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Special Collection
TNBC in 2019: Promising Signals for the
Treatment of a Formidable Disease
Introduction
Triple-negative breast cancer (TNBC) is defined by
the absence of oestrogen, progesterone and human
epidermal growth factor receptor 2 (HER2).1 Taken
as a whole, this heterogeneous group of tumours
display the highest distant metastasis rate and low-
est overall survival (OS) of all breast cancer sub-
types.2 Despite surgery and adjuvant therapies, half
of primary TNBC confined to breast and lymph
nodes recur in distant sites by 5 years, and there is a
strong predilection for metastasis to visceral organs
and the central nervous system.3 Systemic treat-
ment of metastatic TNBC is currently limited to
chemotherapy drugs, with successive regimens dis-
playing diminishing effectiveness. Although the
molecular landscape is largely known, no biologi-
cally targeted therapies have yet demonstrated
applicability to this subtype.
Paradoxically, TNBC in the primary setting is the
most chemotherapy responsive of all subtypes,
revealed by the tumour response assessment pos-
sible when chemotherapy is given in the neoadju-
vant rather than the adjuvant setting.4 A large
prospective study at MD Anderson between 1985
and 2004 was the first to comprehensively docu-
ment the response to neoadjuvant chemotherapy
(NACT) across breast cancer subtypes, and
revealed that double the number of TNBC
achieved pathological complete response (pCR;
no remaining tumour in surgical specimen) than
non-TNBC tumours (22 versus 11%).5 pCR rate
has increased further with more intensive regi-
mens, and has become a major benchmark in
assessing the most effective early breast cancer
treatment regimens.
Why use neoadjuvant rather than adjuvant
as systemic therapy in TNBC?
In contrast to hormone receptor (HR)-positive
breast cancer, HR-negative tumours, including
Controversial issues in the neoadjuvant
treatment of triple-negative breast cancer
Amanda Fitzpatrick and Andrew Tutt
Abstract: Triple-negative breast cancer (TNBC), as a collective group of heterogenous
tumours, displays the highest rate of distant recurrence and lowest survival from metastatic
disease across breast cancer subtypes. However, a subset of TNBC display impressive primary
tumour response to neoadjuvant chemotherapy, translating to reduction in future relapse
and increased overall survival. Maximizing early treatment response is crucial to improving
the outlook in this subtype. Numerous systemic therapy strategies are being assessed in
the neoadjuvant setting and the current paradigm of generic chemotherapy components
in regimens for high-risk breast cancers, regardless of biological subtype, is changing.
Therapeutic approaches with evidence of benefit include platinum drugs, polyadenosine
diphosphate ribose polymerase (PARP) inhibitors, immunotherapy and second adjuvant
therapy for those not achieving pathological complete response. Importantly, molecular
testing can identify subgroups within TNBC, such as deoxyribonucleic acid (DNA) homologous
recombination repair deficiency, lymphocyte-predominant tumours, and TNBC type 4
molecular subtypes. Clinical trials that address the interaction between these biomarkers and
treatment approaches are a priority, to identify subgroups benefiting from additional therapy.
Keywords:
BRCA, breast cancer, immunotherapy, neoadjuvant chemotherapy, PARP inhibitor,
triple negative
Received: 11 May 2018; revised manuscript accepted: 9 September 2019.
Correspondence to:
Amanda Fitzpatrick
Breast Cancer Now
Research Centre, The
Institute of Cancer
Research, 237 Fulham
Road, London SW3 6JB,
UK
amanda.fitzpatrick@icr.
ac.uk
Andrew Tutt
Breast Cancer Now
Research Centre, Institute
of Cancer Research,
London, UK Faculty of Life
Sciences and Medicine,
King’s College London,
London, UK
882581TAM0010.1177/1758835919882581Therapeutic Advances in Medical OncologyA Fitzpatrick and A Tutt
review-article20192019
Review
Therapeutic Advances in Medical Oncology 11
2 journals.sagepub.com/home/tam
those free of lymph node involvement, display a
high risk of distant recurrence. This can be
reduced by chemotherapy as an adjuvant to sur-
gery,6 with equivalent outcomes whether given
before (neoadjuvant) or after (adjuvant) surgery.7
A key benefit of neoadjuvant therapy is the pos-
sibility of ‘real-time’ monitoring of treatment
response, allowing the oncologist to assess chem-
osensitivity, or lack thereof, in each individual’s
tumour prior to surgical resection. Aside from a
higher degree of breast-conserving surgery (BCS)
or improved cosmesis with BCS,8 this approach
also allows for (a) addition of other systemic ther-
apies to improve response during neoadjuvant
therapy, (b) investigation of potential further
‘adjuvant’ therapy after surgery in clinical trials
targeting those at highest risk, and (c) prognosti-
cation of future risk of relapse, with the potential
to adopt close follow-up protocols. Furthermore,
clinical trial design using primary tumour
response to chemotherapy as the primary out-
come expedites the assessment and approval of
new agents, without the requirement to wait for
several years of follow-up data.
