CME International Journal of

Radiation Oncology
biology physics

www.redjournal.org

Critical Review

Breast Cancer Biology: Clinical Implications for

Breast Radiation Therapy
Janet K. Horton, MD, MHS,* Reshma Jagsi, MD, DPhil,y
Wendy A. Woodward, MD, PhD,z and Alice Ho, MDx
*Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina;
y
Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan; zDepartment of
Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; and
x
Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, California

Received Jul 4, 2017, and in revised form Aug 17, 2017. Accepted for publication Aug 21, 2017.

Historically, prognosis and treatment decision making for breast cancer patients have been dictated by the anatomic extent
of tumor spread. However, in recent years, “breast cancer” has proven to be a collection of unique phenotypes with distinct
prognoses, patterns of failure, and treatment responses. Recent advances in biologically based assays and targeted therapies
designed to exploit these unique phenotypes have profoundly altered systemic therapy practice patterns and treatment out-
comes. Data associating locoregional outcomes with tumor biology are emerging. However, the likelihood of obtaining
level I evidence for fundamental radiation therapy questions within each of the specific subtypes in the immediate future
is low. As such, this review aims to summarize the existing data and provide practical context for the incorporation of
breast tumor biology into clinical practice. Ó 2017 Elsevier Inc. All rights reserved.

Introduction growth factor receptor 2 (HER2) signaling, and expression

Biologically based prognostication and treatment in the
management of breast cancer has a robust historical pre-
cedent. As early as 1896, oophorectomy was noted to
shrink breast tumors and improve prognosis. The subse-
quent discovery and characterization of the estrogen re-
ceptor led to the grouping of breast malignancies by
hormone receptor status and decades of hormonally tar-
geted therapy (1). In 2000, Perou et al (2) described the
more modern concept of breast cancer subtypes by identi-
fying multiple breast tumor subgroups that could be defined
by distinct expression patterns in genes related to prolif-
eration, hormone receptor signaling, human epidermal
of basal epithelial markers. Furthermore, these unique ge-
netic signatures were noted along the spectrum from pre-
malignant to metastatic disease, confirming the truly
intrinsic nature of the subtype specific patterns. Today, 4
major subtypes are in routine clinical use: luminal A,
luminal B, HER2-enriched, and basal-like. Although these
subtypes can be most accurately defined by patterns of gene
expression, characteristic immunohistochemistry (IHC)
patterns have been commonly used as a practical surrogate
in published reports. Basal-like has been stratified into
further subtypes; however, to date, this has not affected
clinical decision making, and little is known about
locoregional recurrence (LRR) with these subtypes (3).

NotedAn online CME test for this article can be taken at https:// Reprint requests to: Janet K. Horton, MD, MHS, Department of
academy.astro.org. Radiation Oncology, Duke University Medical Center, DUMC 3085,
Durham, NC 27710. Tel: (919) 668-5213; E-mail: janet.horton@duke.edu
Conflict of interest: none.

Int J Radiation Oncol Biol Phys, Vol. 100, No. 1, pp. 23e37, 2018
0360-3016/$ - see front matter Ó 2017 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ijrobp.2017.08.025
24 Horton et al.
The prognostic value of breast tumor subtypes has been
demonstrated repeatedly and in multiple data sets. In 2011,
Park et al (4) demonstrated that even within the TNM stage
groups, breast tumor subtype could provide significant
additional information, separating patients further into
distinct prognostic groups by stage (Fig. 1). The concept of
using biologically based information, in addition to clinical
data, to guide decision making for breast cancer is being
adopted into practice, as evidenced by the recent incorpo-
ration of biological factors, including tumor grade, estrogen,
progesterone, and HER2 status, and genomic assay scores
(when available) into the 8th edition American Joint Com-
mittee on Cancer staging system for breast cancer (5). In this
new staging system, a 21-gene (Oncotype Dx) recurrence
score of <11 categorizes patients with hormone receptor-
positive (HRþ), HER2-negative (HER2), and lymph
node-negative tumors into the prognostic category of stage I
breast cancer, regardless of the size of the primary tumor (6).
In addition to the role of subtype in determining prog-
nosis, multiple large clinical trials have established the value
of systemic subtype-specific targeted therapies. For example,
in HRþ patients, genomic profiling has been widely used to
guide decisions regarding adjuvant systemic therapy (5, 7-
11). Cardoso et al (8) recently reported that approximately
50% of early-stage breast cancer patients designated as
having a high clinical risk, who would previously have
received chemotherapy, were found to have a low genomic
risk and could be spared the toxicities of systemic chemo-
therapy. In HER2-positive (HER2þ) cancers, clinical trials
evaluating HER2-targeted therapies have now reported 10-
year outcomes confirming the profound effect of adjuvant
A Stage I
1.0
0.8
Probability
Probability
0.6
HR+
0.4
HER2+
TNBC
P<.0001
0.2
0.0
0 12 24 36 48 60 72 84 96 108 120
Months
Fig. 1. Relapse-free survival according to breast cancer subtype at each TNM stage. Relapse-free survival of patients with (A) stage
I, (B) stage II, and (C) stage III disease. Abbreviations: HRþ Z hormone receptor positive; TNBC Z triple-negative breast cancer.
International Journal of Radiation Oncology  Biology  Physics
trastuzumab on disease-free and overall survival (12). Mul-
tiple combination HER2 therapies are currently in clinical
use, and early data have suggested that outcomes are com-
parable to the dramatic results seen in the initial trastuzumab
trials (13). In HRþ patients, studies investigating CDK4/6
inhibition have demonstrated marked improvement in
progression-free survival in a patient population with
advanced disease (14). Investigative trials are also underway
for triple-negative breast cancer (TNBC), the subtype with
the most unfavorable prognosis. Exploiting TNBC’s native
immunogenicity and DNA repair deficiency, planned trials
have combined conventional chemotherapy regimens with
platinum agents and checkpoint inhibitors to treat TNBCs
through the mechanisms of synthetic lethality and immu-
nomodulation. These are only a few examples of the many
therapeutic advances in the past decade that have arisen from
research into the biological composition of breast tumors.
Although much of the existing work has focused on the
refinement of systemic therapy, data are also now available
to describe the relationship between tumor biology and the
risk of LRR. Inherent biological differences have been
clearly demonstrated in data describing subtype-specific
patterns of LRR. These differences can be seen in the
absence of RT (ie, after mastectomy); however, subtype-
specific patterns have persisted, albeit to a lesser extent,
even in the setting of breast conservation therapy (BCT)
including radiation therapy (RT) (15). Similarly, in more
recent years the effect of subtype-specific targeted therapies
on local control has become more evident within specific
tumor subtypes. For example, in reports including patients
treated with HER2-targeted therapy in the neoadjuvant
B Stage II C Stage III
1.0 1.0
0.8 0.8
Probability
0.6 0.6
HR+
0.4
HER2+ 0.4
TNBC HR+
HER2+
P<.0001 TNBC
0.2
0.2
P<.0001
0.0
0.0
0 12 24 36 48 60 72 84 96 108 120
0 12 24 36 48 60 72 84 96 108 120
Months Months
Volume 100  Number 1  2018
setting, the likelihood of LRR for HER2þ patients now
approaches that of the luminal A cohort, although non-
responders continue to have higher LRR rates (16, 17).
Finally, there is also evidence that radiation response may
be subtype-specific. Outcomes from the Oxford Early
Breast Cancer Trialists’ Collaborative Group predating the
routine use of targeted therapies show discrepancies in
breast tumor radiation response, with estrogen receptor
positive (ERþ) tumors seeming to derive a greater benefit
from RT than their ER-poor counterparts (18).
In the accompanying review, we have provided a
subtype-specific overview of the existing data correlating
breast tumor biology to LRR and survival outcomes. Many
of the available studies were primarily observational in
nature. Even the limited data available from randomized
studies have generally not included locoregional outcomes
as a primary measure. Nevertheless, the landscape of breast
cancer treatment is changing, and the goal of this review
was to provide a practical context in which to interpret the
existing data and its role in decision making for breast RT.
HRD, HER2L Breast Cancer
Excellent outcomes among patients diagnosed with
HRþ disease, without amplification of HER2/Neu, have led
to a focus on individualizing decisions to reduce over-
treatment and the associated toxicity and burden for
patients with a favorable prognosis. Given the observation
of extremely low rates of LRR in patients with
HRþ disease in an era of effective long-term hormone
therapies, the appropriate role of RT in the care of these
patients is the subject of ongoing investigation.
The Oxford Early Breast Cancer Trialists’ Collaborative
Group meta-analyses have established a modest survival
benefit for patients with a large predicted absolute recur-
rence reduction from RT (18, 19). However, patients with a
smaller absolute recurrence reduction from RT might not
experience a difference in survival. Rates of LRR have
decreased dramatically since the earliest randomized trials
investigating the effect of RT after either breast-conserving
surgery (BCS) or mastectomy, owing to improvements in
screening, surgical practice, and systemic therapy (20).
This decrease in LRR has been particularly profound
among patients with HRþ disease. Therefore, these
patients have been included in more recent trials seeking to
identify a low-risk population of patients for whom the risk
of recurrence in the absence of RT would be sufficiently
low enough to investigate the omission of RT.
In the setting of breast conservation, numerous
randomized trials that included HRþ patients selected
according to their clinicopathologic characteristics alone
have proven unsuccessful. For example, the landmark Na-
tional Surgical Adjuvant Breast and Bowel Project
(NSABP) B-21 trial sought to evaluate whether tamoxifen
might be used in lieu of RT in a select subgroup of patients
undergoing BCS for tumors 1 cm in size (21). In that
Breast cancer biology and radiation therapy 25
study, the 8-year rate of ipsilateral breast tumor recurrence
(IBTR) was unacceptably high, at 16.5%, with tamoxifen
alone. However, receptor testing was not required, and one
fifth of the patients were young (<50 years of age).
A Canadian randomized trial also demonstrated high
LRR rates in the absence of RT in women aged 50 years
with T1-T2 node-negative breast cancer, randomized after
BCS to RT versus observation in conjunction with tamox-
ifen treatment (22). The 8-year risk of IBTR was 18%
overall and was still unacceptably high at 15% in a planned
subgroup analysis of 611 women with T1, HRþ tumors
treated with tamoxifen alone. However, the investigators
did note in an unplanned subgroup analysis of women with
HRþ tumors 1 cm that the risk of local relapse at 5 years
was 2.6% in the tamoxifen group (nZ139) and 0% in the
tamoxifen plus RT group (nZ124; PZ.02). When this
unplanned subgroup was further restricted to those aged
60 years, the difference was no longer significant between
the 2 arms. However, the investigators urged caution, given
the small number of patients in this subgroup and the
likelihood of further cases of local relapse with longer
follow-up.
Results have been more promising after omission of RT
for older women with early-stage breast cancer. In the
Cancer and Leukemia Group B (CALBG) 9343 trial,
women aged 70 years with clinical stage I, ERþ disease
had a 10-year LRR risk of 10% after lumpectomy and
tamoxifen alone (23). Although the risk was significantly
lower among those who were randomized to RT (2%), that
trial has widely been interpreted as having identified
omission of RT as a reasonable option for older women
with characteristics similar to those patients enrolled in the
trial. More recently, the results from the PRIME II study
have revealed strikingly similar results at 5 years, with 668
patients aged 65 years having only a 4% risk of LRR
without RT compared with 1% for the 658 patients
randomized to RT (24). However, it is worth noting that
within the biologically favorable ERþ group, there may be
patients with aggressive features whose risk of LRR is
significantly higher than that of the group as a whole. For
example, in the CALGB and PRIME studies, patients with
high-grade or HER2þ disease were not well represented
and might not experience the same low risks without RT.
The idea that tumor biology can predict for outcomes
has been further advanced by observational studies that
examined subtypes approximated by various groupings of
receptor status and grade. In an analysis of 1434 patients
who underwent BCS and RT at Harvard from 1997 to 2006,
the 5-year cumulative incidence of local recurrence among
patients designated as having luminal A-like disease (those
with ERþ or progesterone receptor-positive [PRþ],
HER2, and grade 1 or 2 disease) was only 0.8% (25). If
one extrapolates by applying a relative risk reduction in
local recurrence of approximately two-thirds, which was
suggested by the Oxford meta-analyses, one might
conclude that the risk expected in this subgroup would be
<3% at 5 years even without RT. However, such
26 Horton et al. International Journal of Radiation Oncology  Biology  Physics

