Review

Radiation therapy in the locoregional treatment of

triple-negative breast cancer
Meena S Moran

This Review assesses the relevant data and controversies regarding the use of radiotherapy for, and locoregional Lancet Oncol 2015; 16: e113–22
management of, women with triple-negative breast cancer (TNBC). In view of the strong association between BRCA1 Yale University School of
and TNBC, knowledge of baseline mutation status can be useful to guide locoregional treatment decisions. TNBC is Medicine, Department of
Therapeutic Radiology, New
not a contraindication for breast conservation therapy because data suggest increased locoregional recurrence risks
Haven, CT, USA (M S Moran MD)
(relative to luminal subtypes) with breast conservation therapy or mastectomy. Although a boost to the tumour bed
Correspondence to:
should routinely be considered after whole breast radiation therapy, TNBC should not be the sole indication for post- Dr Meena S Moran, Yale
mastectomy radiation, and accelerated delivery methods for TNBC should be offered on clinical trials. Preliminary University School of Medicine,
data implying a relative radioresistance for TNBC do not imply radiation omission because radiation provides an Department of Therapeutic
Radiology, New Haven, CT
absolute locoregional risk reduction. At present, the integration of subtypes in locoregional management decisions is
06520-8040, USA
still in its infancy. Until level 1 data supporting treatment decisions based on subtypes are available, standard Meena.Moran@yale.edu
locoregional management principles should be adhered to.

Introduction patients undergoing mastectomy who are at high risk,

The general principles for locoregional management of
early-stage, invasive breast cancer have increased in
complexity in the past decade because of the introduction
of breast cancer classification by molecular subtypes.
Although the prognostic and predictive value of breast
cancer subtypes are widely recognised and clinically
applicable to decisions regarding systemic treatment,
their value for locoregional management needs further
elucidation. For triple-negative breast cancer (TNBC),
decisions with respect to locoregional management have
increased in complexity because of its inherent rapid
natural history, aggressive clinicopathological features,
high propensity for relapse, and the absence of targeted
treatments. Additionally, because of the substantial
heterogeneity within TNBC, there are no consensus
criteria when defining basal-like or triple-negative
subtypes, and conflicting results from studies of
locoregional outcomes have further complicated the
general principles of locoregional management. In this
Review, pertinent data, strategies, and controversies
associated with the locoregional management of TNBC
are assessed.
post-mastectomy radiation therapy (PMRT) diminishes
locoregional relapses and provides a survival benefit in
selected patients.6 Few phase 3 data or consensus
guidelines recommendations that categorise patients by
breast cancer subtype are available to help to guide
locoregional treatment decisions. In the absence of these
data and guidelines, hormone-receptor negativity versus
positivity has been used as a surrogate measure to
estimate breast cancer subtype.4 In the setting of
neoadjuvant chemotherapy, the principles for breast
conservation therapy are not modified and all patients
should receive WBRT irrespective of their pathological
response. Decisions with respect to PMRT in the setting
of neoadjuvant chemotherapy followed by mastectomy,
which are already complex because of an absence of
level 1 data, have been further complicated by breast
cancer subtyping. Despite the enthusiasm for faster
radiation delivery methods—eg, accelerated partial breast
irradiation (APBI) and hypofractionated WBRT—their
application needs to be considered in the context of
breast cancer subtype before their routine use in the
treatment for TNBC.

Locoregional management Classification and characteristics of TNBC

The two main locoregional treatment pathways for early-
stage, invasive breast cancer are either breast conservation
therapy (defined as lumpectomy followed by whole breast
radiation therapy [WBRT] delivered with conventional
fractionation) or simple mastectomy, both with
appropriate axillary nodal assessment and management.
Findings from several phase 3 studies1–3 have shown the
long-term equivalence of breast conservation therapy
and mastectomy, and a meta-analysis4 of these data
suggested locoregional and survival benefits with the
addition of WBRT to patients undergoing lumpectomy.4
Use of a radiation boost to dose-escalate a restricted area
surrounding the lumpectomy site provides an additional
reduction in local relapse after WBRT.5 Similarly for
Gene expression profiling, based on RNA expression
arrays of breast cancer samples with similar patterns of
gene expression, has led to the classification of
five distinct molecular subtypes (luminal A or B, HER2-
positive, basal-like, and normal) of breast cancer.7,8 The
basal-like subtype was described by molecular absence or
minimum expression of receptors either for oestrogen
(ER), progesterone (PR), and HER2 (EGFR2), in addition
to high expression of c-Kit, myoepithelial cytokeratins 5,
6, and 17, and HER1 (EGFR1). For practical clinical
purposes, the basal-like subtype has been defined by
immunohistochemistry with ER, PR, and HER2 (the so-
called triple-negative disease). As a result, although
basal-like and triple-negative are often used

