The Mina/Sledge Article Reviewed
Twenty Years of Systemic Therapy for Breast Cancer
ANTONIO C. WOLFF, MD, FACP
Associate Professor of Oncology
NANCY E. DAVIDSON, MD
Professor of Oncology
The Sidney Kimmel
Comprehensive Cancer Center
at Johns Hopkins
Baltimore, Maryland |
January 1, 2006
ver a 30-year period in the
20th century, human flight
evolved from the propeller to
the jet engine and then managed to
send us to the moon and back. The
changes over the past 30 years in our
understanding of the biology of breastcancer and its application to treatment
are no less startling. Since 1975, we
have witnessed an astounding evolution
in our strategies to prevent,
diagnose, and manage a disease
that affects the lives of so many in the
United States and around the
world. These efforts have generated
many headlines and an occasional
stumble. Nonetheless, they have had
a dramatic impact on the lives of millions
of people, and it is hoped that
the rate of improvement will further
accelerate in years to come.
Randomized trials that were started
in the 1970s disproved long-established
dogmas emphasizing aggressive local
therapy as the key for controlling breastcancer and preventing recurrence. As a
consequence, most women with earlystage
breast cancer are now able to
preserve their breasts[6,7] and often
undergo removal of just a few sentinel
nodes from the axilla. Further, a generation
of studies starting with seminal
trials published in the mid-1970s confirmed
that adjuvant systemic therapy
significantly reduces the risk of breast
cancer recurrence, thereby confirming
that invasive breast cancer must be
viewed as a systemic disease from its
A key tool underlying these accomplishments
was the concept of the
controlled clinical trial first introduced
by Sir Richard Doll almost 60 years
ago.[11,12] While many of the initialadjuvant breast cancer trials were too
small to detect the small improvements
that might be clinically significant,
the systematic review exercises
held by the Early Breast Cancer Trialists
Collaborative Group every 5 years
since 1985 have proven invaluable to
confirm the survival benefit offered
by adjuvant chemotherapy for the average
patient with early-stage disease
(especially younger women) and by tamoxifen(Drug information on tamoxifen)
for any patient with estrogen
receptor alpha (ER)-positive disease
regardless of age. In fact,
National Surgical Adjuvant Breast and
Bowel Project investigators have suggested
that some form of adjuvant
therapy should be considered for even
women with invasive tumors of 1 cm
or less and negative axillary lymph
nodes, although such recommendations
have been considered too
broad by many and do not account
for individual variability.
In this issue of ONCOLOGY
and Sledge chronicle the development
of adjuvant systemic therapy for breast
cancer since the 1985 National Institutes
of Health Consensus Development
Conference on early-stage breast
cancer and provide a comprehensive
summary of critical advances in
the last 20 years. Many of these developments
have been distilled into
expert panel consensus recommendations
and clinical practice guidelines
like those released every 2 years following
the St. Gallen meetings and at
least yearly by the National Comprehensive
Cancer Network (NCCN). As
a result, most clinicians have been
exposed to the principles of evidencebased
medicine,[16,17] and cancer
specialists have become quite familiar
with the concept of relative and
absolute risk reduction. Medical oncologists
often employ validated online
instruments[18,19] for real-time
discussions with patients regarding the
actual average improvement in 10-
year risk of cancer-related recurrence
and mortality offered by various chemotherapy
and endocrine regimens.
Treatment guidelines and software
tools have proven invaluable in clinicalpractice, but their use highlights
some of the challenges oncologists
face while translating population and
clinical trial evidence into recommendations
for individual patients. In most
cases, we have information about the
average risk and average benefit for a
group of patients with similar riskstratification
features who were given
the same or similar therapy, when in
fact the actual variability within such
a group can be substantial. But it is
now clear that breast cancer is actually
a collection of diseases that share a
common name but have an extremely
diverse biologic behavior. This is unquestionably
a disease for which onesize
treatment will not fit all patients.