extrapolations must be made with caution, given studies
that imply the relative risk reductions vary by subtype and
may be the highest in luminal A-like patients (26). It is
nevertheless encouraging that in a retrospective analysis of
a subset of 501 samples from the Canadian trial cited
previously (22), patients designated as luminal A according
to ER, PR, HER2, CK5/6, epidermal growth factor recep-
tor, and Ki67 evaluation had only a 3.1% risk of IBTR at
10 years, even in the absence of RT, if restricted to the
subgroup with favorable clinical features (age 60 years,
stage T1, and grade 1 or 2) (27).
Other studies have also suggested that even more
sophisticated genomic assays might be useful in predicting
LRR risk for women who have undergone BCS. For
example, Mamounas et al (28, 29) have demonstrated that
LRR risk is significantly associated with the 21-gene
recurrence score (Oncotype-DX) risk groups in tamoxifen-
treated patients with node-negative or node-positive,
ERþ breast cancer. Similarly, for 3714 postmenopausal
ERþ women enrolled in the ABCSG 8 trial, the Endopredict
genomic assay was also shown to predict local recurrence
(locoregional recurrence-free survival 91% for high-risk
lesions, 97.5% for low-risk lesions; hazard ratio 1.31;
P<.005) (30). Genomic profiling appears to discriminate
particularly well in nonirradiated patients, prompting interest
in using such information to further refine selection of pa-
tients beyond the IHC based identification of luminal-like A
patients.
In alignment with these concepts, several open trials are
exploring whether a subgroup of HRþ patients might have
a sufficiently low risk of LRR in the absence of RT to merit
omission after BCS (Table 1). The LUMINA study is a
Canadian prospective multicenter cohort study of RT
omission after BCS for patients aged 55 years with uni-
focal stage I disease, grade 1 or 2, HRþ, HER2, and
luminal A based on centralized assessment of Ki67 (not
>13%); the trial opened in 2013 and expects to enroll 500
patients (31). The IDEA study is a prospective multicenter
cohort study of RT omission after BCS at 14 centers in the
United States, led by the University of Michigan. The study
includes patients aged 50 to 69 with unifocal stage I dis-
ease, HRþ, HER2, and an Oncotype-DX recurrence score
of 18; the trial opened in 2015 and expects to enroll 200
patients (32). Finally, the PRECISION study is a prospec-
tive cohort study led by the Dana FarbereBrigham and
Women’s Hospital of patients aged 50 to 75 with unifocal
stage I disease that is at least ERþ with a Prosigna PAM50
score of <40; the trial opened in 2016 and expects to enroll
345 patients (33). Two large studies are also underway in
the United Kingdom (PRIMETIME, a single-arm study)
and in Australia/New Zealand (EXPERT, a randomized
trial that will likely open in late 2017) (33, 34). In the
PRIMETIME study, the risk groups will be determined
according to IHC4þclinical, a refinement of IHC pheno-
typing that combines the protein expression of ER, PR,
HER2, and Ki67 with clinicopathologic parameters (35).
After BCS, eligible women (>60 years old, stage T1N0,
grade 1 or 2, and ERþPRþHER2) with very, very low
IHCþ4 scores will be recommended to omit RT. In
contrast, those with low-, intermediate-, and high-risk
IHCþ4 scores will be recommended to undergo RT. All
patients will receive standard of care hormone therapy. In
the EXPERT trial, women aged 50 years with stage I,
biologically low-risk luminal A early-stage breast cancer
(defined using the PAM50-based Prosigna assay) will be
randomized to hormone therapy alone or RT plus hormone
therapy (34). As the primary endpoint of the study is local
recurrence after BCS at 10 years, the results will not be
available in the immediate future.
A similar biologically directed investigation is under
active consideration for patients undergoing mastectomy.
The Oxford meta-analysis has convincingly demonstrated a