pCR serves as a surrogate marker for improved
distant relapse-free survival and OS in TNBC.
Substantial evidence for this association comes
from the CTNeoBC (Collaborative Trials in
Neoadjuvant Breast Cancer) international work-
ing group, who performed a pooled analysis of 12
trials of anthracycline and taxane-based neoadju-
vant regimens between 1990 and 2011.9 The rate
of achievement of pCR after chemotherapy was
found at 34% in TNBC, 30% in HER2-positive
(50% with addition of trastuzumab), 16% in
high-grade HR positive, and 7.5% in low grade
HR-positive tumours. All subgroups of breast
cancer except for low grade, HR-positive tumours,
revealed a significant association between achieve-
ment of pCR and event-free survival, with the
largest magnitude of effect seen in the TNBC
subgroup, where achievement of pCR was associ-
ated with 75% lower risk of recurrence. This
analysis also demonstrated that the association
with survival was stronger when complete tumour
response was seen in both the breast and lymph
nodes (ypT0 pN0 and ypT0/is ypN0) rather than
the breast alone (ypT0/is), highlighting the
importance of lymph node response to chemo-
therapy. The former is used as the definition of
pCR throughout this review.
Failure to achieve pCR does not necessarily spell
poor prognosis; however, there is clear evidence
that lower volume of residual tumour following
chemotherapy equates to better outcome. The
quantity of residual disease in the surgical speci-
men, or residual cancer burden (RCB), following
neoadjuvant therapy in breast cancer is interna-
tionally classified as RCB-0, I, II and III, consid-
ering size and cellularity of the tumour in the
surgical specimen, where RCB-0 is equivalent to
pCR, and RCB-III signifies no response or
tumour progression.10 The predictive value of
RCB was investigated by Symmans and col-
leagues in a prospective clinical trial of neoadju-
vant systemic chemotherapy conducted at the
MD Anderson Cancer Centre. In the triple-
negative cohort (n = 219), 10-year relapse-free
survival rates were 86%, 81%, 55%, and 23% for
pCR/RCB-0, RCB-I, RCB-II and RCB-III,
respectively.11 Hence, with appropriate therapy,
subgroups within TNBC achieving RCB-0/I with
neoadjuvant therapy can achieve long-term prog-
noses similar to the non-TNBC setting.
There is therefore a strong rationale to aim for
maximal response to the initial, presurgical sys-
temic therapy in TNBC, with the knowledge that
this can translate to improved overall outlook for
this breast cancer subtype.
Taxane use in the neoadjuvant setting
for TNBC
The incorporation of taxane chemotherapy into
adjuvant regimens has become standard of care
for ‘high-risk’ breast cancers, which generally
includes all TNBC and HER2-positive tumours,
and HR-positive/HER2-negative tumours which
are high-grade and node positive. Numerous key
adjuvant studies and a meta-analyses have dis-
played improved overall and relapse-free survival
with postsurgical anthracycline–taxane versus
anthracycline alone.12,13 In the context of neoad-
juvant therapy, the addition of taxanes also results
in a higher pCR rate, for example, 26% for AC
(doxorubicin and cyclophosphamide) followed by
docetaxel, compared with 14% with AC alone in
the B27 study.14 The GeparTrio study, where
participants received up to eight cycles of neoad-
juvant TAC (docetaxel, doxorubicin, cyclophos-
phamide) displayed a pCR rate of 37% in the
TNBC cohort.15 The choice and schedule of the
soluble taxane drug has not been evaluated spe-
cifically in the neoadjuvant setting; however, in
the adjuvant setting, there is evidence that weekly
paclitaxel may be more effective than docetaxel
given 3 weekly.16,17
A Fitzpatrick and A Tutt
journals.sagepub.com/home/tam 3
Albumin-bound paclitaxel (nab-paclitaxel) has
the advantage of reduced rates of anaphylaxis and
hypersensitivity. Its antitumour activity in the
neoadjuvant setting has been investigated in two
studies. The GeparSepto trial demonstrated that,
in sequential combination with epirubicin and
cyclophosphamide, pCR was significantly higher
at 38% with nab-paclitaxel than 29% with soluble
paclitaxel, both given weekly for 12 weeks.18
Survival data recently published also showed a sig-
nificant disease-free survival, but not OS benefit.19
However, this result was not reproduced by the
ETNA trial, which reported a small, but not sta-
tistically significant increase in pCR with nab-
paclitaxel (22.5%) over paclitaxel (18.6%).20 Both
trials were similar in size, however study design
differed in terms of nab-paclitaxel dose, which was
150 mg/m2 in GeparSepto and 125 mg/m2 in
ETNA, and the administration schedule, with
continuous weekly dosing in GeparSepto and in
ETNA.
