early Breast Cancer
Trialists’ Collaborative Group (EBCTCG) dates back to
1984 when investigators responsible for trials of systemic
adjuvant systemic therapy from all around the globe met
initially, not in Oxford, but at Heathrow Airport to examine
the first meta-analysis of adjuvant systemic therapy trials.
The Overview has always involved collaboration between
the Oxford “Secretariat” led by Sir Richard Peto and a
consortium of investigators. A series of distinguished past
chairs have included I. Craig Henderson, MD, a prominent
breast cancer medical oncologist initially from Harvard
University and later the University of California San Francisco
Helen Diller Family Comprehensive Center, and
William C. Wood, MD, then Chief of Surgery at Emory
University. The EBCTCG is currently chaired by Kathy
Pritchard, MD, of Toronto and Martine Piccart, MD, PhD,
of Brussels. The Steering Committee and Executive of the
EBCTCG—both of which include members of the Oxford
Secretariat and clinical investigators (the Trialists)—extensively
meet, teleconference, and e-mail to bring analyses
and publications to fruition. Between 2005 and 2011,
data collection and analyses have resulted in five major
publications. 1-5
The Overview concept dating back to 1984 has not
changed. Collaboration between physicians and biostatisticians
based in Oxford and around the world was sought,
built, and sustained. Data were initially collected from all
randomized trials of systemic adjuvant and, later, localregional
therapy. The Overview methodology involves the
collection of individual patient data, which includes a wide
variety of items such as dates of randomization and treatment
allocation. Patients can be stratified by age, node
status, and other criteria and the log-rank statistics from
each trial are combined to give an overall estimate of the
effect of different treatments either in the whole patient
population or in various stratified subsets.
Outcomes include recurrence, which can be adjusted to
include or exclude contralateral breast cancers and deaths.
Deaths from unknown causes are usually included with
deaths from breast cancer unless specifically stated otherwise.
Recurrences can be divided into local and/or distant
with and without contralateral breast cancers. The
EBCTCG has also been interested in collecting information
on deaths from cardiac events, stroke, and other cancers.
In addition, the overview finds that nearly all subsets of
patients with ER-positive tumors also benefit from modern
adjuvant chemotherapy regimens. Meanwhile, retrospective
subset analyses of specific trials or populations suggests that
the benefits of chemotherapy are not so uniform, and in
particular that molecular diagnostics assays can identify patients
who do not warrant chemotherapy. This article will
highlight recent data and controversies in personalizing adjuvant
breast cancer therapy.
In 1984, the Oxford Overview showed unequivocally for
the first time that tamoxifen improved survival and that
cyclophosphamide, methotrexate, and 5-fluorouracil (CMF)
chemotherapy improved survival. It was also shown that
ovarian ablation, which had been mainly tested in small
underpowered trials with nonsignificant results, did, in and
of itself, improve overall survival, particularly in women
whose tumors had positive estrogen receptors (ER). By 1990,
it became clear that 5 years of tamoxifen was better than 1
or 2 years and that tamoxifen effects were greater in women
with ER-positive cancers. It was first shown in 1990 that
tamoxifen reduced the rate of contralateral breast cancer
and that chemotherapy was effective in both older and
younger women.
By 1995, the huge effect of 5 years of tamoxifen was
clearly demonstrated, and it was obvious from both direct
and indirect comparisons within the Overview that 5 years
of tamoxifen was superior to shorter durations of treatment.
It was seen for the first time that tamoxifen prevented
contralateral breast cancers only in women whose initial
tumors were ER positive. That year, the Overview also
demonstrated that anthracycline-containing regimens, at
least when given in higher dosages, were better than CMFtype
chemotherapy.
By 2000, the Overview was able to report on long-term
results, such as 15-year outcomes with chemotherapy, demonstrating
sustained benefit in older and in younger women.
There was great controversy at this time suggesting that,
particularly in the CMF trials, the effects of chemotherapy
might be greater in women with ER-negative tumors than in
those with ER-positive tumors, a controversy which continues
to this day. In 2000, it was also clearly seen that the
15-year effects of 5 years of tamoxifen were sustained and
of great magnitude. The ATLAS, ATtOM, and a few other
small trials were combined and opened the door to the
suggestion that 5 years of tamoxifen might not be optimal
and that longer tamoxifen might further reduce disease-free
From the Odette Cancer Center, McMaster University, Hamilton, ON, Karolinska
Institutet, Stockholm, Sweden, and the Dana-Farber Cancer Institute, Boston, MA.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Harold J. Burstein, Dana-Farber Cancer Institute, 450
Brookline Avenue, Boston, MA 02215; email: hburstein@partners.org.
© 2012 by American Society of Clinical Oncology.
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