Table 1 North American studies underway evaluating hormone therapy alone after BCS for selected biologically low-risk tumors
Criteria
Study Cohort Age (y) Pathologic Receptor Other
LUMINA (31) Prospective multicenter 60 Unifocal stage I (pN0); ERþ, PRþ, HER2 Luminal A tumors (by
cohort study in Canada lumpectomy, negative IHC; centralized Ki67
margins (2 mm), no not >13%)
lobular, no EIC, no
LVI, no grade 3
IDEA (32) Prospective multicenter 50-69 Unifocal stage I (pN0); ERþ, PRþ, HER2 Low Oncotype-DX
cohort study in USA lumpectomy, negative RS (18)
margins (2 mm)
PRECISION (33) Prospective multicenter 50-75 Unifocal, stage I (pN0); ERþ, PRþ, HER2 Low-risk PAM50 score
cohort study in Boston lumpectomy, no ink on
tumor; no grade 3
Abbreviations: EIC Z extensive intraductal component; ERþ Z estrogen receptor positive; HER2 Z human epidermal growth factor receptor 2
negative; IDEA Z individualized decisions for endocrine therapy alone; IHC Z immunohistochemistry; LUMINA Z a prospective cohort study
evaluating risk of local recurrence following breast conserving surgery and endocrine therapy in low risk luminal A breast cancer; LVI Z lymphovascular
invasion; PRþ Z progesterone receptor positive; PRECISION Z profiling early breast cancer for radiotherapy omission: a phase II study of breast-
conserving surgery without adjuvant radiotherapy for favorable-risk breast cancer; RS Z recurrence score.
Volume 100  Number 1  2018
benefit from postmastectomy RT (PMRT) in all node-
positive patients treated in the historical randomized trials
(19). However, results from single-institution studies have
suggested that for selected patients with more limited node-
positive disease treated in the modern era, the rates of LRR
can be quite low even without RT (36). Intriguing data from
analyses of the outcomes of patients undergoing mastec-
tomy for N1 disease in the NSABP B28 trial, who received
no RT, suggested that even among those ERþ patients with
a high recurrence score, the LRR rate was only 6%, and the
rates for patients with lower recurrence scores were even
lower (29). Similarly, in a planned subset analysis of the
MA20 randomized clinical trial, ERþ patients appeared to
have less benefit from regional nodal irradiation (RNI) (37).
Although that particular study was conducted in the setting
of BCT, it provides another link between biology and
locoregional therapy. A Canadian randomized trial inves-
tigating the omission of RNI in patients with biologically
defined low-risk disease with 1 to 3 positive nodes after
BCS or mastectomy (MA.39; TailorRT) is actively in
development and will likely open to accrual in 2017 or
2018 (Fig. 2).
HER2D Breast Cancer
The introduction of HER2-neu targeted therapies has
dramatically changed the landscape for patients with tumors
that overexpress HER2-neu. Although the effect of tras-
tuzumab on LRR has been well demonstrated, the possibility
of potentiation with RT and how to tailor RT for HER2þ
patients receiving anti-HER2 therapies is less clear. We will
Recommendation
HR+, HER2- BREAST CANCER
Omission of whole-breast RT after BCS in
women >70 years old with stage I, ER+ breast
cancer who plan to receive hormone therapy
Omission of boost for women ≥50 with ER+
breast cancer who lack adverse pathologic
features
Omission of whole-breast RT after BCS in
women <70 years old with stage I, ER+ breast
cancer of favorable tumor biology based on
subtype and genomic assays
Omission of PMRT or RNI for women with
limited nodal involvement and favorable
tumor biology based on subtype and genomic
assays
Fig. 2. Table of recommendations for hormone receptor-positive (HRþ), human epidermal growth factor receptor
2-negative (HER2) breast cancer. Abbreviations: BCS Z breast-conserving surgery; ERþ Z estrogen receptor positive;
PMRT Z postmastectomy radiation therapy; RNI Z regional nodal irradiation; RT Z radiation therapy.
Breast cancer biology and radiation therapy 27
review the LRR rates with and without RT in the pre- and
post-trastuzumab era and examine the effect of subtype
variation within the HER2-neu overexpressing cohort.
Several large randomized trials have demonstrated the
advantages of adjuvant trastuzumab in the setting of HER2-
neu overexpressing disease (12, 38-42), although most
reports have focused on the systemic endpoints of event-free
survival and overall survival rather than LRR. In all these
trials, RTwas administered as per the standard of care to those
deemed at risk of LRR (BCS patients and mastectomy pa-
tients with increased risk factors) rather than as protocol-
specified treatment. The LRR rates across trials have been
summarized in a meta-analysis (43). In the adjuvant setting,
the odds ratio (OR) for LRR with concurrent trastuzumab
was 0.48 (95% confidence interval [CI] 0.37-0.61) and with
sequential dosing was 0.53 (95% CI 0.44-0.65). In both cases,
the OR was measured using both fixed and random effects
methods with consistent results. RT in these trials was typi-
cally administered after systemic chemotherapy, such that
RT would have been delivered concurrently with trastuzu-
mab. No increase in acute adverse or early cardiac events was
seen with concurrent administration of trastuzumab and RT
in an analysis of 1503 patients treated in the randomized
NCCTG (North Central Cancer Treatment Group) N9831
trial (44). Numerous preclinical studies have demonstrated
the radiosensitizing effect of trastuzumab in breast cancer
cells, which might contribute to the improvement in LRR
rates. However, this is speculative and can only be considered
a hypothesis from these data. Of interest, the ORs for LRR
crossed 1.0 in the FinHer and FNCLCC-PACS04 trials, in
which RT was not delivered concurrently with trastuzumab
(39, 42).
Quality of Recommendation
Reasonable now
Reasonable now if consistent with patient
values and preferences
Cautionary; worthy of study
Reasonable on a case-by-case basis; worthy of
study to determine subgroups that will benefit
from PMRT or whole breast + RNI after BCS
(eg, TailorRT)
28 Horton et al.
As in the adjuvant setting, RT has typically been
delivered concurrently with trastuzumab after neoadjuvant
chemotherapy (NAC) and surgical resection, because there
is no evidence of added toxicity and the standard duration
of trastuzumab is 1 year. Unfortunately, few details
regarding RT (in particular, the specific RT fields used) or
LRR were reported in the neoadjuvant HER2þ trials from
which to assess the potential benefit of concurrent RT and
trastuzumab. Gianni et al (40) noted that RT concurrent
with trastuzumab was given at the discretion of the
oncologist but provided no data on the LRR rates inde-
pendent of event-free survival. In NeoALTTO all RT was
delivered concurrently with trastuzumab, and the crude
LRR rate was 5 of 148 (3%) (45). No LRR events were
explicitly reported. All RT in the GeparQuattro study was
given after the completion of trastuzumab; however, the
LRR rates were not reported (46, 47).
In summary, data from randomized trials with or without
adjuvant trastuzumab reveals that #1) trastuzumab reduces
the OR for LRR by approximately 50% in cohorts for whom
RT was given in accordance with standard guidelines and #2)
it can be safely given with RT. It is possible that given the
radiosensitizing benefits from concurrent administration of
trastuzumab and RT, the effect size may be even larger after
excluding studies of sequential administration. Monitoring
the toxicities of concurrent RTand trastuzumab, in particular,
in the setting of RNI, is a relevant clinical concern. To date,
limited data are available evaluating cardiac toxicities in
women who have received concurrent trastuzumab and RT
that specifically included treatment of the internal mammary
nodes. In a prospective, single-arm trial conducted in France
of 308 women with HER2þ breast cancer, RT to the internal
mammary nodes was given to 227 of the patients (73.7%)
(48). The median follow-up period was 48 months. After
completion of RT, 8.4% of the patients presented with an
impaired left ventricular ejection fraction. However, the
incidence of grade 2 was only 2.9%, comparable to the low
rates of clinically significant left ventricular dysfunction
observed in major randomized trials demonstrating survival
benefits with the addition of trastuzumab to anthracycline-
containing chemotherapy in women with HER2þ breast
cancer. Given the limited data available, minimizing the
cardiac dose to women who undergo concurrent RT and anti-
HER2 therapy after anthracycline-based chemotherapy re-
mains a high priority goal, especially in the setting of RNI.
Baseline knowledge of the efficacy of RT in HER2þ
patients is also important in considering the biological ef-
fect of HER2 amplification in clinical RT decisions. Kyndi
et al (26) reported the LRR rates from the Danish Breast
Cancer Group randomized trial of PMRT in node-positive
women. The investigators retrospectively analyzed the
HR subtype and found that ERþ disease was the most
dramatic predictor of RT efficacy in HER2þ and HER2
disease (26). The absolute reduction in 10-year LRR rate
with PMRT was 45% compared with 12% for ERþHER2þ
and ER/HER2þ patients. The ERþHER2þ patients
experienced a 10-year LRR rate of 3% after PMRT, and the
International Journal of Radiation Oncology  Biology  Physics
ER/HER2þ patients had a LRR rate of 21% despite the
use of PMRT. However, these rates reflect the LRR risk in
the pretrastuzumab era, which was much greater than that
observed with trastuzumab use.
Several large retrospective series have provided
comparisons for 5-year LRR with and without trastuzumab
in HER2þ patients. All demonstrated a reduction in LRR
with trastuzumab of 50%, consistent with the randomized
data and perhaps reflecting more uniform delivery of
concurrent RT and trastuzumab (16, 17, 49-53) (Table 2).
Furthermore, they all demonstrated very low absolute rates
of LRR, ranging generally from 2% to 5% with trastuzu-
mab and 4% to 10% without trastuzumab, suggesting that,
in cohorts for whom RT is used per standard guidelines,
HER2þ patients receiving trastuzumab will have excellent
local control. This appears to be evident even in HER2þ
patients with more advanced disease features receiving
PMRT. Lanning et al (51) reported a 5-year LRR rate of 2%
among trastuzumab-treated HER2þ patients with stage I to
III disease. In determining the role of PMRT in this cohort,
however, a trend was found for worse LRR without PMRT
(0% vs 5%; PZ.06). In a review of the National
Comprehensive Cancer Network data, Tseng et al (16)
reported only a single event among patients receiving
PMRT and trastuzumab. Use of RT was significantly and
independently associated with improved LRR (hazard ratio
0.12; PZ.006) (16). Collectively, these data highlight the
importance of enhancing our understanding of the interac-
tion between trastuzumab and RT and suggest caution when
considering omission of RT for these patients. Efforts to
reduce the dose might warrant further study, given the
favorable current rates and expected synergism between
these therapies.
Similarly, whether the favorable outcomes observed for
HER2þ breast cancer patients receiving anti-HER2 therapy
obviate the need for RNI is another subject of increasing
controversy. A retrospective analysis by Gingras et al
reported the disease-free survival outcomes for 1664
women with node-positive, HER2þ breast cancer who had
undergone BCT with or without RNI in the ALTTO trial, a
randomized trial that studied various combinations of anti-
HER2 therapy, including trastuzumab, lapatinib, sequential
trastuzumab followed by lapatinib, and concurrent trastu-
zumab and lapatinib. Patients who had undergone RNI
(nZ878) had more advanced disease, with larger tumors
and a greater number of involved lymph nodes. RNI was
defined as RT to any nodal site; however, further details of
the dose and field arrangements were not collected. At a
median follow-up of 4.5 years, no statistically significant
difference had been found between disease-free survival in
the RNI group versus the non-RNI group (84.3% vs 88.3%,
respectively). However, owing to the imbalances within
groups in this nonrandomized comparison, it is possible
that RNI might have mitigated higher risk characteristics
among the patients who received it (54). As the results of
trials testing the efficacy of pertuzumab and other new anti-
HER2 therapies become available, it is possible that even
Volume 100  Number 1  2018 Breast cancer biology and radiation therapy 29

Table 2 Locoregional recurrence rates in studies of HER2þ breast cancer patients treated with trastuzumab and RT
LRR rate (%) No RT RT
Investigator Cohort Endpoint With T Without T Reduction With/Without T With/Without T
Aalders et al (49) <35 y 5-y LRR w5 w10 50 NA NA
Jwa et al (50) BCT/NAC 5-y LRR 7 21 66 NA NA
Swisher et al (17) BCT/NAC/T 5-y LRR w5 NA NA NA NA
Tseng et al (16) NCCN, unselected 5-y LRR 0.26 3.6 93 NA NA
Lanning et al (51) M with or without PMRT 5-y LRR 2 4 50 3% vs 6%; 0% vs 5%;
PZNS PZ.07
Kim et al (52) Unselected 5-y LRR w4 6 NA HR 2.0 NA
Cao et al (53) All RT 3-y LRR 2.4 7 66 NA NA
Summary 0.26-7 3.6-21
Excluding Jwa et al (50)/Tseng et al (16) 2-5 4-10
Abbreviations: BCT Z breast-conserving therapy; HER2þ Z human epidermal growth factor receptor 2 positive; HR Z hazard ratio; LRR Z
locoregional recurrence; M Z mastectomy; NA Z not applicable; NAC Z neoadjuvant chemotherapy; NCCN Z National Comprehensive Cancer
Network; NS Z not significant; PMRT Z postmastectomy radiation therapy; RT Z radiation therapy; T Z trastuzumab.