Currently, the albumin-bound formulation
remains reserved for those who have experienced
hypersensitivity to standard taxanes; however, the
results of GeparSepto may lead some clinicians to
choose this formulation for potential increased
efficacy.
Is there a role for antiangiogenesis agents in
TNBC neoadjuvant therapy?
Angiogenesis, a key step in tumourigenesis, is
upregulated in TNBC compared with other sub-
types, with higher tumour microvessel density21
and increased levels of a key regulator, vascular
endothelial growth factor (VEGF).22 Bevacizumab,
a monoclonal antibody directed against VEGF,
was initially assessed in the metastatic TNBC set-
ting, and displayed improved progression-free
survival (PFS), but not OS across three phase II
studies.23
Although no OS benefit, there was a clear ration-
ale to assess antiangiogenesis at the primary
tumour setting, since invasion and metastasis
require blood vessels for tumour cell escape and
intravasation to the circulation.24,25
GeparQuinto, a phase III neoadjuvant study,
assessed the addition of bevacizumab to anthra-
cycline–taxane chemotherapy, and found pCR
improved from 33% to 43% with bevacizumab;26
however, the 3.8-year survival data have since
shown no difference in disease-free, nor overall,
survival.27
A UK-led phase III study, ARTemis, evaluated
the addition of four cycles of bevacizumab to neo-
adjuvant anthracycline–taxane chemotherapy for
HER2-negative breast cancer. A total of 800
patients were recruited, of which 31% were also
HR negative, therefore categorized as TNBC.
The rate of pCR for both HR positive and nega-
tive combined was 22% with bevacizumab and
17% with chemotherapy alone.28 Similar to
GeparQuinto, 3.5-year survival data in ARTemis
showed that the improved pCR was not associ-
ated with improved survival.29 There was no
effect of bevacizumab on survival in the adjuvant
study BEATRICE.30,31 Bevacizumab does not
confer a reduction in distant recurrence and
therefore is not recommended for routine use in
neo/adjuvant TNBC. However, it may have a role
in primary tumour downstaging, in the setting of
large tumours, to achieve BCS.
Defining ‘BRCA-ness’ in TNBC
TNBC displays a high prevalence of chromo-
somal genome instability.32 This is suggested as
arising through frequent defects in deoxyribonu-
cleic acid (DNA) repair pathways, in particular,
those involving homologous recombination repair
(HRR), a cellular mechanism for repairing DNA
double-strand breaks (DSBs). HRR uses a
homologous DNA sequence to guide repair at the
DSB, thereby conserving the DNA sequence and
integrity. In the setting of defective HRR, cells
must rely instead on the error-prone pathway
nonhomologous-end joining (NHEJ), which
although effective in repairing the DSB, can result
in DNA sequence aberrations and chromosome
rearrangements.33
Defective HRR has been proposed as an impor-
tant therapeutic vulnerability in TNBC. Cells can
be pushed into replication fork crisis and thus cell
death by use of DNA-damaging agents, such as
platinum chemotherapy or polyadenosine diphos-
phate ribose polymerase (PARP) inhibitors, lead-
ing to DNA replication fork arrest and associated
DSBs.34
At a molecular level, defective HRR in TNBC
can in part be explained by somatic or germline
mutations in HRR-pathway genes, such as
BRCA1 and BRCA2.35 Germline BRCA1/2
Therapeutic Advances in Medical Oncology 11
4 journals.sagepub.com/home/tam
mutation carriers (gBRCAm) have a markedly
increased lifetime risk of developing breast and
ovarian cancer.36 There is a strong association
between BRCA1 and TNBC with 80–90% of
BRCA1-mutated breast cancers being triple nega-
tive.37 However not all TNBCs occur in the set-
ting of germline BRCA mutation, as evidenced by
a recent a large analysis of the germline DNA of
1824 patients with TNBC, which found 11% to
have germline BRCA aberrations, and a further
4% having deleterious germline mutations in
genes involved in other homologous recombina-
tion genes, such as PALB2 and RAD51.38 In the