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 Review
interchangeably, they are not synonymous, with a
25–30% discordance between molecular profiling
and routine three-marker immunohistochemistry
classification.9 For example, the claudin-low subtype was
recently identified as a subgroup of TNBC with low
expression of the claudin genes, which are involved in
epithelial cell interactions and junctions. This TNBC
subtype, characterised by an intense immune cell
infiltrate, has stem-cell features and characteristics of
epithelial–mesenchymal transition (EMT) and is also
thought to be triple-negative, yet is regarded as distinct
from basal-like cancers.10 Thus, in this Review, the term
TNBC will pertain to relevant studies classified with the
three-marker clinical assays and the term basal-like used
for classifications based on tissue microarrays, more
comprehensive immunohistochemistry methods, or
molecular profiling.
TNBC, which comprises 15–20% of breast cancers, has
aggressive clinicopathological features that result in worse
outcomes compared with other subtypes of breast
cancer.11–13 TNBC is associated with young age, BRCA1
mutations, the black population, less mammographic
detection, aggressive morphological features (tumour
necrosis, high mitotic indices, nuclear–cytoplasmic ratios,
high grade difference), and worse outcomes that do not
always correlate with traditional prognostic features, such
as stage, tumour size, or nodal involvement.14–17 Data are
conflicting as to whether patients with TNBC have a
higher propensity for axillary node metastasis at
presentation than other cancer subtypes.18,19 In relation to
local relapses in luminal subtypes (ranges between 5 and
15 or more years), local relapses in TNBC tend to occur
much earlier (typically <5 years), presenting more
frequently with simultaneous distant metastasis than
isolated local recurrences, a higher frequency of brain and
pulmonary metastasis, and worse post-recurrence survival
outcomes.9,12,16
Association with BRCA1 mutations
Although only 10–20% of sporadic TNBCs harbour germ-
line BRCA1 mutations,20 75% or more of breast cancers
associated with BRCA1 present the basal-like subtype of
TNBC.21,22 Furthermore, there are striking clinicopatho-
logical similarities between BRCA1-associated breast
cancers and sporadic TNBC, such as high grade, high
proliferative indices, lymphocytic infiltrate and pushing
margins (a pathological characteristic) resembling
medullary disease, a greater propensity for visceral than
bone or lymphatic metastases, and notable overlaps in
gene expression assays, TP53 mutations, and other
chromosome abnormalities.23 Although the exact
mechanisms of action of BRCA1 are not yet fully
understood, it is involved in various cellular functions,
including crucial roles in DNA repair via homologous
recombination, cell-cycle checkpoint control and
transcriptional regulation, X-chromosome inactivation,
and mammary gland development.24,25 Collectively, the
e114
likenesses between sporadic TNBC and BRCA1-
associated cancers suggest some shared similarities in
the defects of underlying biological pathways, possibly a
fundamental defect in the BRCA1 pathway of sporadic
TNBC.13,22,23
Thus, determination of the germ-line BRCA mutation
status is crucial in making decisions for locoregional
management. In view of the strong association of
BRCA1-associated breast cancer with TNBC, present
guidelines for genetic screening have incorporated
TNBC so that all patients younger than 60 years with this
form of cancer, irrespective of family history, should be
considered for genetic testing.26,27 Patients should be
clearly informed about the distinction between the risks
of breast conservation therapy for BRCA carriers, which
has an overall increased lifetime risk of both ipsilateral
and contralateral local recurrence,28 by comparison with
patients with sporadic TNBC in which this increased risk
does not seem to be present after breast conservation
therapy.12 However, cause-specifıc and overall survival
outcomes are similar for BRCA-associated breast cancers
with either breast conservation therapy or mastectomy.28
Thus, the presence of a BRCA mutation is not a con-
traindication for breast conservation in otherwise
appropriately selected candidates. Nevertheless, only
BRCA carriers who are highly motivated to preserve their
breasts will typically choose breast conservation therapy,
with most carriers of BRCA mutation electing to undergo
definitive ipsilateral mastectomy, often with simul-
taneous prophylactic contralateral mastectomy.
Locoregional relapse outcomes
In the assessment of locoregional outcomes for TNBC,
there are two crucial and distinct questions that need to
be addressed. First is the determination of locoregional
outcomes after breast conservation therapy or
mastectomy for TNBC in relation to other subtypes.
Second, the more clinically relevant question is to
establish whether the more aggressive natural history of
TNBC warrants mastectomy instead of breast
conservation therapy to provide an advantage in
outcomes.
Outcomes relative to other breast cancer subtypes
Although randomised trials of both breast conservation
therapy and PMRT predated classification by breast cancer
subtype, a growing body of data from retrospective studies
have classified outcomes of patients who have had breast
conservation therapy and mastectomy by breast cancer
subtype using clinical assays. For breast conservation
therapy, although data are conflicting, an overall temporal
trend (from 2006 up to now) suggests that TNBC (and
HER2-positive disease) have higher risks of locoregional
relapses than the luminal subtypes (table 1). In 2006, when
initial reports of outcomes for TNBC were investigated,
similar 5-year local relapses (12–17%) were reported for
TNBC and non-TNBC subtypes.12,29 On the basis of these
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 Review