further reductions in LRR could be achieved and that the
risk/benefit balance of RNI might need to be re-evaluated.
Most of the studies we have discussed addressing LRR in
HER2þ patients receiving RT have provided scant
information regarding the effect of ER status, which places
the luminal B, predominantly ERþHER2þ cases in the
same group as the predominantly ER/HER2þ, HER2-
enriched cases. There is also have limited data on the impact
of locoregional response to therapy. In a 1000-patient na-
tional study of women aged <35 years from the Netherlands,
most LRR events observed after trastuzumab were among
ER/HER2þ patients, and no regional recurrence events
occurred among ERþHER2þ patients who had received
trastuzumab (49). Again, RT was used in accordance with
the standard of care guidelines. Kim et al (52) explicitly
studied the effect of ER status in HER2þ patients and re-
ported that LRR with and without trastuzumab was not
different in ER/HER2þ patients. In contrast, the use of
trastuzumab in ERþHER2þ patients significantly reduced
the rates of LRR, making them indistinguishable from
ERþHER2 patients (52). In a subsequent study of patients
from the same institution, LRR among HER2þ patients was
significantly reduced by achievement of pathologic complete
response (pCR) with neoadjuvant therapies containing tras-
tuzumab (2.6% vs 13.3%) (17).
These data lead us to hypothesize that in the era of
trastuzumab therapy, LRR in HERþ breast cancer remains
driven by ER status, such that patients who receive trastuz-
umab and guideline-concordant RT with ERþHER2þ
disease or ER/HER2þ and achieve a pCR can be expected
to have exceedingly low LRR. These subgroups potentially
could be considered for no boost or dose de-escalation trials,
along with the luminal A cohort. Omitting RT entirely should
be studied cautiously, because the interaction between RT and
trastuzumab is potentially important, and the existing 5-year
outcome data for ERþHER2þ patients receiving hormone
therapy is likely less than needed to fully consider the risk of
LRR in this cohort. This leaves only ER/HER2þ patients
who receive trastuzumab and guideline-concordant RT but
have residual disease. These patients are clearly in need of
further improvements in local control. As such, we recom-
mend routine use of a boost in this group based on ran-
domized data demonstrating the benefit of a boost in
unselected patients (55). We further recommend exploration
of radiosensitizers that could be incorporated into treatment
when a boost is not feasible (Fig. 3).
Triple-Negative Breast Cancer
TNBC, defined as breast cancer with <1% ER and PR
nuclear staining and a lack of HER2 overexpression by IHC
or fluorescence in situ hybridization (56), comprises 15% to
20% of all breast cancers. TNBC has disproportionately
aggressive clinical behavior and an increased propensity for
visceral and central nervous system metastases compared
with other breast cancer subtypes (2, 57, 58). Furthermore,
TNBC more commonly affects younger women and
African American women and is frequently associated with
BRCA1 or BRCA2 mutations (59, 60). Although cytotoxic
chemotherapy is considered the backbone of treatment, no
one particular regimen has become standard or been
uniquely effective. The rates of overall survival, distant
relapse, and LRR have all been suboptimal, underscoring
the need to identify effective therapies for TNBC.
Biological heterogeneity of TNBC
The challenges of identifying effective targeted therapies
for TNBC result from its complex biological framework.
Basal-like breast cancer is characterized by a lack of ER/
PR/HER2 expression and overexpression of basal cyto-
keratins 5, 6, 14, and 17, P-cadherin, epidermal growth
factor receptor, and CAV1 and CAV2 (2, 59, 60). Despite
their similarities, however, basal-like breast cancer and
TNBC are not entirely synonymous. Approximately 15% of
TNBC cases are not basal-like on gene array, including a
subtype of TNBC called claudin-low, which is enriched for
stem cell-like features (61). In contrast, it is possible for
30 Horton et al. International Journal of Radiation Oncology  Biology  Physics

Recommendation Quality of Recommendation

HER2+ BREAST CANCER
Omission of chest wall/breast boost in women ≥50 Reasonable on a case-by-case basis*
years who obtain a pCR with neoadjuvant
chemotherapy (NAC) including anti-HER2 agents

Use of boost >10 Gy to chest wall/breast in women Reasonable on a case-by-case basis*

<50 years who do not obtain a pCR with NAC
including anti-HER2 agents

Omission of whole-breast RT in women ≥70 years old Cautionary; worthy of study

after BCS with stage I, ER+ breast cancer receiving
trastuzumab

Omission of RNI/PMRT in women with stage II Cautionary; currently being investigated in NSABP
HER2+ breast cancer who achieve a pCR in the lymph B-51/RTOG 1304 trial
nodes with NAC + anti-HER2 therapies

De-escalation of RT dose in ER+, HER2+ patients Cautionary; worthy of study

receiving concurrent trastuzumab + RT
* The recommendations regarding omission or intensification of boost in HER2+ breast cancer patients who receive NAC are not
guideline-concordant; however, they are considered reasonable on a case-by-case basis, given absence of information about
subtypes from currently available studies evaluating boost.

Fig. 3. Table of recommendations for human epidermal growth factor receptor 2-positive (HER2þ) breast cancer.
Abbreviations: BCS Z breast-conserving surgery; ERþ Z estrogen receptor positive; pCR Z pathologic complete response;
PMRT Z postmastectomy radiation therapy; RNI Z regional nodal irradiation; RT Z radiation therapy.

breast cancers to appear basal-like on gene array but not be
triple negative because of HR positivity or HER2 expres-
sion (62).
A classification system for TNBC has been proposed by
investigators at Vanderbilt University, who categorized
TNBC into 6 distinct molecular signatures using gene
expression profiling: basal-like 1, basal-like 2, mesen-
chymal, mesenchymal stem-like, luminal androgen recep-
tor, and immunomodulatory subtypes (3). Although clinical
validation of these subtypes is required before using them
in everyday practice, this classification system is among the
first to highlight the significant molecular heterogeneity of
TNBC and illustrates the potential to tailor therapy selec-
tion based on its various subtypes.
Locoregional outcomes in TNBC
Compared with the luminal subtypes of breast cancer,
TNBC is characterized by greater rates of local recurrence
after BCT (Table 3). In a recent update of a large series of
2233 women with early-stage breast cancer who under-
went BCT from 1998 to 2007 at a large academic center,
an enhanced risk of LRR in women with noneluminal A
subtypes, including TNBC, was observed (63, 64). With a
median follow-up of 106 months in the entire cohort, the
8-year risk of local recurrence was substantially greater
for TNBC, compared with other subtypes (9.8% vs 1.8%
in luminal A, 5.5% luminal B, 2.2% in luminal-HER2, and
11.7% in HER2 patients treated in the pretrastuzumab
era). In a study of 498 breast cancer patients who under-
went BCT, Millar et al (65) reported a 5-year LRR rate of
14.8% for the basal subtype compared with 15.3% for
HER2þ, 2% for luminal A, and 4.3% for luminal B. In a
series of 1461 patients who underwent BCT, Voduc et al
(15) reported a 10-year LRR rate of 14% for patients with
TNBC versus 21%, 10%, and 8% for HER2, luminal B,
and luminal A patients, respectively (15). This pattern has
recapitulated itself even in the very smallest of TNBCs
that are microinvasive or measure 1 cm, for which the
risk of developing either local or distant relapse after BCT
was increased compared to the luminal A subtype (hazard
ratio 3.58; 95% CI 1.40-9.13) (66). The caveat for all
these studies was that they were conducted in the pre-
trastuzumab era; therefore, the rates of LRR in the HER2
group were greater than would be expected for HER2þ
breast cancer patients treated with trastuzumab today.
Although data sets examining the LRR outcomes for
mastectomy patients are smaller, the overall results have
paralleled those for patients with TNBC who underwent
BCT (Table 4). Kyndi et al (26) demonstrated a 5-year LRR
rate of 21% for patients with TNBC who had undergone
Volume 100  Number 1  2018 Breast cancer biology and radiation therapy 31

Table 3 Subtype and locoregional recurrence rates after breast-conserving therapy

LRR rate (%)
Study Median follow-up (y) Patients (n) Luminal A Luminal B HER2þ* TNBC
Nguyen et al (64) 5 793 0.8 1.5 8.4 7.1
Arvold et al (25) 5 1434 0.8 2.3 10.8 6.7
Millar et al (65) 5 498 1.0 4.3 7.7 9.6
Voduc et al (15) 10 1461 8 10 21 14
Abbreviations: HER2þ Z human epidermal growth factor receptor 2 positive; LRR Z locoregional recurrence; TNBC Z triple-negative breast cancer.
* No adjuvant trastuzumab.