remaining 85%, no deleterious mutations were
found in DNA repair genes; however, it has been
suggested that a high proportion of TNBC exhibit
functional evidence of defective homologous
recombination, so called ‘BRCA-ness’.39
There are currently many translational research
groups endeavouring to deliver a clinically applica-
ble test of defective HRR. This would also provide
the opportunity to discover multiple potentially
novel genetic and epigenetic drivers of HRR
deficiency.40
Specific mechanisms such the epigenetic silenc-
ing of BRCA1 by promotor methylation, or
reduced BRCA messenger ribonucleic acid
(mRNA), may be easily assayed from tumour tis-
sue specimens. A wide-angle approach to identi-
fying HRR-deficient tumours is to identify
genomic ‘scars’ of defective HRR: loss of hete-
rozygosity (LOH), telomeric allelic imbalance
(TAI), and large-scale state transitions (LST).40
These can be assessed using genome-wide single-
nucleotide-polymorphism (SNP) arrays, or
whole-genome sequencing, with the former being
more cost effective and potentially clinically
applicable. Myriad Genetics have developed a
commercial test which measures all three
genomic features using a custom whole-genome
SNP profiling, and has been evaluated for its pre-
dictive value in response to DNA-damaging
agents in both breast and ovarian cancer.41 The
resultant homologous recombination deficiency
(HRD) score has now been used in various clini-
cal trials to try defining potential TNBC sub-
groups beyond germline BRCA mutant who may
benefit from additional therapies exploiting this
vulnerability. While there has been some evi-
dence from analysis of phase II trials that the
Myriad HRD assay may predict of increase pCR
with a platinum-containing regimen,41 this assay
did not distinguish between prediction of
response to the carboplatin-containing regimen
and the anthracycline and taxane control in the
GeparSixto trial,42 and is discussed below.
Furthermore, the recently published TNT trial43
did not show any evidence of predictive perfor-
mance of a similar Myriad HRD assay for plati-
num selection over taxane in the metastatic
setting. More recently a new ‘HRDetect’ assay44
has been developed that requires whole-genome
sequencing and the field eagerly awaits analysis
of its performance as a specific platinum or
PARP-inhibitor-response predictor.
Should platinums now be used in
neoadjuvant management of TNBC?
Platinum drugs create DNA DSBs by creating
adducts in DNA that arrest DNA replication.
Striking responses are seen both preclinically and
clinically to platinum chemotherapy in a BRCA-
defective setting.45,46 Platinum drugs appear more
active in the TNBC subtype than other breast
cancers. A Cochrane review of platinum-contain-
ing regimens concluded little to no effect on PFS
or OS in unselected metastatic breast cancer, but
evidence of a modest PFS improvement (hazard
ratio 0.59; 95% confidence interval 0.49–0.70) in
metastatic TNBC.47 A direct comparison to doc-
etaxel in the first-line metastatic setting was car-
ried out in the TNT trial (n = 376), which
concluded that carboplatin is active in unselected
metastatic TNBC, but offers no advantage over
docetaxel.43 However, the bona de BRCA-
defective subgroup, gBRCAm carriers, did dis-
play carboplatin sensitivity in the TNT trial, with
doubling of response rates (68 versus 33%) over
docetaxel, whereas ‘BRCA-ness’ subgroups, clas-
sified as tumours with BRCA1 methylation, low
levels of BRCA1 mRNA, or high Myriad Genetics
HRD score, displayed no increase in response
with platinum over docetaxel.
Therefore, in the metastatic setting, platinum is
an active chemotherapy agent and response
appears enriched in germline BRCA mutation
carriers, but not in epigenetically driven ‘BRCA-
ness’ TNBC.
Three phase II/III studies have assessed the addi-
tion of platinum to neoadjuvant therapy:
GeparSixto (n = 595 total, 315 TNBC), CALGB
40603 (n = 454 all TNBC), and BrighTNess
(n = 634, all TNBC).