initial studies, TNBC was concluded not to be a

n with Ntotal Median follow- Local or locoregional outcomes
contraindication for breast conservation therapy. TNBC up (years)
Additional series30 that have subsequently, but not
Haffty et al29 (2006) 117 482 7·9 TNBC 17%; non-TNBC 17%
consistently, analysed outcomes with four or more
Dent et al12 (2007) 180 1601 8·1 TNBC 12%; non-TNBC 13%
subtypes of breast cancer have suggested more locoregional
Nguyen et al30 (2008) 89 793 5·8 Luminal A 1·8%; luminal B 1·5%;
relapses after breast conservation therapy for TNBC (and HER2 8·4%; basal or TNBC 7·1%
HER2-positive disease) than for luminal subtypes, and Millar et al31 (2009) 52 482 7 Luminal A 5·1%; luminal B 8·7%;
collectively suggest about a 50% higher local or locoregional HER2-enriched 15·4%; basal-like 17·3%
relapse risk for TNBC relative to luminal subtypes. Voduc et al32 (2010) 556 2985 12 Luminal A 8%; luminal B 10%;
Differences between conclusions of series during the past luminal-HER2 9%; HER2-enriched 21%;
few years might be attributed to improved classification basal-like 14%; TNBC non-basal 8%

with guidelines to define HER2-positive disease and
increased routine use of gene amplifıcation (fluorescence
in-situ hybridisation) to test for equivocal HER2
immunohistochemistry,36 and analysis of outcomes by
more than two subtype groups (not only by TNBC vs non-
TNBC). An additional factor that might contribute to the
differences between earlier and later studies is the
development and widespread use of targeted therapies,
such as trastuzumab and aromatase inhibitors, the effects
of which decrease the risk of local relapse for patients with
HER2-positive or ER-positive disease.37,38 Therefore, use of
these targeted therapies in later studies might have
contributed to differences in outcomes between breast
cancer subtypes reported by the series. .Although the
HER2-positive subtype was historically associated with
poor locoregional relapse similar to TNBC, most of these
data were from the pre-trastuzumab era.30 Advances in
receptor-specifıc antibody therapy and newer EGFR-
pathway inhibitors have substantially improved loco-
regional relapse outcomes for women with HER2-positive
disease.39 Outcomes from cohorts in which patients with
HER2-positive disease were routinely treated with
trastuzumab suggest significantly more locoregional
relapses only in the TNBC subgroup; patients with HER2-
positive disease had similar or fewer locoregional relapses
than those with luminal tumours.33
Worse outcomes for TNBC with breast conservation
therapy are also alluded to by the latest Oxford meta-
analysis4 of 17 randomised controlled trials of breast
conservation therapy. An analysis of outcomes of patients
who received WBRT by hormone receptor status
stratified by T stage, age, and grade showed that
locoregional relapse was more common in ER-poor than
in ER-rich cohorts (29% vs 14%).4
Similarly, outcomes for mastectomy (with or without
radiation) by subtype suggest a higher locoregional
relapse risk for basal-like TNBC than luminal subtypes.
For example, a large study32 analysed locoregional
relapses after precise classification into six subtypes that
included distinguishing basal-like tumours from those
with triple-negative phenotype (with analysis of EGFR
and cytokeratins 5 or 6) and reported the highest risk of
local relapse after mastectomy in basal-like and HER2-
positive groups; the TNBC phenotype did not have this
raised risk. Patients with basal-like or HER2-positive
disease who received breast conservation therapy had
Billar et al33 (2010) 123 1061 2·6 Luminal A 1%; luminal B 2·9%;
HER2-enriched 2·9%; TNBC 5·7%
Arvold et al34 (2011) 171 1434 7·1 Luminal A 0·8%; luminal B 2·3%;
HER2-enriched 10·8%; TNBC 6·7%
Gangi et al35 (2014) 234 1851 5·0 Luminal A 5%; luminal B 4%;
HER2-enriched 4%; TNBC 7%
TNBC=triple-negative breast cancer.
Table 1: Selected breast conservation therapy studies that reported outcomes of triple-negative breast
cancer relative to other subtypes
similarly raised risks of locoregional relapses.32 Of three
meta-analyses40–42 that analysed locoregional outcomes in
TNBC, the primary focus of two was outcomes of TNBC
in relation to other subtypes of breast cancer. One of
these42 analysed 15-year outcomes in nearly 22 000 patients
treated with breast conservation therapy from 15 studies,
and showed that TNBC, by comparison with non-TNBC,
had significantly worse local relapse (hazard ratio [HR]
3·31, 95% CI 1·69–6·45, p<0·01) and overall recurrence
(3·19, 1·91–5·31, p<0·01). The third meta-analysis40
included more than 12 000 patients from 15 studies
treated with either breast conservation therapy or
mastectomy and reported lower risk of locoregional
relapse for non-TNBC than for TNBC with breast
conservation therapy (relative risk [RR] 0·49, 95% CI
0·33–0·73, p=0·0005) and with mastectomy (0·66,
0·53–0·83, p=0·0003). The authors concluded that
patients with TNBC are at an increased risk of developing
locoregional relapses (compared with other subtypes)
irrespective of breast conservation therapy or mastectomy
(figure 1).
Breast conservation therapy versus mastectomy
The poor prognosis of TNBC suggests the need for an
aggressive locoregional surgical approach, possibly
necessitating removal of all breast tissue. As a result, the
general longstanding principle that outcomes after
breast conservation therapy and mastectomy are
equivalent has been challenged in the context of patients
with early-stage TNBC. Although knowledge of TNBC is
rapidly increasing, outcomes data from phase 3 studies
for TNBC with breast conservation therapy in
comparison with mastectomy are scarce. In fact,
emerging data paradoxically suggest that breast
conservation therapy might provide improved
locoregional outcomes compared with mastectomy for