mastectomy compared with 13%, 3%, and 2% in HER2,
luminal B, and luminal A, respectively (26). In a series of
2985 patients treated with mastectomy, Voduc et al (15)
reported a 10-year local recurrence rate of 19% for those
with TNBC compared with 17%, 14%, and 8% for those
with HER2, luminal B, and luminal A, respectively. Taken
together, these data suggest that regardless of the type of
locoregional treatment selected (BCT or mastectomy), pa-
tients with TNBC and HER2-expressing cancer who are not
treated with trastuzumab have a greater risk of LRR
compared with patients with HRþ breast cancer treated
with hormone therapy. In addition, these results have been
corroborated by a large meta-analysis in which local
recurrence as a function of breast cancer subtype was
assessed in 12,862 patients (67). After both BCT and
mastectomy, patients with non-TNBC were less likely to
develop locoregional recurrence as compared to their
TNBC counterparts (RR 0.49 BCT, 0.66 mastectomy). The
association between LRR and TNBC was further
strengthened in the BCT and mastectomy groups with the
removal of patients with HER2þ cancers, most of whom
had not received trastuzumab.
Based of these results, the question of whether
mastectomy improves outcomes compared with BCT in
patients with TNBC has also been explored in several
retrospective studies. A Canadian study analyzed the LRR
outcomes in patients with stage T1-T2N0 TNBC who had
undergone BCT compared with modified radical mastec-
tomy and reported an absolute reduction in the LRR risk of
6% in their BCT cohort, after matching for tumor size (68).
The main criticism of this study was the low rate of
chemotherapy receipt for patients with TNBC, limiting
extrapolation of these findings to current-day practice in
which chemotherapy is considered an essential component
of care in patients with TNBC. The MD Anderson Cancer
Center performed a similar examination of outcomes for
patients with TNBC stratified by surgery type and
demonstrated that no survival advantage was evident for
patients with TNBC who had undergone mastectomy
versus BCT (69). Finally, 2 studies from Memorial Sloan
Kettering Cancer Center, 1 of which included patients with
very small, T1a-T1b TNBC (58% of whom had received
chemotherapy) and 1 of which examined patients with
larger TNBCs (80% of whom had received chemotherapy),
found no difference in LRR between those patients who
had undergone BCT and those who had undergone mas-
tectomy without RT (70, 71).
In summary, although patients with TNBC have inferior
10-year locoregional outcomes compared with other sub-
types, this finding has no specific surgical implications,
because the risk of LRR is unaltered, regardless of whether
BCT or mastectomy is elected. This reinforces the concept
that the prognosis of TNBC is driven by the biology of the
disease, rather than by the extent of the surgery.
Locoregional control for patients with TNBC
undergoing NAC
The relationship between LRR, response to NAC, and
breast cancer subtype has been described in a few large
single-institution studies and a meta-analysis (17, 72-74). A
large study of 751 breast cancer patients (219 with TNBC)
by the MD Anderson Cancer Center group showed that
TNBC patients treated with NAC not only had a high pCR
rate compared with the HRþ/HER2 patients (42% vs
16.5%, respectively) but also that survival outcomes
differed among TNBC patients according to chemotherapy
response (17). The TNBC patients with residual disease
after NAC had a 5-year LRR-free survival rate of 89.9%
compared with 98.6% in TNBC patients with a pCR. On
multivariate analysis, TNBC, clinical stage III disease, and

Table 4 Subtype and local recurrence rates after mastectomy

LRR rate (%)
Study Median follow-up (y) Patients (n) Luminal A Luminal B HER2þ* TNBC
Kyndi et al (26) 5 498 2 3 13 21
Voduc et al (15) 10 2985 8 14 17 19
Abbreviations: HER2þ Z human epidermal growth factor receptor 2 positive; LRR Z locoregional recurrence; TNBC Z triple-negative breast cancer.
* No adjuvant trastuzumab.
32 Horton et al.
failure to achieve a pCR were associated with lower LRR-
free survival. These results were corroborated by those
from the CTNeoBC (collaborative trials in neoadjuvant
breast cancer) trial, the largest and most robust study
examining the clinical outcomes of breast cancer patients
after NAC (74). The analysis of locoregional outcomes,
reported thus far in abstract form only, included 5252 pa-
tients from 7 different trials of NAC in the final cohort. The
trial was remarkable, not only for its size, substantial
number of LRR events (nZ391), and long follow-up period
(median 42 months), but also for the number of details
examined on multivariable analysis. Among the 1094 pa-
tients with TNBC in the study, 775 received BCT and 319
received mastectomy (74). Of the latter group, approxi-
mately one-third received PMRT. Low rates of LRR were
observed if a pCR had been achieved; however, the LRR
rate was as high as 22% when residual nodal disease was
present after NAC.
Similar patterns have been reported in a study from
Memorial Sloan Kettering Cancer Center of 233 patients
who had undergone neoadjuvant anthracycline- and/or
taxane-based chemotherapy, mastectomy, and PMRT (73).
Among the TNBC and HER2þ patients who obtained a
pCR, no LRR events occurred. In contrast, in the TNBC
patients with residual disease after NAC, the 5-year risk of
LRR failure was 26%, magnifying the need to identify
effective radiosensitizers that can enhance locoregional
control and be safely delivered to patients with TNBC
receiving RT.
Controversies in RT for TNBC
To date, only 1 randomized trial has examined the benefit
of PMRT specifically for patients with TNBC (75). In this
prospective study from China, 681 patients with TNBC
were randomized to PMRT versus observation after
mastectomy and adjuvant chemotherapy. Although most
patients had node-negative disease (82%), small subsets of
patients had N1 and N2 disease. At a median follow-up of
64 months (range 62-119), the addition of PMRT resulted
in an absolute benefit of approximately 14% and 11% for
relapse-free survival (88% vs 75%; PZ.02) and overall
survival (90% vs 79%; PZ.03), respectively. However,
scant details regarding radiation technique, the absence of
LRR outcomes, and possible differences in factors such as
pathologic and surgical techniques have limited its uni-
versal applicability (75). At present, the evidence is insuf-
ficient for the routine administration of PMRT for patients
with TNBC with negative nodes (56). However, in view of
this available evidence, it is reasonable to consider PMRT
for node-negative TNBC on a case-by-case basis, with
consideration of any additional adverse clinical or patho-
logic features.
The relatively low representation of patients with TNBC
and the lack of consistency among major trials in defining
TNBC groups have also precluded uniform extrapolation of
International Journal of Radiation Oncology  Biology  Physics
their results to patients with TNBC. In the American
College of Surgeons Oncology Group Z0011 trial evalu-
ating omission of axillary dissection for select patients with
node-positive disease, only 16% to 17% of the patients
were ER/PR and HER2 status was not assessed (76). In
the National Cancer Institute of Canada MA-20 and Eu-
ropean Organization for Research and Treatment of Cancer
22922 trials, TNBC subgroups were not specifically
defined; rather, the analysis was performed according to ER
status (37, 77). Subset analyses in the MA-20 trial
demonstrated that the addition of RNI was more effective in
the ER than in the ERþ groups. The disease-free survival
benefit in the MA-20 study was observed within approxi-
mately 1 year of RNI, suggesting that ER tumors are
more likely to harbor occult disease in the regional
lymphatics that can act as a nidus for metastatic spread
(without necessarily becoming clinically apparent) if
untreated. Extrapolation of these results would suggest that
the incremental benefit of comprehensive nodal RT might
be the greatest in TNBC; however, this remains to be
validated in other series.
Because of the high prevalence of high-grade tumors in
TNBC, another question germane to the radiotherapeutic
management of TNBC is the effectiveness of hypofrac-
tionated RT for patients who underwent BCT. A landmark
Canadian study that compared hypofractionation to stan-
dard fractionation for early-stage breast cancer patients
after BCS highlighted the possibility that the hypofractio-
nated regimen was less effective in patients with high-grade
tumors. In an exploratory subset analysis, the cumulative
incidence of local recurrence at 10 years was 4.7% in the
standard fractionated RT group compared with 15.6% in
the hypofractionated RT group (PZ.01) (78). However, this
finding was not corroborated in other large randomized
studies of hypofractionation for breast cancer, nor was it
confirmed in a subsequent central pathology review and
analysis of the Canadian trial that included both subtype
and grade (79, 80). Although the breast cancer subtype
defined by IHC and fluorescence in situ hybridization
predicted for local recurrence, no interaction was found
(albeit with numbers too small to allow for definitive con-
clusions) between subtype and treatment arm, suggesting
that ER, PR, and HER2 status cannot inform the choice to
use either hypofractionated or standard fractionated regi-
mens after BCT.
Despite these caveats, these studies have collectively
highlighted the importance of how a deeper understanding
of the biology of breast cancer should dictate the breadth,
volume, and intensity of RT, not just for TNBC, but also for
all breast cancer subtypes.
Strategies combining RT and biological-based
therapies for TNBC
During the past 5 years, a plethora of clinical trials has
aimed to leverage the biological heterogeneity of TNBC by
Volume 100  Number 1  2018
integrating systemic agents with RT. Most hereditary breast
cancers (BRCA-mutant) are TNBC. However, the converse
is not true, because most unselected TNBC cases are wild
type for BRCA1/2 (60). In the absence of a BRCA muta-
tion, a significant proportion of TNBC cases will still
demonstrate biological similarities to BRCA-associated
breast cancer, leading to the description “BRCA-ness.”
These characteristics of altered BRCA functionality and the
enrichment of TNBC for homologous recombination repair
deficiencies have generated significant interest in studying
platinum-based chemotherapy or PARP (poly ADP ribose
polymerase) inhibitors as a method of enhancing locore-
gional control when combined with RT.
The preliminary results from the Translational Breast
Cancer Research Consortium 024 trial, a phase I study of
combined veliparib and standard RT doses (50 Gy in 25
fractions, plus a 10-Gy boost) to the chest wall and lymph
nodes in 30 women with recurrent or inflammatory breast
cancer, were recently reported (81). These results pave the
way for the development of a phase II randomized trial
comparing standard RT alone with PARP inhibition plus
RT.
Several studies evaluating cisplatin and RT for TNBC
are also actively underway. A clinical trial at Memorial
Sloan Kettering Cancer Center is assessing homologous
recombination status as a biomarker of response to cisplatin
and concurrent RT in women with metastatic TNBC
who receive palliative RT to a recurrent or metastatic site
(44, 82). At the Dana Farber Cancer Institute, the safety of
concurrent cisplatin chemotherapy with whole-breast RT is
being evaluated in a phase I dose escalation trial for
patients with stage II-III TNBC after BCT or mastectomy
(19, 44, 83). Finally, the results of a phase I-II trial of
adjuvant carboplatin with concurrent whole-breast irradia-
tion (40.5 Gy in 15 fractions to the whole breast and
46.5 Gy in 17 fractions to the tumor bed) in a cohort of 36
patients with TNBC treated at the New York University
Medical Center were recently reported (84). With a median
follow-up of 48 months, 8 patients (22%; exact 95% CI,
10%-39%) developed grade 2 acute radiation dermatitis.
Overall, grade 2 adverse events were seen in 9 patients and
grade 3 in 2 patients, demonstrating the safety of this
approach in the acute setting (84).
Table 5 RT checkpoint inhibitor trials in metastatic breast cancer
Institution BC type Patients (n)
MSKCC TNBC 17
MSKCC All BC 20
Netherlands TNBC 84
U Chicago* All BC 18*
U Penn* All BC 70*
Abbreviations: BC Z breast cancer; Fx Z fraction; IT Z immunotherapy; MD Z physician; MSKCC Z Memorial Sloan Kettering Cancer Center;
RT Z radiation therapy; TNBC Z triple-negative breast cancer; U Chicago Z University of Chicago; U Penn Z University of Pennsylvania.
* Basket trials, including other solid tumor types.
Breast cancer biology and radiation therapy 33
The potential for RT to contribute to systemic and local
control in breast cancer has also recently been recognized by
the influx of clinical trials that have combined immuno-
therapies with RT for breast cancer (Table 5). In addition to
the single-institution studies listed in Table 5, the national
Southwestern Oncology Group 1418-NRG BR006 trial is
evaluating adjuvant pembrolizumab in patients with high-
risk TNBC. In that trial, RT delivered concurrent with
immunotherapy will be encouraged, which will allow for
comparative effectiveness analyses of the combination in this
setting. The innate immunogenicity of TNBC and HER2þ
breast cancer has been suggested by the high prevalence of
tumor-infiltrating lymphocytes in TNBC and HER2þ breast
cancer (85). This feature, combined with the immunosti-
mulatory properties of RT, has led to the hypothesis that RT
combined with checkpoint inhibitors might promote the
abscopal effect, a phenomenon in which distant sites outside
the radiation field can regress after treatment. Although no
consensus has been reached on the optimal dose fraction-
ation, timing, and sequencing of RT with immunotherapies,
the promise of improving distant control rates with RT is
particularly compelling for patients with TNBC, who expe-
rience high rates of distant metastases (Fig. 4).
Future Directions
In addition to the implications of existing breast cancer
subtypes on clinical practice, work is ongoing to refine
molecular assays that might identify radiation response
subtypes that will allow for the prescription of individual-
ized RT. Tramm et al (86) used tissue from the Danish
Breast Cancer Group 82bc studies to correlate gene
expression with locoregional outcomes. They identified 7
genes, including a 4-gene adaptation for formalin-fixed
paraffin-embedded tissues, that were both prognostic and
predictive of radiation response. Perhaps more importantly,
the investigators noted that using the intrinsic subtypes as a
surrogate could not replace the added value of the radiation
response signature (86). More recently, Zhang et al (87)
reported a centromere and kinetochore misexpression-
based gene signature score that predicted the radiation
sensitivity of breast cancer and other tumors.
IT RT dose
Pembrolizumab 30 Gy/5 Fx
Tremelimumab Brain RT per MD choice
Nivolumab 20 Gy/1 Fx
Pembrolizumab 30-50 Gy/3-5 Fx (NRG
BR001)
Durvalumab plus 24 Gy/3 Fx vs 17 Gy/1 Fx
tremelimumab
34 Horton et al. International Journal of Radiation Oncology  Biology  Physics