A Fitzpatrick and A Tutt
journals.sagepub.com/home/tam 5
GeparSixto48 investigated the addition of carbo-
platin to paclitaxel and liposomal doxorubicin
given weekly for 18 weeks preoperatively in
HR-negative breast cancer. In the TNBC sub-
group (n = 315), pCR was significantly higher at
57% versus 41% with the addition of carbopl-
atin,49 and there was a superior recurrence-free
survival at 3 years with carboplatin than without
(86 versus 76%), although no significant OS
difference.50
CALGB 4060351 employed a more standard
chemotherapy backbone of weekly paclitaxel for
12 weeks followed by dose-dense doxorubicin
and cyclophosphamide for four cycles. Analysis
revealed that the pCR rate was significantly
increased with carboplatin (54%) compared with
the control arm (41%). The survival data at
3 years did not demonstrate a significant improve-
ment with carboplatin; however, the study was
not powered to detect event-free survival.
BrighTNess52 again demonstrated the additive
effect of carboplatin, in terms of achieving pCR.
This study was primarily designed to determine
the effectiveness a PARP inhibitor, veliparib, in
combination with carboplatin, added to the
standard backbone of paclitaxel followed by dox-
orubicin and cyclophosphamide as NACT for
TNBC. pCR rate was 31% in the standard treat-
ment group and rose significantly to 58% with
addition of either carboplatin alone, or 53% with
the added combination of carboplatin and veli-
parib. Survival data from this study have not yet
been published.
Although clear that pCR rates are significantly
higher with the addition of carboplatin to NACT,
the survival data are currently equivocal and the
BrighTNess data are eagerly awaited.
An explanation for the difference in survival
results between GeparSixto and CALGB 40603
could be the use of cyclophosphamide in the
chemotherapy backbone of the latter study.
Cyclophosphamide is an alkylating drug, which,
in a manner similar to carboplatin, exerts a cyto-
toxic effect by creating DSB-inducing DNA
interstrand crosslinks. Therefore, in the absence
of cyclophosphamide (GeparSixto), response to
the DNA crosslinking effect of carboplatin may
have been more apparent, whereas in CALGB
40603, the additional benefit of carboplatin may
have been blunted.
The effect of cyclophosphamide is also supported
by the GeparOcto trial, addressing the question
of whether the high-dose intensity combination
of epirubicin, taxane and cyclophosphamide
(iddEPC) is equivalent to the carboplatin-
containing treatment GeparSixto regimen of pacli-
taxel, liposomal doxorubicin and carboplatin
(PMCb). This study suggests carboplatin and
high-dose cyclophosphamide may be interchange-
able, in combination with taxane and anthracy-
cline, with similar pCR rates of 48.3% in the
iddEPC arm and 48.0% in the PMCb arm.53
Given the current inconclusive survival benefit
data, carboplatin is not yet universally considered
standard of care in neoadjuvant therapy for
TNBC. Many centres take an individualized
approach per patient, adding carboplatin to the
taxane phase of treatment in patients with higher
stage of disease or sequentially, if tumour response
is suboptimal following an initial anthracycline–
cyclophosphamide phase of treatment. Adding
carboplatin is not without toxicity, with increased
haematological adverse events of neutropenia
(including febrile neutropenia), anaemia and
thrombocytopenia; therefore, there is a need to
carefully define the patient subgroup that will
benefit most with fewest complications. It seems
most logical to consider adding platinum for
patients with stage II or III cancers and few
comorbidities, who have both higher recurrence
risk and greater need for tumour response to
improve cosmesis.
As with trials of platinum drugs in the metastatic
setting, BRCA defectiveness has been investi-
gated as a predictive biomarker for platinum-
responsive subgroups in neoadjuvant trials.