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 Review

early-stage TNBC. For instance, investigators of a large for patients with TNBC.54 Steward and colleagues55
series analysing locoregional relapse outcomes for compared survival outcomes of TNBC by type of surgery
patients with T1–2, N0 TNBC treated with either breast and showed that treatment with radiation significantly
conservation therapy or mastectomy (no PMRT) reported improved survival in the lumpectomy group (HR 0·30,
a 6% absolute benefit in reducing locoregional relapses 95% CI 0·16–0·58, p=0·001), but PMRT did not improve
with breast conservation therapy compared with survival in the mastectomy cohort (0·38, 95% CI
mastectomy (p<0·001).40 This result suggests that breast 0·05–3·04, p=0·34), suggesting an increased biological
conservation therapy, which routinely incorporates responsiveness of TNBC to radiation (when breast tissue
radiation, might be more appropriate than mastectomy is present). Lastly, findings from two meta-analyses40,41 of
outcomes by subtype for breast conservation therapy in
A comparison with mastectomy indicated fewer loco-
Breast conserving Non-TNBC vs TNBC Relative risk (95% Cl) regional relapses after breast conservation therapy than
treatment trial mastectomy in early-stage TNBC. One41 of these meta-
Straver et al43 0·22 (0·04–1·24) analyses did a direct statistical comparison between
breast conservation therapy and mastectomy for TNBC,
Voduc et al32 0·73 (0·56–0·97)
showing fewer locoregional relapses (16·9% vs 21·9%;
31
Millar et al 0·36 (0·22–0·63) RR 0·75, 95% CI 0·65–0·87, p<0·0001) and fewer
Solin et al44 0·51 (0·23–1·18) distant metastases (23·6% vs 34·4%; RR 0·68, 95% CI
Freedman et al 45
0·85 (0·27–2·69)
0·60–0·76, p<0·00001) with breast conservation therapy
than with mastectomy. Furthermore, in the adjusted
Arvold et al34 0·26 (0·15–0·48)
analysis of only stage I or II TNBC, locoregional relapses
Haffty et al 29
0·99 (0·64–1·58) were 2·5 times more common and distant metastases
Ihemelandu et al46 0·57 (0·17–2·01) were twice as common with mastectomy than with
47
breast conservation therapy. The authors concluded that
Gabos et al 2·46 (0·46–14·41)
although TNBC is associated with worse locoregional
Meyers et al48 0·18 (0·00–1·63)
relapse outcomes than luminal subtypes, locoregional
Wong et al 49
0·09 (0·03–0·28) relapses in TNBC are diminished to a greater extent with
Siponen et al50 0·58 (0·19–1·78) breast conservation therapy than with mastectomy.41
Ultimately, the decision for patients with TNBC to have
Combined (random) 0·49 (0·33–0·73)
breast conservation therapy or mastectomy should
0·01 0·1 0·2 0·5 1 2 5 10 100 incorporate their personal preference after an in-depth
discussion about the implications of their treatment
B options in context of their individual disease specifics.
Mastectomy Non-TNBC vs TNBC Relative risk (95% Cl) Patients should be made aware that the existing data
Straver et al43 0·37 (0·07–2·08) suggest that although locoregional relapses are more
common in TNBC by comparison with luminal subtypes
Voduc et al32 0·75 (0·55–1·03) after breast conservation therapy, this risk is similarly
raised with mastectomy. Optimisation of systemic therapy
Ihemelandu et al46 0·47 (0·13–1·73) for TNBC will inevitably result in improved survival
outcomes, especially in view of their high risk of harbouring
Kyndi et al51 0·78 (0·54–1·15) micrometastasis at the time of diagnosis and competing
risk of distant relapse simultaneously with locoregional
Gabos et al47 0·38 (0·18–0·83)
relapses. On the basis of the present outcome data, the risk
of isolated locoregional relapses is low enough to support
Wang et al52 0·76 (0·47–1·27)
either breast conservation therapy or mastectomy for
Meyers et al48 0·27 (0·09–0·89)
patients with TNBC.