Eschrich et al (88) also focused on identifying a radia-
tion response signature. Their work was originally devel-
oped in vivo using radiated cells in culture to identify genes
of importance in radiation response. This has subsequently
been validated across multiple tumor types and in large
clinical cohorts (89, 90). Ten genes involved in the DNA
damage response, histone deacetylation, cell cycle,
apoptosis, and proliferation have been shown to predict for
relapse in patients undergoing RT. In a cohort enriched for
patients with local failure, the investigators were able to
identify a patient subset within the biologically aggressive
ER cohort that was both responsive to radiation and
experienced greatly improved outcomes after RT (91). In
those with luminal tumors resistant to RT, they were able to
document a benefit with dose escalation. In their most
recent report, 8271 tumor samples across 20 disease sites
from the prospective observational Total Cancer Care
protocol were used to calculate a genomic-adjusted radia-
tion dose and correlate this to clinical outcomes (92). If
ultimately prospectively validated, this assay could serve as
a guide for precision RT and establish a baseline from
which to assess RT modifications.
Other groups have focused on exploiting tumor biology
to enhance treatment delivery. In the studies by van der Leij
et al (93), Nichols et al (94), and Horton et al (95), a pre-
operative RT approach was used for patients with biologi-
cally favorable tumors. Partial breast irradiation was
delivered to the intact tumor, resulting in much smaller
target treatment volumes. Most significantly, prospective
pre- and post-RT assessment of response was incorporated
into all 3 trials. Imaging and tissue biomarkers of RT
response have been described and open the door to an
enhanced understanding of breast tumor radiation biology
in the future. Though outcomes overall are improving as
systemic therapy becomes more effective, lessons learned
from radiation response in early-stage disease can poten-
tially be exploited for the enhanced treatment of locally
advanced breast tumors.
Conclusion
Knowledge of breast tumor biology has transformed the
care of breast cancer in the 21st century. Our under-
standing of prognosis and ability to target specific sub-
types with relevant therapies have led to rapid
advancements and improvements in outcomes for patients
with breast cancer. Much of the early progress focused on
systemic therapies; however, as outlined in our review,
knowledge regarding the relationship among locoregional
outcomes, radiation response, and specific subtypes is
increasing and already affecting clinical practice. With
continued advancement, the practice of RT could be
similarly transformed. While it is unlikely that every
locoregional question can or will be addressed in a ran-
domized clinical trial, the existing data suggest that

Recommendation Quality of Recommendation

TRIPLE-NEGATIVE BREAST CANCER
RNI in women with high-risk node negative TNBC Reasonable now if consistent with patient values and
who receive adjuvant chemotherapy preferences

PMRT in women with pT1-2N0 TNBC who receive Reasonable on a case-by-case basis
adjuvant chemotherapy

Use of boost >10 Gy to chest wall/breast in women Reasonable on a case-by-case basis*

who do not obtain a pCR with NAC

Omission of RNI/PMRT in patients with clinical stage Cautionary; currently being investigated in NSABP
II TNBC who achieve a pCR in the lymph nodes to B-51/RTOG 1304 trial
NAC following BCS/mastectomy

Concurrent RT and radiosensitizing chemotherapy Cautionary; worthy of study

(platinums, gemcitabine)
* The recommendations regarding intensification of boost in TNBC patients who receive NAC are not guideline -concordant;
however, they are considered reasonable on a case-by-case basis, given absence of information about subtypes from currently
available studies evaluating boost and the enhanced risk of LRR in TNBC subtypes after BCS, relative to other BC subtypes.

