2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Targeting Molecular Aberrations in Breast
Cancer: Is It about Time?
By Laura Esserman, MD, MBA, Christopher Benz, MD, and Angela DeMichele, MD
Overview: Breast cancer is not one homogeneous disease; it
is a heterogeneous cancer with remarkable genomic variation
and variable risk for systemic spread, time to recurrence, and
response to treatment. Although it is increasingly clear that a
substantial proportion of newly diagnosed patients with
breast cancer carry only minimal risk of developing metastatic
disease, our inability to accurately prognosticate leads to
systemic overtreatment. The recent introduction of multigene
predictors for baseline risk assessment and treatment response
in breast cancer subsets heralds the beginning of
BREAST CANCER is the first solid tumor to demonstrate
the effectiveness of targeted therapy. The discovery
more than three decades ago that the steroid
hormone receptors (HRs), estrogen receptor (ER) and progesterone
receptor (PR), are overexpressed in the majority of
human breast cancers led to the eventual understanding
that endocrine therapy only benefits women with either ERor
PR-positive disease. Initially thought to provide clinical
benefit only to postmenopausal patients with breast cancer,
ER-targeted agents such as tamoxifen were later shown to
reduce disease burden, decrease recurrence rates, and improve
disease-free survival in premenopausal patients, 1
demonstrating that targeting the ER pathway is a biologically
based—not an age-based—therapeutic approach.
Another successful example of breast cancer receptor
targeting is the HER2/neu story. The discovery by Slamon
and colleagues 25 years ago that a substantial proportion
(approximately 20%) of breast cancers possess genomic amplification
of the HER2/neu oncogene and overexpress its
membrane-bound protein receptor, and that this is associated
with worse outcome, 2 spurred development of HER2
receptor–targeted therapies. The first of these anti-HER2
therapeutics was the humanized monoclonal antibody, trastuzumab,
that was approved for the treatment of metastatic
HER2-positive breast cancer 3 after 13 years, and later
approved for treatment in the adjuvant setting on the basis
of its significant improvement in disease-free survival and
overall survival in patients with HER2-positive disease. 4
The total time from identification that the receptor was a
critical driver to drug approval in the adjuvant setting was
18 years.
The subsequent introduction of prognostic and predictive
breast cancer biomarkers and multigene assays has had
some impact on our ability to determine who is most at risk
for developing metastatic recurrence and who would benefit
most from interventions such as systemic adjuvant chemotherapy.
Bernie Fisher put forward the hypothesis that, for
most women, breast cancer is a systemic disease. 5 A series of
large randomized clinical trials and meta-analyses have
proven conclusively that adjuvant chemotherapy can reduce
future recurrence of metastatic disease and markedly improve
patient survival, verifying Fisher’s hypothesis. The
same data, however, have provided us with the sober realization
that only some women benefit from this aggressive
systemic therapy. Many women do not need such aggressive
therapy because their tumors have indolent growth charac-
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personalized cancer care and the transition to precision
medicine. At the same time, rapid clinical adoption of these
predictors illustrates the voracious unmet need for better and
more finely tuned prognostic and predictive tools. Recent
advances in clinical trial designs have enabled the testing of
novel agents in combination with standard therapy in the
neoadjuvant setting, with a goal of identifying the specific
biomarker-drug pairs that should be advanced for confirmatory
trials and accelerated approval on the basis of response
to therapy.
teristics and would not likely recur in their lifetime; for
others, their tumors are not innately sensitive to the empirically
determined drug combinations typically used in adjuvant
treatment.
With the advent of widespread mammographic screening,
some aggressive breast cancers are detected at an earlier
(and more curable) clinical stage, but more common is the
detection of indolent tumors that are less likely to present a
life-threatening problem. 6,7 We once provided treatment
with chemotherapy and endocrine therapy for any woman
with a tumor larger than 1 cm; 1 there are now multigene
predictors that have enabled a more tailored approach. 8,9
Chemotherapy is actually more effective against highly
proliferative tumors and less effective against low-grade,
slowly proliferating tumors, and commercially approved
multigene predictors that commonly interrogate proliferation
genes have recently been introduced into clinical practice
to tailor individual therapy. 10 Interestingly, currently
approved multigene predictors have been unable to prognosticate
the outcome of women diagnosed with HR-negative
tumors, which are usually more proliferative than ER- or
PR-positive tumors, but whose risk of dissemination may be
more dependent on yet-to-be-understood host factors. This is
just one of several obvious areas of unmet clinical need, in
which challenges and opportunities exist to expand the use
of gene profiling for developing novel predictors, and to tailor
existing and emerging therapies for those who will receive
the greatest clinical impact. 11
The translational research community has produced several
validated gene signatures, and many more gene signature
candidates that can potentially push the field forward
have been described. Such signatures may answer questions
about response to our current medications—including powerful
biostatistical approaches that combine and order several
predictors, such as hormone therapy sensitivity and
chemotherapy sensitivity—ultimately allowing us to iden-
From the Carol Franc Buck Breast Care Center, University of California, San Francisco;
Cancer and Developmental Therapeutics Program, Buck Institute for Research on Aging,
Novato, CA; Breast Cancer Program, Abramson Cancer Center, University of Pennsylvania,
Philadelphia, PA.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Laura Esserman, MD, MBA, University of California, San
Francisco, 1600 Divisadero St., 2nd Floor, Box 1710, San Francisco, CA 94115; email:
laura.esserman@ucfsmedctr.org.
© 2012 by American Society of Clinical Oncology.
1092-9118/10/1-10