Contrary to the metastatic setting, germline
BRCA mutation status was not a predictive bio-
marker for neoadjuvant carboplatin response in
CALGB 40603. This was explored by a second-
ary analysis,54 which discovered that in the 17%
harbouring gBRCAm, the high pCR rate of 65%
was not increased further by addition of carbopl-
atin. Disease-free survival data showed that
gBRCAm carriers had preferable prognoses
regardless of chemotherapy regimen, whereas
germline BRCA wild-type patients did experi-
ence additional improvement in 5-year survival
rates with carboplatin. Recent reports of the
gBRCAm subgroup of the GeparOcto study sug-
gest, however, that mutation carriers with high-
stage disease do gain greater benefit from the
Therapeutic Advances in Medical Oncology 11
6 journals.sagepub.com/home/tam
high alkylating-agent-containing regimens and
perhaps platinum regimens, specifically.55
In total, these data suggest that in the neoadju-
vant setting, a gBRCAm subgroup with smaller
tumours, perhaps receiving NACT while consid-
ering bilateral risk-reducing mastectomy, could
perhaps be spared of the addition of carboplatin,
since they already experience very high levels of
chemotherapy response and excellent survival
outlook with sequential anthracycline/cyclophos-
phamide and taxane regimens. Most patients with
gBRCA1/2 mutations and particularly those with
stage II or III tumours, and those who opt for
breast conserving surgery who need to maximize
tumour response for good cosmesis, should still
be considered for platinum-based therapy. Some
patients with stage I tumours or comorbidities
should not be committed to receiving a platinum-
based regimen based on BRCA1/2 mutation sta-
tus alone.
Further exploratory analysis of the GeparSixto
trial assessed responses in HRR-deficient sub-
groups, using tumour BRCA1/2 mutation status
and the Myriad HRD score.56 Of the 193 patient
samples analysed, 136 were assessed to be HR
deficient, while 129 had a high HRD score, 54 of
which harboured either somatic or germline
BRCA mutation, and an additional 7 tumours
had BRCA mutation without high HRD score.
HRR-deficient tumours had a higher pCR rate
with chemotherapy overall (50% pCR rate in
HRR deficient versus 24.6% pCR in nondefi-
cient). Although HRR-deficient tumours experi-
enced a higher pCR with added carboplatin
(63.5% pCR rate) than without (33.9% pCR
without carboplatin), the test for interaction was
negative, therefore the HRD score did not act as
a treatment selection biomarker to aid platinum
selection in TNBC.
Assessment of alternative HR-deficiency assays,
such as ‘HRDetect’, as therapy-specific predictive
biomarkers in neoadjuvant trials is warranted to
define TNBC subgroups who may benefit from
additional therapy targeting defective HRR, and
spare patients who may not benefit from the addi-
tional toxicity associated with platinum use.
The investigation of PARP inhibitors as
neoadjuvant therapy for TNBC
In the setting of BRCA mutation, the inhibition
and trapping on DNA of the PARP1 enzyme
leads to cell death by synthetic lethality, as these
cancers are more reliant on DNA repair pathways
other than HRR.
Recently, olaparib became the first PARP inhibitor
licensed by the US Food and Drug Administration
(FDA) in the setting of gBRCAm breast cancer.
This approval followed results of the phase III
OlympiAD trial,57 where olaparib was tested
against clinicians’ choice of chemotherapy in meta-
static gBRCAm, HER2-negative breast cancer.
Radiological response occurred in 60% of partici-
pants in the olaparib group compared with 29%
with chemotherapy, and disease progression was
delayed from 4.2 months to 7.0 months by olapa-
rib. Subgroup analysis showed that HR-negative
breast cancers were more responsive to PARP
inhibition, with risk of progression decreased two-
fold compared with HR-positive subgroups (haz-
ard ratio 0.43 versus 0.82).
In the neoadjuvant setting, PARP inhibitors are
not yet used outside of clinical trials. Researchers
in BrighTNess, as mentioned above in relation to
carboplatin, assessed whether adding the combi-
nation of carboplatin and veliparib to Adriamycin®
and cyclophosphamide (AC)–paclitaxel was
superior to AC–paclitaxel alone or AC–paclitaxel
plus carboplatin. Although the benefit of the
addition of carboplatin was clear, there was no
additional benefit from veliparib.52
There is an increasing understanding of the mode
of action of PARP inhibitors. PARP1 enzymatic
inhibition or PARP1 depletion leads to unre-
paired single-strand breaks, which ultimately
cause cell death in the setting of defective HRR, a
phenomenon known as synthetic lethality. A
more potent cytotoxic activity is via the ‘trapping’
of PARP onto DNA.58 The various PARP inhibi-
tors have differing PARP-trapping potency, with
veliparib displaying very little, offering explana-
tion for lack of effect in BrighTNess. Olaparib
exhibits significant PARP-trapping activity and is
currently being evaluated in the OlympiA adju-
vant study59 and in combination with platinum in
the PARTNER neoadjuvant study [ClinicalTrials.
gov identifier: NCT03150576].