Fig. 4. Table of recommendations for estrogen receptor-negative, progesterone receptor-negative, human epidermal growth
factor receptor 2-negative breast cancer. Abbreviations: BCS Z breast-conserving surgery; NAC Z neoadjuvant chemo-
therapy; NSABP Z National Surgical Adjuvant Breast and Bowel Project; pCR Z pathologic complete response;
PMRT Z postmastectomy radiation therapy; RNI Z regional nodal irradiation; RT Z radiation therapy; RTOG Z Radiation
Therapy Oncology Group; TNBC Z triple-negative breast cancer.
Volume 100  Number 1  2018
biology should certainly inform the development and
support of future clinical trials and must be carefully
considered in clinical decisions regarding the omission,
intensity, and escalation of breast RT.
References
1. Jensen EV, Jordan VC. The estrogen receptor: A model for molecular
medicine. Clin Cancer Res 2003;9:1980-1989.
2. Perou CM, Sørlie T, Eisen MB, et al. Molecular portraits of human
breast tumours. Nature 2000;406:747-752.
3. Lehmann BD, Bauer JA, Chen X, et al. Identification of human
triple-negative breast cancer subtypes and preclinical models for
selection of targeted therapies. J Clin Invest 2011;121:2750-2767.
4. Park YH, Lee SJ, Cho EY, et al. Clinical relevance of TNM staging
system according to breast cancer subtypes. Ann Oncol 2011;22:
1554-1560.
5. Sparano JA, Gray RJ, Makower DF, et al. Prospective validation of a
21-gene expression assay in breast cancer. N Engl J Med 2015;373:
2005-2014.
6. Amin MB, Greene FL, Edge SB, et al. The eighth edition AJCC
cancer staging manual: Continuing to build a bridge from a
population-based to a more “personalized” approach to cancer
staging. CA Cancer J Clin 2017;67:93-99.
7. Harris LN, Ismalla N, McShane LM, et al. Use of biomarkers to
guide decisions on adjuvant systemic therapy for women with early-
stage invasive breast cancer: American Society of Clinical Oncology
clinical practice guideline. J Clin Oncol 2016;34:1134-1150.
8. Cardoso F, van’t Veer LJ, Bogaerts J, et al. 70-Gene signature as an
aid to treatment decisions in early-stage breast cancer. N Engl J Med
2016;375:717-729.
9. Filipits M, Nielsen TO, Rudas M, et al. The PAM50 risk-of-
recurrence score predicts risk for late distant recurrence after endo-
crine therapy in postmenopausal women with endocrine-responsive
early breast cancer. Clin Cancer Res 2014;20:1298-1305.
10. Filipits M, Rudas M, Jakesz R, et al. A new molecular predictor of
distant recurrence in ER-positive, HER2-negative breast cancer adds
independent information to conventional clinical risk factors. Clin
Cancer Res 2011;17:6012-6020.
11. Sgroi DC, Sestak I, Cuzick J, et al. Prediction of late distant recur-
rence in patients with oestrogen-receptor-positive breast cancer: A
prospective comparison of the breast-cancer index (BCI) assay, 21-
gene recurrence score, and IHC4 in the TransATAC study popula-
tion. Lancet Oncol 2013;14:1067-1076.
12. Perez E, Suman V, Davidson N, et al. Results of chemotherapy
alone, with sequential or concurrent addition of 52 weeks of tras-
tuzumab in the NCCTG N9831 HER2-positive adjuvant breast
cancer trial. Cancer Res 2009;69(24 Suppl):80.
13. Swain SM, Basselga J, Kim SB, et al. Pertuzumab, trastuzumab, and
docetaxel in HER2-positive metastatic breast cancer. N Engl J Med
2015;372:724-734.
14. Turner NC, Ro J, André F, et al. Palbociclib in hormone-receptor-
positive advanced breast cancer. N Engl J Med 2015;373:209-219.
15. Voduc KD, Cheang MC, Tyldesley S, et al. Breast cancer subtypes
and the risk of local and regional relapse. J Clin Oncol 2010;28:
1684-1691.
16. Tseng YD, Uno H, Hughes ME, et al. Biological subtype predicts
risk of locoregional recurrence after mastectomy and impact of
postmastectomy radiation in a large national database. Int J Radiat
Oncol Biol Phys 2015;93:622-630.
17. Swisher SK, Vila J, Tucker SL, et al. Locoregional control according
to breast cancer subtype and response to neoadjuvant chemotherapy
in breast cancer patients undergoing breast-conserving therapy. Ann
Surg Oncol 2016;23:749-756.
Breast cancer biology and radiation therapy 35
18. Early Breast Cancer Trialists’ Collaborative Group, Darby S,
McGale P, Correa C, et al. Effect of radiotherapy after breast-
conserving surgery on 10-year recurrence and 15-year breast can-
cer death: Meta-analysis of individual patient data for 10,801 women
in 17 randomised trials. Lancet 2011;378:1707-1716.
19. Early Breast Cancer Trialists’ Collaborative Group, McGale P,
Taylor C, Correa C, et al. Effect of radiotherapy after mastectomy
and axillary surgery on 10-year recurrence and 20-year breast cancer
mortality: Meta-analysis of individual patient data for 8135 women
in 22 randomised trials. Lancet 2014;383:2127-2135.
20. Bouganim N, Tsvetkova E, Clemons M, et al. Evolution of sites of
recurrence after early breast cancer over the last 20 years: Implica-
tions for patient care and future research. Breast Cancer Res Treat
2013;139:603-606.
21. Fisher B, Bryant J, Dignam JJ, et al. Tamoxifen, radiation therapy, or
both for prevention of ipsilateral breast tumor recurrence after
lumpectomy in women with invasive breast cancers of one centimeter
or less. J Clin Oncol 2002;20:4141-4149.
22. Fyles AW, McCready DR, Manchul LA, et al. Tamoxifen with or
without breast irradiation in women 50 years of age or older with
early breast cancer. N Engl J Med 2004;351:963-970.
23. Hughes KS, Schnaper LA, Belton JR, et al. Lumpectomy plus
tamoxifen with or without irradiation in women age 70 years or older
with early breast cancer: Long-term follow-up of CALGB 9343. J
Clin Oncol 2013;31:2382-2387.
24. Kunkler IH, Williams LJ, Jack WJ, et al. Breast-conserving surgery
with or without irradiation in women aged 65 years or older with
early breast cancer (PRIME II): A randomised controlled trial.
Lancet Oncol 2015;16:266-273.
25. Arvold ND, Taghian AG, Niemierko A, et al. Age, breast cancer
subtype approximation, and local recurrence after breast-conserving
therapy. J Clin Oncol 2011;29:3885-3891.
26. Kyndi M, Sørensen FB, Knudsen H, et al. Estrogen receptor, pro-
gesterone receptor, HER-2, and response to postmastectomy radio-
therapy in high-risk breast cancer: The Danish Breast Cancer
Cooperative Group. J Clin Oncol 2008;26:1419-1426.
27. Liu FF, Shi W, Done SJ, et al. Identification of a low-risk luminal A
breast cancer cohort that may not benefit from breast radiotherapy. J
Clin Oncol 2015;33:2035-2040.
28. Mamounas EP, Tang G, Fisher B, et al. Association between the
21-gene recurrence score assay and risk of locoregional recurrence
in node-negative, estrogen receptor-positive breast cancer: Results
from NSABP B-14 and NSABP B-20. J Clin Oncol 2010;28:1677-
1683.
29. Mamounas EP, Liu Q, Paik S, et al. 21-Gene recurrence score and
locoregional recurrence in node-positive/ER-positive breast cancer
treated with chemo-endocrine therapy. J Natl Cancer Inst 2017;
109.
30. Fitzal F, Filipits M, Rudas M, et al. The genomic expression test
EndoPredict is a prognostic tool for identifying risk of local recur-
rence in postmenopausal endocrine receptor-positive, her2neu-
negative breast cancer patients randomised within the prospective
ABCSG 8 trial. Br J Cancer 2015;112:1405-1410.
31. A prospective cohort study evaluating risk of local recurrence
following breast conserving surgery and endocrine therapy in low
risk luminal A breast cancer (LUMINA). Available at: https://
clinicaltrials.gov/ct2/show/NCT01791829. Accessed 10 April, 2017.
32. IDEA study. Available at: https://clinicaltrials.gov/ct2/show/
NCT02400190. Accessed 10 April, 2017.
33. The PRECISION Trial (profiling early breast cancer for radiotherapy
omission): A phase II study of breast-conserving surgery without
adjuvant radiotherapy for favorable-risk breast cancer. Available at:
https://clinicaltrials.gov/ct2/show/NCT02653755. Accessed 10 April,
2017.
34. EXPERT: Examining Personalized Radiation Therapy for Low-risk
Early Breast Cancer. Available at: https://clinicaltrials.gov/ct2/
show/NCT02889874. Accessed April 10, 2017.
36 Horton et al.
35. Kirwan CC, Coles CE, Bliss J, and PRIMETIME Protocol Working
Group. It’s PRIMETIME. Postoperative avoidance of radiotherapy:
Biomarker selection of women at very low risk of local recurrence.
Clin Oncol (R Coll Radiol) 2016;28:594-596.
36. Moo TA, McMillan R, Lee M, et al. Impact of molecular subtype on
locoregional recurrence in mastectomy patients with T1-T2 breast
cancer and 1-3 positive lymph nodes. Ann Surg Oncol 2014;21:1569-
1574.
37. Whelan TJ, Olivotto IA, Parulekar WR, et al. Regional nodal
irradiation in early-stage breast cancer. N Engl J Med 2015;373:
307-316.
38. Slamon DJ, Layland-Jones B, Shak S, et al. Use of chemotherapy
plus a monoclonal antibody against HER2 for metastatic breast
cancer that overexpresses HER2. N Engl J Med 2001;344:783-792.
39. Joensuu H, Bono P, Kataja V, et al. Fluorouracil, epirubicin, and
cyclophosphamide with either docetaxel or vinorelbine, with or
without trastuzumab, as adjuvant treatments of breast cancer: Final
results of the FinHer trial. J Clin Oncol 2009;27:5685-5692.
40. Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant chemo-
therapy with trastuzumab followed by adjuvant trastuzumab versus
neoadjuvant chemotherapy alone, in patients with HER2-positive
locally advanced breast cancer (the NOAH trial): A randomised
controlled superiority trial with a parallel HER2-negative cohort.
Lancet 2010;375:377-784.
41. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant
chemotherapy for operable HER2-positive breast cancer. N Engl J
Med 2005;353:1673-1684.
42. Spielmann M, Roché H, Delozier T, et al. Trastuzumab for patients
with axillary-node-positive breast cancer: Results of the FNCLCC-
PACS 04 trial. J Clin Oncol 2009;27:6129-6134.
43. Yin W, Jiang Y, Shen Z, et al. Trastuzumab in the adjuvant treatment
of HER2-positive early breast cancer patients: A meta-analysis of
published randomized controlled trials. PLoS One 2011;6:e21030.
44. Halyard MY, Pisansky TM, Dueck AC, et al. Radiotherapy and
adjuvant trastuzumab in operable breast cancer: Tolerability and
adverse event data from the NCCTG phase III trial N9831. J Clin
Oncol 2009;27:2638-2644.
45. de Azambuja E, Holmes AP, Piccart-Gebhart M, et al. Lapatinib with
trastuzumab for HER2-positive early breast cancer (NeoALTTO):
Survival outcomes of a randomised, open-label, multicentre, phase 3
trial and their association with pathological complete response.
Lancet Oncol 2014;15:1137-1146.