Mersin et al53 0·32 (0·11–0·93) PMRT

PMRT reduces the risk of locoregional relapses and
Combined (random) 0·66 (0·53–0·83) provides a survival benefit in selected patients.6,56
Traditional indications for PMRT include positive nodes,
0·01 0·1 0·2 0·5 1 2 5
positive margins, or a tumour size of more than 5 cm.57
Relative risk The higher risk for locoregional relapses in TNBC after
mastectomy raises the question as to whether the
Figure 1: Forest plots showing locoregional outcomes with breast conserving treatment (A) and mastectomy
(B) for non-TNBC relative to TNBC presence of this subtype should affect decisions to use
TNBC=triple-negative breast cancer. Figure adapted from Lowery and colleagues,40 by permission of PMRT in the absence of other high-risk features. A
Breast Cancer Research and Treatment. phase 3 trial58 of 681 patients from China with

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A B C

D E F

Figure 2: Radiation delivery techniques

(A) Right whole breast radiation therapy (WBRT) showing the medial tangent beam. (B) Skin rendition WBRT, medial and lateral beams. Pink section represents the
lumpectomy cavity with a margin of normal tissue. Orange line represents radiation field borders on skin. (C) Treatment-planning scan (WBRT volume), medial and
lateral beams. Axial image of treatment planning scan through the mid-chest. (D) Radiation boost. (E) Treatment-planning scan (post-mastectomy radiation therapy
volume), several beamlets generate conformal plan on chest wall. (F) Treatment-planning scan (accelerated partial breast irradiation volume): 2 cm around
lumpectomy excluding ribs; methods for delivery vary. Red sections represent areas receiving high-dose volume. Other colours represent the so-called drop-off of
radiation dose, with blue as lowest (negligible) aggregate dose.

stage I–II TNBC, all treated with mastectomy plus
chemotherapy and randomly assigned to receive PMRT
or no radiation, reported data after a median follow-up of
longer than 7 years. Of note, more than 80% of patients
were node-negative, and more than 70% had tumours of
2 cm or smaller in size. The 5-year relapse-free survival
(88·3% vs 74·6%; HR 0·77, 95% CI 0·72–0·98, p=0·02)
and overall survival (90·4% vs 78·7%; HR 0·79, 0·74–0·97,
p=0·03) were significantly improved with the addition of
PMRT compared with no radiation.58 Unfortunately, the
clinical applicability of this study58 is limited by the
absence of detailed reporting of locoregional outcomes
and radiation methods, and the findings should therefore
be regarded as hypothesis generating.
Present guidelines for PMRT do not incorporate
subtypes of breast cancer in their recommendations. For
example, the use of PMRT “solely based on HER2+ or
TNBC” has been rejected by the St Gallen International
Expert Consensus.59 The American Society of Clinical
Oncology has recommended PMRT for patients with four
or more positive nodes, stage T3, or stage III tumours,
but state insufficient evidence to make recommendations
for modification of the guideline based on other tumour,
patient, or treatment-related factors.60 Although PMRT
might improve outcomes in TNBC, data reporting
outcomes for these patients in the absence of other PMRT
indications are sparse. Additional confirmatory level 1
studies with adequate long-term follow-up are needed
before TNBC subtype alone should affect standard PMRT
locoregional management decisions.
Use of a radiation boost (after WBRT)
A radiation boost is usually given to the area surrounding
the tumour bed after WBRT to dose-escalate the region at
highest risk of local recurrence (figure 2). Although a
radiation boost is regarded as optional in breast
conservation therapy for early-stage invasive breast cancer,
level 1 data with long-term follow-up have shown its direct
effect in further reducing local relapse beyond the benefit
reported with WBRT.5 This additional benefit was
significant for all age groups, with the largest proportional
benefit in women younger than 50 years and in patients
with high-grade tumours.61 Patients with TNBC, who are
characteristically young with high-grade tumours, have an
increased risk of harbouring microscopic disease after
lumpectomy.62 Thus, especially for TNBC, incorporation of
a radiation boost to the tumour bed after WBRT is highly
likely to provide an additional benefit in reducing the risk
of local relapse and should be strongly considered in
treatment.
Faster radiation delivery methods
Although a complete overview of accelerated partial
breast irradiation (APBI) and hypofractionated WBRT is
beyond the scope of this Review, the widespread use of
these approaches warrants their mention in the context
of TNBC. Both APBI and hypofractionated WBRT have
shorter delivery times than the standard 5–6·5 weeks of
conventionally fractionated WBRT, and could improve
convenience for patients and lower treatment costs.
APBI is typically used to deliver therapeutic doses to a