Practitioners should therefore enthusiastically
welcome the most recent
update of the algorithms for adjuvant
therapy selection issued by the 2005
St. Gallen consensus panel and the
NCCN.[20,21] These panels have now
placed primary emphasis on measures
of potential response to therapy rather
than risk stratification. The impact of
these seemingly subtle changes goes
beyond a simple switch in their order
of consideration. Rather, these new
guidelines reflect our increasing ability
to move beyond prognostic factors to
focus on individual predictive factors,
ie, those unique features that could potentially
determine an individual's likelihood
of benefiting (or not) from
specific therapies. Only then do the
traditional markers-such as tumor size
and lymph node status-that aid in
prognostic but not predictive assessment
come into play.
Seven years ago, the American
Society of Clinical Oncology annual
meeting was dominated by presentations
of adjuvant high-dose chemotherapy
trials that emphasized
dose-intensification strategies for
high-risk patients without much attention
to individual biologic features.
Fast forward a few years. Factors long
thought to carry a modest prognostic
value like expression of ER and the
human epidermal growth factor receptor
2 (HER2) are now fully validated
as strong predictive markers of
response to specific therapies thatcould potentially provide a substantial
survival benefit for the right patients.[
3,22-24] Perhaps equally
important, patients whose tumors lack
expression of these specific markers
and who are unlikely to be helped by
these therapies can be spared from
exposure to a costly "placebo."
These types of studies are now accelerating
in the molecular era as geneexpression
profile assays appear to
identify several major breast cancer
subtypes with prognostic implications.[
25] At least one commercial assay
using paraffin(Drug information on paraffin)
-embedded tissue has
undergone strict assay standardization,
and was shown in retrospective validation
studies to have strong prognostic[
26] and predictive value for
patients with lymph node-negative,
ER-positive disease. The same assay
also predicted the likelihood of pathologic
complete response in patients
treated with preoperative chemotherapy
for locally advanced disease, an
area that merits further study.
In 2006, the promise of selecting
therapy based on tumor characteristics
is now an established part of clinical
practice. Until now, the reliability,
accuracy, and reporting standards for
many assays used in clinical practice
have often not been given much needed
attention. In many cases, immunohistochemistry
assays have not been
used as stand-alone tests. Rather, they
have often been used to complement
conventional pathology evaluation
and confirm a specific diagnosis or to
stratify patients among various prognostic
As new assays are introduced in
clinical practice to serve as the sole
determinant of therapy selection, pathologists
and labs performing these
assays will bear a much higher degree
of responsibility for patient outcome.
Equally important, clinicians using
these results must understand the nuances
of their use, going beyond a
simple interpretation of a positive or
negative test result. They must understand
how the test was done, be familiar
with potential variables that may
affect results, and know what ques-tions to ask the pathologist.
Concerns about the accuracy and
reproducibility of assays of hormone
receptor[29,30] and HER2[31,32] expression
have been well documented,
and we now understand that both presence
and intensity of expression are
critical features for determining benefit
to biologically based therapy with
tamoxifen, aromatase inhibitors, and trastuzumab(Drug information on trastuzumab)
(Herceptin). In addition,
much of our focus thus far has been
on specific tumor characteristics, but
there is now increasing recognition
that individual host factors can influence
response and toxicity to individual
In other words, proper assay performance
by labs and pathologists and
interpretation of results by oncologists
is crucial, and the need to address
platform standardization and
reproducibility issues is expected to
be further compounded as we introduce
more complex gene array
and pharmacogenetic assays into
routine breast cancer clinical practice.
Addressing these technical issues[
36,37] and disseminating this
information to all end users is a big
challenge, but these are indeed exciting
times for us and for our patients.
We look forward to the next 30 years!
Antonio C. Wolff, MD, FACP
Nancy E. Davidson, MD
This commentary refers to the following article
LIDA MINA, MD and GEORGE W. SLEDGE, JR, MD
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Lower Back Pain in an Elderly Man With a History of Localized Prostate Cancer
James B. Yu, MD1
, May 17, 2013
A 70-year-old man with a history of localized prostate cancer treated with whole-pelvis radiation therapy with a boost to the prostate, in conjunction with androgen deprivation therapy 7 years prior, presented with lower back pain. A bone scan revealed an area of activity in the sacrum. What is the most likely diagnosis?