46. Limentani SA, Brufsky AM, Erban JK, et al. Phase II study of
neoadjuvant docetaxel, vinorelbine, and trastuzumab followed by
surgery and adjuvant doxorubicin plus cyclophosphamide in
women with human epidermal growth factor receptor 2-
overexpressing locally advanced breast cancer. J Clin Oncol
2007;25:1232-1238.
47. Untch M, Rezai M, Loibl S, et al. Neoadjuvant treatment with
trastuzumab in HER2-positive breast cancer: Results from the
GeparQuattro study. J Clin Oncol 2010;28:2024-2031.
48. Jacob J, Belin L, Pierga JY, et al. Concurrent administration of
trastuzumab with locoregional breast radiotherapy: Long-term results
of a prospective study. Breast Cancer Res Treat 2014;148:345-353.
49. Aalders KC, Postma EL, Strobbe LJ, et al. Contemporary locore-
gional recurrence rates in young patients with early-stage breast
cancer. J Clin Oncol 2016;34:2107-2114.
50. Jwa E, Shin KH, Kim JY, et al. Locoregional recurrence by tumor
biology in breast cancer patients after preoperative chemotherapy
and breast conservation treatment. Cancer Res Treat 2016;48:
1363-1372.
51. Lanning RM, Morrow M, Riaz N, et al. The effect of adjuvant
trastuzumab on locoregional recurrence of human epidermal growth
factor receptor 2-positive breast cancer treated with mastectomy. Ann
Surg Oncol 2015;22:2517-2525.
52. Kim MM, Dawood S, Allen P, et al. Hormone receptor status in-
fluences the locoregional benefit of trastuzumab in patients with
nonmetastatic breast cancer. Cancer 2012;118:4936-4943.
International Journal of Radiation Oncology  Biology  Physics
53. Cao L, Cai G, Xu F, et al. Trastuzumab improves locoregional
control in HER2-positive breast cancer patients following adjuvant
radiotherapy. Medicine (Baltimore) 2016;95:e4230.
54. Bellon JR. Regional nodal irradiation in the anti-HER2 era. J Natl
Cancer Inst 2017;109.
55. Bartelink H, Maingon P, Poortmans P, et al. Whole-breast irradiation
with or without a boost for patients treated with breast-conserving
surgery for early breast cancer: 20-Year follow-up of a randomised
phase 3 trial. Lancet Oncol 2015;16:47-56.
56. Goldhirsch A, Winer EP, Coates AS, et al. Personalizing the treat-
ment of women with early breast cancer: Highlights of the St Gallen
International Expert Consensus on the Primary Therapy of Early
Breast Cancer 2013. Ann Oncol 2013;24:2206-2223.
57. Kennecke H, Yerushalmi R, Woods R, et al. Metastatic behavior of
breast cancer subtypes. J Clin Oncol 2010;28:3271-3277.
58. Dent R, Hanna WM, Trudeau M, et al. Pattern of metastatic spread in
triple-negative breast cancer. Breast Cancer Res Treat 2009;115:423-
428.
59. Bauer KR, Brown M, Cress RD, et al. Descriptive analysis of
estrogen receptor (ER)-negative, progesterone receptor (PR)-nega-
tive, and HER2-negative invasive breast cancer, the so-called triple-
negative phenotype: A population-based study from the California
Cancer Registry. Cancer 2007;109:1721-1728.
60. Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer.
N Engl J Med 2010;363:1938-1948.
61. Perou CM. Molecular stratification of triple-negative breast cancers.
Oncologist 2010;15(Suppl 5):39-48.
62. Parker JS, Mullins M, Cheang MC, et al. Supervised risk predictor of
breast cancer based on intrinsic subtypes. J Clin Oncol 2009;27:
1160-1167.
63. Braunstein LZ, Taghian AG, Niemierko A, et al. Breast-cancer
subtype, age, and lymph node status as predictors of local recurrence
following breast-conserving therapy. Breast Cancer Res Treat 2017;
161:173-179.
64. Nguyen PL, Taghian AG, Katz MS, et al. Breast cancer subtype
approximated by estrogen receptor, progesterone receptor, and HER-
2 is associated with local and distant recurrence after breast-
conserving therapy. J Clin Oncol 2008;26:2373-2378.
65. Millar EK, Graham PH, O’Toole SA, et al. Prediction of local
recurrence, distant metastases, and death after breast-conserving
therapy in early-stage invasive breast cancer using a five-biomarker
panel. J Clin Oncol 2009;27:4701-4708.
66. Cancello G, Maisonneuve P, Rotmensz N, et al. Prognosis in women
with small (T1mic, T1a, T1b) node-negative operable breast cancer
by immunohistochemically selected subtypes. Breast Cancer Res
Treat 2011;127:713-720.
67. Lowery AJ, Kell MR, Glynn RW, et al. Locoregional recurrence after
breast cancer surgery: A systematic review by receptor phenotype.
Breast Cancer Res Treat 2012;133:831-841.
68. Abdulkarim BS, Cuartero J, Hanson J, et al. Increased risk of
locoregional recurrence for women with T1-2N0 triple-negative
breast cancer treated with modified radical mastectomy without
adjuvant radiation therapy compared with breast-conserving therapy.
J Clin Oncol 2011;29:2852-2858.
69. Adkins FC, Gonzalez-Angulo AM, Lei X, et al. Triple-negative
breast cancer is not a contraindication for breast conservation. Ann
Surg Oncol 2011;18:3164-3173.
70. Ho AY, Gupta G, King TA, et al. Favorable prognosis in patients with
T1a/T1bN0 triple-negative breast cancers treated with multimodality
therapy. Cancer 2012;118:4944-4952.
71. Zumsteg ZS, Morrow M, Arnold B, et al. Breast-conserving therapy
achieves locoregional outcomes comparable to mastectomy in
women with T1-2N0 triple-negative breast cancer. Ann Surg Oncol
2013;20:3469-3476.
72. Caudle AS, Yu TK, Tucker SL, et al. Local-regional control ac-
cording to surrogate markers of breast cancer subtypes and response
to neoadjuvant chemotherapy in breast cancer patients undergoing
breast conserving therapy. Breast Cancer Res 2012;14:R83.
Volume 100  Number 1  2018
73. Yang TJ, Morrow M, Modi S, et al. The effect of molecular subtype
and residual disease on locoregional recurrence in breast cancer
patients treated with neoadjuvant chemotherapy and postmastectomy
radiation. Ann Surg Oncol 2015;22(Suppl 3):S495-S501.
74. Eleftherios P, Mamounas PC, Zhang L, et al. Locoregional recur-
rence (LRR) after neoadjuvant chemotherapy (NAC): Pooled-
analysis results from the collaborative trials in neoadjuvant breast
cancer (CTNeoBC). Presented at the American Society of Clinical
Oncology Breast Symposium, 2014, San Francisco, CA. J Clin Oncol
2014;32(Suppl 26). abstract 61.
75. Wang J, Shi M, Ling R, et al. Adjuvant chemotherapy and radiotherapy
in triple-negative breast carcinoma: A prospective randomized
controlled multi-center trial. Radiother Oncol 2011;100:200-204.
76. Giuliano AE, Hunt KK, Ballman KV, et al. Axillary dissection vs no
axillary dissection in women with invasive breast cancer and sentinel
node metastasis: A randomized clinical trial. JAMA 2011;305:569-575.
77. Poortmans PM, Struikmans H, Bartelink H. Regional nodal irradia-
tion in early-stage breast cancer. N Engl J Med 2015;373:1879-1880.
78. Whelan TJ, Pignol JP, Levine MN, et al. Long-term results of
hypofractionated radiation therapy for breast cancer. N Engl J Med
2010;362:513-520.
79. Haviland JS, Owen JR, Dewer JA, et al. The UK Standardisation of
Breast Radiotherapy (START) trials of radiotherapy hypofractiona-
tion for treatment of early breast cancer: 10-Year follow-up results of
two randomised controlled trials. Lancet Oncol 2013;14:1086-1094.
80. Bane AL, Whelan TJ, Pond GR, et al. Tumor factors predictive of
response to hypofractionated radiotherapy in a randomized trial
following breast conserving therapy. Ann Oncol 2014;25:992-998.
81. Jagsi R, Griffith KG, Bellon JR, et al. TBCRC 024 initial results: A
multicenter phase 1 study of veliparib administered concurrently
with chest wall and nodal radiation therapy in patients with inflam-
matory or locoregionally recurrent breast cancer. Int J Radiat Oncol
Biol Phys 2015;93(Suppl):S137.
82. Homologous recombination repair status as a biomarker of response
in locally recurrent/metastatic triple negative breast cancer patients
treated with concurrent cisplatin and radiation therapy. Available at:
https://clinicaltrials.gov/ct2/show/NCT02422498. Accessed 10 April,
2017.
83. Cisplatin þ RT for triple negative breast cancer. Available at: https://
clinicaltrials.gov/ct2/show/NCT01674842. Accessed 10 April, 2017.
84. Formenti SC, Golden EB, Goldberg JD, et al. Results of a phase I-II
study of adjuvant concurrent carboplatin and accelerated
Breast cancer biology and radiation therapy 37
radiotherapy for triple negative breast cancer. Oncoimmunology
2017;6:e1274479.
85. Adams S, Gray RJ, Demaria S, et al. Prognostic value of tumor-
infiltrating lymphocytes in triple-negative breast cancers from two
phase III randomized adjuvant breast cancer trials: ECOG 2197 and
ECOG 1199. J Clin Oncol 2014;32:2959-2966.
86. Tramm T, Mohammed H, Myhre S, et al. Development and vali-
dation of a gene profile predicting benefit of postmastectomy
radiotherapy in patients with high-risk breast cancer: A study of
gene expression in the DBCG82bc cohort. Clin Cancer Res 2014;
20:5272-5280.
87. Zhang W, Mao JH, Zhu W, et al. Centromere and kinetochore gene
misexpression predicts cancer patient survival and response to
radiotherapy and chemotherapy. Nat Commun 2016;7:12619.
88. Eschrich S, Zhang H, Zhao H, et al. Systems biology modeling of the
radiation sensitivity network: A biomarker discovery platform. Int J
Radiat Oncol Biol Phys 2009;75:497-505.
89. Eschrich SA, Fulp WJ, Pawitan Y, et al. Validation of a radiosensi-
tivity molecular signature in breast cancer. Clin Cancer Res 2012;18:
5134-5143.
90. Eschrich SA, Pramana J, Zhang H, et al. A gene expression model
of intrinsic tumor radiosensitivity: Prediction of response and
prognosis after chemoradiation. Int J Radiat Oncol Biol Phys 2009;
75:489-496.
91. Torres-Roca JF, Fulp WJ, Caudell JJ, et al. Integration of a radio-
sensitivity molecular signature into the assessment of local recur-
rence risk in breast cancer. Int J Radiat Oncol Biol Phys 2015;93:
631-638.
92. Scott JG, Berglund A, Schell MJ, et al. A genome-based model for
adjusting radiotherapy dose (GARD): A retrospective, cohort-based
study. Lancet Oncol 2017;18:202-211.
93. van der Leij F, Bosma SC, van de Vijver MJ, et al. First results of the
preoperative accelerated partial breast irradiation (PAPBI) trial.
Radiother Oncol 2015;114:322-327.
94. Nichols E, Kesmodel SB, Bellavance E, et al. Preoperative acceler-
ated partial breast irradiation for early-stage breast cancer: Pre-
liminary results of a prospective, phase 2 trial. Int J Radiat Oncol
Biol Phys 2017;97:747-753.
95. Horton JK, Blitzblau RC, Yoo S, et al. Preoperative single-fraction
partial breast radiation therapy: A novel phase 1, dose-escalation
protocol with radiation response biomarkers. Int J Radiat Oncol
Biol Phys 2015;92:846-855.