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 Review
focal 2–3 cm area around the lumpectomy cavity in a
treatment time typically of 5 days or less, and uses
various high-dose rate brachytherapy, external beam, or
intraoperative delivery methods. By contrast,
hypofractionated WBRT delivers higher daily fractions
and a lower (but biologically equivalent) total dose to the
whole breast, thus shortening time of radiation
treatment typically to 3–4 weeks or less. Hypofractionated
WBRT is based on theoretical radiobiological modelling
of the underlying sensitivities of normal cells and
tumours to changes in fractionation schedules.63
APBI
Data suggest a higher residual tumour burden for TNBC
after lumpectomy than for other subtypes, raising
concerns regarding the use of APBI for this subtype. For
example, patients with TNBC have shown more so-called
true recurrences (within 3 cm of the lumpectomy cavity)
after breast conservation therapy,64 whereas the recur-
rences of hormone-enriched tumours present more
often as so-called new primaries (developing remotely
from the original lumpectomy site).65 Furthermore,
analysis of the re-excision specimens suggests a higher
risk of residual invasive disease for TNBC than with
other subtypes of breast cancer (odds ratio [OR] 3·28,
95% CI 1·56–6·89, p=0·002).62
Prospective data for clinical outcomes for TNBC treated
with APBI are scarce and conflicting. Most are
retrospective reviews or single-group, single-institutional
studies with relatively short follow-up. The American
Society of Breast Surgeons MammoSite Registry Trial66
reported that ER-negative disease was associated with a
higher risk of ipsilateral recurrence after APBI than with
ER-positive tumours (OR 4·01, 95% CI 1·87–8·57,
p=0·0003). Similarly, single-institutional studies have
reported significantly higher in-breast failure rates in
patients with ER-negative breast cancer than in patients
with ER-positive disease who were treated with APBI.67,68
A single-institutional prospective APBI study69 recorded
an excessive 5-year actuarial in-breast local recurrence
rate of 33% in the group with TNBC. Similarly, the ELIOT
(electron intra-operative radiation therapy) off-protocol,
retrospective APBI study70 reported higher risks of true
failures and elsewhere failures (breast failures) in patients
with TNBC after APBI.
By contrast, other single-institutional, retrospective
APBI series71,72 have reported excellent 5-year actuarial in-
breast failure of 0–3% for TNBC. These conflicting data
are difficult to interpret because of the diversity in delivery
techniques, patient selection, and level of expertise for
delivering APBI. Of note, ongoing phase 3 trials have yet
to report long-term outcomes, and the NSABP B-39/
RTOG 0413 trial (WBRT vs APBI), which is now closed to
accrual and in active follow-up, was slowest to accrue
patients with ER-negative disease (ClinicalTrials.gov
NCT00103181). In view of the documented increased risk
of locoregional relapse in patients with ER-poor disease,
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even among those receiving WBRT from the trials of
breast conservation therapy,4 the low accrual for patients
with hormone receptor-poor disease was probably an
expected conservative bias of treating physicians.
Existing APBI consensus guidelines from various
organisations have subtle differences in eligibility
criteria, but notably only differentiate by ER status and
not by subtypes of breast cancer. Although conclusions
are difficult to make about the efficacy or safety of APBI
for TNBC from the existing data, the overall poor
outcomes of TNBC and association with young age
warrant restraint. In the absence of outcomes by breast
cancer subtypes from mature phase 3 trials, APBI should
only be used, at present, for TNBC in the context of a
clinical trial.
Hypofractionated WBRT
In many countries, hypofractionated WBRT has become
the standard of care for appropriately selected patients
with early-stage cancer after breast conservation therapy,
with mature phase 3 data supporting its safety and
effıcacy for replacing conventional fractionation. Because
the preponderance of existing data supporting
hypofractionated WBRT is derived from ER-positive
tumours, the outcomes for hypofractionated WBRT have
not been adequately assessed for TNBC. Present guide-
line recommendations for hypofractionated WBRT also
do not specifically factor breast cancer subtypes into their
recommendations to identify the most appropriate
patients. In view of the potential for breast cancer subtype
to have differences in underlying sensitivities to changes
in radiation fractionation schedules (which forms the
basis of hypofractionation schemas), assessment with
radiobiological modelling and clinical trials needs to be
done before routine use of this treatment for TNBC.
Until then, hypofractionated WBRT should be used with
some caution for TNBC. Irrespectively, the high frequency
of chemotherapy, often young age, and advanced disease
of patients with TNBC often precludes the clinical
applicability of hypofractionated WBRT for this subtype.
Increased radiosensitivity or radioresistance?
An area of controversy that might affect decisions for the
locoregional management of TNBC pertains to whether
the subtype is biologically radioresistant or predisposed
to radiosensitivity. These concerns regarding radio-
resistance stem from interpretation of data from patients
treated on the PMRT trials and, to a lesser extent, trials of
breast conservation therapy. In a subset of patients with
available tissue from the Danish post-mastectomy trials
82b/c73 treated with and without PMRT, breast cancer
subtypes were retrospectively established by clinical
assays and outcomes were analysed as a function of these
subtypes. Although the baseline (without PMRT)
probability of locoregional relapse for TNBC was signi-
ficantly increased by comparison with luminal subtypes,
and the addition of PMRT resulted in a significant
www.thelancet.com/oncology Vol 16 March 2015
 Review