Talazoparib, the most potent PARP inhibitor for
both trapping and catalytic activity, has shown
significant responses (78–88% tumour shrinkage)
when used as monotherapy in the neoadjuvant
setting in gBRCAm patients.60 Results of a small
phase II study comprising 20 patients with
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journals.sagepub.com/home/tam 7
confirmed gBRCAm who received talazoparib
monotherapy for 6 months prior to surgery, fol-
lowed by adjuvant chemotherapy, were presented
at the American Society of Clinical Oncology
(ASCO) conference 2018.61 The majority of
patients were triple negative (n = 17), with the
remainder being HR positive/HER2 negative.
The rate of achieving RCB-0/I following neoadju-
vant talazoparib monotherapy was 59%, and the
larger-scale evaluation of this potent PARP inhib-
itor will be conducted.
There is a need to define whether benefit from
PARP inhibitors is limited to the gBRCAm set-
ting, or whether other the ‘BRCA-ness’ group
may also benefit. A phase II study is currently
underway in the advanced setting addressing tala-
zoparib responses in germline BRCA wild-type
TNBC with either high HRD score or germline
or somatic mutation in other HRR-pathway genes
[ClinicalTrials.gov identifier: NCT 02401347].62
Should gene expression subtypes of TNBC
impact therapeutic strategies?
Classification of the molecular heterogeneity in
TNBC has been sought using gene expression
panels. PAM50 intrinsic subtypes segregate most
TNBC as basal like (80%), however the remain-
der can fall into luminal-A, luminal-B and HER2-
enriched subtypes.63 To date, PAM50 basal-like
subtype has not been found a validated predictive
biomarker influencing NACT regimen selection;
for example, for patient selection for addition of
carboplatin, in contrast to the apparent interac-
tion between basal-like and nonbasal-like status
with the single-agent platinum versus taxane effect
in the metastatic setting in the TNT trial.43,64
Lehmann and colleagues developed the TNBC
type 4 classifier, using publicly available gene
expression datasets, and classified 587 TNBC as
BL-1 (basal-like 1), BL-2 (basal-like 2), M (mes-
enchymal tumour) and LAR (luminal androgen
receptor).65,66 The two basal-like tumour sub-
groups, BL-1 and BL-2, comprise 35% and 22%
of TNBC, respectively, and are highly prolifera-
tive tumours with enriched expression of cell cycle
and proliferation genes, with predominant DNA
damage response profile in BL-1 and growth fac-
tor signalling in BL-2. BL-1, although highly pro-
liferative, displays the best prognosis in terms of
OS, most likely due to being enriched for BRCA-
defective tumours known to have better prognosis
and improved chemotherapy response.67 M type,
comprising 25% of tumours, are mesenchymal
in nature with expression of genes involved in
epithelial–mesenchymal-transition and growth fac-
tor pathways. Clinically, M type displays a pattern
of early relapse and preferential metastasis to lungs.
The LAR subtype, also identified in oestrogen-
receptor-positive and HER2-positive breast can-
cers, comprised 16% of the TNBC analysed, and
has a luminal pattern of gene expression and
androgen-receptor signalling, and in keeping with
other endocrine-regulated cancers, frequent
metastasis to bone, lymph node and late relapses.
TNBC type 4 has been investigated prospectively
as a predictive biomarker tool in a nonrandomized
trial of neoadjuvant docetaxel and carboplatin.
BL-1 displayed the highest pCR rate (65.6%) fol-
lowed by BL-2 (47.4%), M (36.4%) and LAR the
lowest (21.4%).66 Therefore, TNBC type 4 clas-
sification may have implications for approaches
to neoadjuvant therapy. The lower pCR rates in
the LAR subtype are in keeping with its luminal
phenotype, and therapy targeting the androgen
receptor may offer improvements. Various andro-
gen-targeting agents are already available and
used widely in prostate cancer, such as bicaluta-
mide, enzalutamide and abiraterone. In addition
to numerous metastatic studies of these agents in
TNBC–LAR subtype, a neoadjuvant trial is cur-
rently underway at the MD Anderson Cancer
Centre using enzalutamide plus paclitaxel
[ClinicalTrials.gov identifier: NCT02689427].
Does immune infiltrate in TNBC help
decision making?
