2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

How Does Biology Affect Local
Therapy Decisions?
Overview: Breast cancer represents a biologically diverse
set of diseases. Previous data suggest that the estrogen/
progesterone receptor (ER/PR) status and HER2/neu status
are important determinants of prognosis and response to
various systemic treatments. Recent data also suggest that
these receptors correlate with outcomes of local-regional
therapies. Specifically, patients with ER-positive HER2/neunegative
disease have an excellent outcome with radiation
GENOMIC AND molecular analyses of breast cancer
have elucidated that breast cancer represents a biologically
diverse group of diseases. Studies indicate that molecular
subtypes of breast cancer differ with respect to tumor
biology, prognosis and response to hormone therapy, targeted
therapy, and chemotherapy. In part, these subtypes
are driven by differences in ER signaling and HER2/neu
status. While breast cancer biology has had a major role in
determining systemic treatment approaches, it is less clear
how biologic markers of disease should affect surgery and
radiation decisions. Fewer data exist correlating breast
cancer biology and local-regional treatment outcome compared
with the available data correlating molecular markers
with response to systemic treatments, overall recurrence,
distant metastases, and death. This article will highlight
some of the emerging data that suggest biology plays an
important role in local treatment outcome of breast cancer.
Breast Conservation
The local-regional treatment outcomes after breastconservation
surgery and whole-breast radiation are excellent.
Improvements in imaging techniques, increased
attention to surgical margins, and increased use of systemic
therapy have helped reduce recurrence rates to very low
levels. For example, our institutional experience of BCT
(lumpectomy plus whole-breast radiation) for 974 patients
treated between 1973 and 1993 noted a 5-year risk of
in-breast recurrence of 5.7%. This compared with a 5-year
recurrence risk of only 1.3% noted in the 381 patients
treated between 1994 and 1996. 1
Despite these overall excellent outcomes, recent data have
demonstrated that some subtypes of breast cancer have
higher local recurrence rates. For example, investigators
from the Harvard Radiation Oncology program analyzed a
cohort of 1,223 patients treated with BCT and noted 5-year
breast recurrence rates of 4.4% for patients with triplenegative
disease, 9% for those with HER2-positive disease
(predated trastuzumab), and only 1% for patients with
ER-positive disease. 2 These data are similar to a report
from University of Texas M. D. Anderson Cancer Center
(MDACC) that analyzed 911 patients treated with BCT for
primaries under 1 cm and negative lymph nodes and found
8-year breast recurrence rates of 18% in HER2/neu-positive
disease (predated trastuzumab), 11% for those with ERnegative
disease, and only 4% for those with ER-positive
disease. 3 Finally, an elegant study from British Columbia
that investigated more than 1,400 patients with BCT reported
a higher 10-year local-regional recurrence rate in
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By Thomas A. Buchholz, MD
treatments, either given as a component of breast-conservative
therapy (BCT) or for those with more advanced disease, when
given after mastectomy. For patients with triple-negative
disease, data suggest that the proportional benefits offered
from radiation in reducing local-regional recurrences may be
less. This article will highlight some of these data and discuss
strategies for new local-regional research avenues that are
based on breast cancer biologic subtype.
patients with HER2/neu-enriched (21%) and basal-like (16%)
cancers compared with the much more common luminal A
subtype (8%). 4
Some groups have analyzed local recurrence after BCT
using more sophisticated genomic signatures. For example,
a cDNA microarray-based wound signature successfully
classified patients into two groups with either high or low
risk of local-regional recurrence. 5 In a different study, investigators
from the National Surgical Adjuvant Breast and
Bowel Project (NSABP) analyzed the 21-gene profile (Oncotype
DX) in more than 1,500 patients with node-negative
ER-positive disease and reported that patients with a higher
gene profile score had a higher risk of local recurrence. 6
It remains a question how data such as these should affect
local-regional treatment decisions. The majority of patients
treated with BCT have ER-positive or luminal A type
tumors and these data collectively indicate very low rates of
breast recurrence. Accordingly, the focus of future studies
in this population should be aimed at minimizing the cost,
inconvenience, and toxicity of such treatments. For patients
with higher-risk biologic features, improvements in systemic
treatments may help mitigate risks. For example, the
NSABP study of oncotype noted only an 8% 10-year risk for
patients with high recurrence scores who received chemotherapy
and tamoxifen compared with a 16% risk for those
who received tamoxifen alone. 6 Systemic treatments also
likely overcome some of the adverse effects of HER2/neu
overexpression. Data from the B-31/N9831 trials indicated
the use of adjuvant trastuzumab reduced the risk of localregional
recurrence in HER2/neu-positive cancers by 42%
(crude event rates, 47 of 1,679 for no trastuzumab compared
with 27 of 1,672 with trastuzumab). 7 In addition, a study
from Memorial Sloan-Kettering Cancer Center noted 3-year
local-regional recurrence rates of 10% for patients with
HER2/neu-positive tumors treated before trastuzumab and
only a 1% rate in those receiving adjuvant trastuzumab. 8
The one cohort of patients who remain at higher risk of
recurrence after BCT appears to be those with triplenegative
disease. For such patients, it is reasonable to help
From the Division of Radiation Oncology, Department of Radiation Oncology, University
of Texas M. D. Anderson Cancer Center, Houston, TX.
Author’s disclosure of potential conflicts of interest are found at the end of this article.
Address reprint requests to Thomas A. Buchholz, MD, 1515 Holcombe Blvd., Division of
Radiation Oncology, Unit 97, University of Texas M. D. Anderson Cancer Center, Houston,
TX 77030; email: tbuchhol@mdanderson.org.
© 2012 by American Society of Clinical Oncology.
1092-9118/10/1-10