improvement in locoregional relapses for every subtype A possible explanation for these opposing theories for
(table 2), the proportional benefit was substantially less differential responses with radiation might be related to
for the triple-negative subtype than for the luminal and the present clinical categorisation of TNBCs into one
hormone-receptor positive cohorts. This finding was general subtype, which might be an oversimplification of
interpreted to suggest a relative radioresistance in a diverse subgroup of cancers with different underlying
patients with TNBC (and HER2-positive) disease.73 Data tumorigenic pathways. This concept has similarly been
from the 2011 Oxford meta-analysis4 of breast suggested for the differential responses noted with
conservation therapy trials similarly suggested an neoadjuvant systemic chemotherapy, in which TNBCs
inherent difference in radio-response based on the extent are generally thought to be chemo-sensitive with
of hormone receptor expression. Patients stratified by relatively high pathological complete response rates
receipt of radiotherapy, T stage, ER status, age, and grade relative to luminal subtypes. For example, despite the
were analysed by outcomes. Concordant with the high proportion of patients achieving pathological
findings from PMRT trials, the overall relapse risk was complete response (nearly 30%) for TNBC, this subtype
higher for patients with ER-poor than ER-enriched has a substantially higher frequency of distant metastasis
disease after lumpectomy alone; with the addition of and worse survival outcomes than other subtypes of
radiation, the benefit in local relapse was proportionally breast cancer. Although the proportion of patients who
less in patients with ER-poor disease, which has been achieve a pathological complete response have outcomes
suggested to be a relative radioresistance for patients
with poor expression of hormone receptors.4
LRR (%) Absolute difference
Although these reported differences in radiation
response from the PMRT and breast conservation Without PMRT With PMRT
therapy trials are striking, these analyses have not been Lum A 32% 3% 29%
validated in other cohorts and thus should be interpreted Lum B 48% 3% 48%
with caution. Importantly, for the TNBC analysis from TNBC 32% 15% 17%
PMRT trials, the addition of radiation did provide a HER2+ 33% 21% 12%
significant benefit of more than 50% in reducing isolated
Greater relative benefit of radiation is suggested for luminal subtypes or those
locoregional relapses (32% with no PMRT vs 15% with with oestrogen receptors, than for those with the TNBC subtype. Data are from
PMRT; p<0·001; table 2). Thus, radiation should not be Kyndi and colleagues73 (patients treated in the Danish post-mastectomy trials).
omitted in TNBC on the basis of these data, particularly LRR=locoregional relapses. PMRT=post-mastectomy radiation therapy.
Lum A=luminal A. Lum B=luminal B. TNBC=triple-negative breast cancer.
when the conflicting hypothesis that patients with TNBC
have a defect in the BRCA1 pathway (which should make Table 2: Radiation treatment for patients of different breast cancer
them inherently more radiosensitive) in combination subtypes who had a mastectomy
with clinical data that suggested a benefit with radiation
with TNBC in both breast conservation therapy and
PMRT settings, are taken into consideration.41,55,58 At A B
present, the traditional general principles of adjuvant Cell cycle or Androgen, oestrogen, or Pathological complete response
DNA repair genes steroid metabolism genes rate by subtype
radiation should be applied for TNBC until its predictive Luminal 10% Luminal androgen receptor
value by breast cancer subtype is better understood. androgen 33% Unstable
The opposing theory of radiosensitivity is from 30% Immunomodulatory
Basal-like 31% Mesenchymal
theoretical and preclinical data that suggest the inherent Unstable 23% Mesenchymal stem-like
inability of BRCA carriers to repair treatment-induced 52% Basal-like 1
0% Basal-like 2
damage, which would potentially provide a benefit in
tumour-cell killing, but simultaneously would make
surrounding normal tissue susceptible to radiation- Immunomodulatory
related complications. TNBC, sharing clinical-
pathological similarities with BRCA1 carriers, is often Mesenchymal-like
Immune
characterised by an impaired DNA repair process. As response
such, the increased sensitivity to specific chemo- genes

therapeutic drugs (ie, platinum-based drugs) and

radiotherapy has been extrapolated from BRCA carriers
to include sporadic TNBC. However, the preclinical data
for increased radiosensitivity (with respect to increased
toxic effects on normal tissues) are conflicting,74,75 and
from a clinical standpoint there is a paucity of data to
support the suggestion that BRCA carriers or patients
with TNBC have worsened acute or chronic radiation
toxic effects with the use of this treatment.76,77
Cellular differentiation,
motility, or growth
factor pathways
Figure 3: Proposed triple-negative breast cancer subtypes that are predictors of neoadjuvant chemotherapy
response
Data are from Lehmann and colleagues79 and from Masuda and colleagues.80 (A) Relative frequency of basal triple-
negative breast cancer (TNBC) subtypes. (B) Proportion of patients with every subtype who have a pathological
complete response rate. Pathological complete response rates vary significantly (p=0·043) by TNBC subtype
(adjusted for age, clinical stage treatment type, and nuclear grade).

www.thelancet.com/oncology Vol 16 March 2015 e119

 Review
Search strategy and selection criteria
References for this Review were identified through searches
of PubMed for papers published before Aug 10, 2014, and in
English with the search terms “triple-negative”, “radiation
therapy”, and “local relapse”. Articles were also identified
through searches of the author’s personal files. The final
reference list was generated on the basis of relevance to the
broad scope of this Review; those articles deemed not
pertinent were excluded.
that are nearly identical to patients who do not have the
TNBC subtype (non-TNBC), the overall unfavourable
outcomes of TNBC subtype are attributed to the subset of
patients whose disease is relatively chemo-resistant and
who have residual disease after neoadjuvant chemo-
therapy.78
On the basis of findings from gene-expression profiling
of breast cancer reported in 2011, at least seven distinct
subtypes of TNBC have been defined (figure 3): two basal-
like (BL1/BL2), two mesenchymal (mesenchymal and
mesenchymal stem-like), one immunomodulatory, one
luminal, and an unstable variant.79 Although the initial
clinical relevance of this subclassification for TNBC was
unclear, pivotal studies have made progress towards their
clinical application. For example, these TNBC subtypes
have been correlated to the likelihood of pathological
complete response with standard neoadjuvant chemo-
therapy regimens (p=0·04379).66 Furthermore, data from a
trial81 suggest a direct association between the quantities
of tumour-infiltrating lymphocytes in individual TNBC
tumours and improved survival outcomes in the setting
of adjuvant anthracycline-based chemotherapy. Different
subtypes of TNBC might be sensitive to different
therapeutic regimens based on their main underlying
defects;82 if so, novel therapeutic strategies using targeted
drugs directed towards underlying defects of the TNBC
subtype (eg, immune modulation in tumour-infiltrating
lymphocyte-depleted TNBC) might provide better
responses to improve overall outcomes for patients.
Similarly, the different radiosensitivities of TNBC could
be associated with differences in underlying biological
mechanisms and, with further elucidation, the addition
of radiosensitising drugs to radiation therapy might help
to provide additional reductions in locoregional relapse.
However, with respect to present clinical practices,
contemporary series show that absolute local recurrence
risk of TNBC is acceptable and only slightly increased
relative to the other subtypes,35 which supports the view
that TNBC (and BRCA1-associated) tumours are, in fact,
responsive to DNA-damaging drugs.
Conclusions
Classification of breast cancers by molecular subtype
has proven to be prognostic, allows for tailoring of
systemic therapy, and has led to improvements in
e120
patient outcomes. Although the associations between
subtypes of breast cancer and locoregional relapses are
equally compelling, integration of these subtypes into
the decision making for local management is lagging
because of the paucity of level 1 data to support
treatment decisions. Although TNBC poses a great
challenge because of its aggressive nature, the absence
of targeted drugs, heterogeneity within this subtype,
and our understanding of this subtype still in its infancy,
the general principles of locoregional management with
radiation should not be changed. Individualised care is
expected to be based on phenotypic markers of
individual tumour characteristics and might, one day,
direct adjuvant treatment decisions by taking into
account the intrinsic risks of locoregional relapses. For
TNBC, subclassification based on underlying defects
could provide more targeted treatments that might
directly enhance local control and possibly provide
radiosensitising effects. Present data discussed in this
Review should be regarded as hypothesis-generating,
because no single locoregional management approach
has consistently been reproduced to show benefits over
another approach. Thus, at this juncture, TNBC subtype
alone should not guide locoregional treatment decisions
as it does for systemic treatment. Patients with TNBC
should be encouraged to participate in clinical trials to
further elucidate the many unanswered questions
surrounding the management of this aggressive subtype
of breast cancer. Until phase 3 trials provide data to
adequately redirect present standard locoregional
management principles based on subtypes of breast
cancer, major deviations from the existing clinical
practices should be avoided outside of a clinical trial
setting.
Contributors
MSM researched and reviewed the existing literature and wrote the
manuscript.
Declaration of interests
I declare no competing interests.
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