The complex interplay between immune and
tumour cells in the breast cancer microenviron-
ment continues to be characterized. In TNBC,
there is growing evidence that presence of tumour-
infiltrating lymphocytes (TILs) is both predictive
of response to chemotherapy and prognostic for
better OS.68–70
TNBC in general has a relatively higher muta-
tional load71 and increased infiltration of TILs
than other subtypes.68 Some 70% TNBC has at
least 20% TILs in the tumour itself or tumour
stroma.68 The definition of lymphocyte-predom-
inant breast cancer (LPBC) defines a population
which have more than 50–60% TIL abun-
dance.68 A prospective study involving both
TNBC and HER2-positive breast cancer sub-
jects from the GeparSixto trial, identified LPBC
subtype in 28% of TNBC and in 20% of HER2-
positive tumours.72 Lymphocyte infiltrated
Therapeutic Advances in Medical Oncology 11
8 journals.sagepub.com/home/tam
tumours displayed a significantly higher response
to carboplatin than non-infiltrated tumours (pCR
rate 75% LPBC versus 34% non-LPBC). The
small pCR increase with ‘standard’ chemotherapy
in LPBC (45% LPBC versus 34% non-LPBC)
was not statistically significant, suggesting that
the LPBC associated increase in chemotherapy
response was attributable to carboplatin.
Combined with the discovery that BRCA1 muta-
tion associated breast cancers demonstrate
increased lymphocyte infiltration,73 and plati-
nums may cause immunogenic cell death,74 there
is strong rationale underpinning the selection of
platinum chemotherapy in the setting of BRCA1-
mutated LPBCs.
Survival data pertaining to TIL content has been
sought retrospectively by the BIG 02-98 trial
group examining intratumoural TIL content in
an adjuvant chemotherapy study. Using a thresh-
old of 50% or greater TIL content, 10.6% of
TNBC and 11.1% of HER2 positive were classi-
fied as LPBC, while only 2.9% of HR-positive/
HER2-negative tumours were classified as such.
Disease-free survival was demonstrated to be
92% at 5 years with an LPBC phenotype versus
62% for non-LPBC.70
Rather than using LPBC status as a dichotomous
variable, it is now appreciated that the gradient of
TIL-infiltrated breast cancer is important, with
each 10% increase in TIL content equating to an
increment in pCR rate and 14% reduction in
recurrence or death.75
TIL content can be readily assessed from the tis-
sue section on haematoxylin and eosin staining,
does not involve expensive molecular testing plat-
forms and can predict outcome following NACT.
This information raises a new controversy: could
assessment of TIL content be introduced as a
standard reporting parameter for TNBC to aid in
treatment selection?
Despite evidence for the predictive and prognos-
tic role of TIL content, reporting has not been
incorporated into routine clinical practice. This
may be because TNBC tumours, regardless of
high or low TIL content, would still be recom-
mended neo/adjuvant chemotherapy. However,
knowledge of TIL content may aid in the selec-
tion of patients who would benefit from addi-
tional chemotherapy, such as carboplatin. It
should also be noted that there is considerable
complexity within TIL populations, for example
CD8+ cytotoxic T cells are antitumourigenic,
whereas Foxp3+ regulatory T cells repress anti-
tumour immune response;76 therefore, this may
need to be taken into account when incorporating
immune assessment into clinical practice.
With the emerging use of immune-checkpoint
inhibitors in breast cancer, increased TIL count
may also be a predictive biomarker for response, as
demonstrated in the Keynote-086 study of the
programmed death-1 (PD-1) inhibitor pembroli-
zumab.77 Furthermore, expression of programmed
death-ligand 1 (PD-L1) on tumour-infiltrating
immune cells was shown to predict response to ate-
zolizumab in advanced TNBC in the IMpassion130
trial, and will be discussed further below.78
How much does the future of TNBC therapy
involve immunotherapy?
PD-L1 is a transmembrane protein which can be
expressed by a variety of cell types, including
tumour cells and tumour-infiltrating T cells, and
inhibits antitumour immune activity when bound
to the cell-surface receptor PD-1 on CD8+ cyto-
toxic T cells. PD-1/PD-L1 immune-checkpoint
inhibitors enhance the endogenous adaptive anti-
tumour immune response and have brought
major therapeutic advancement to a growing
number of solid tumours.
Currently, major research efforts are underway to
determine applicability of checkpoint inhibitors
targeting the PD-1/PD-L1 immune checkpoint in
breast cancer, appearing most promising in
TNBC and HER2-enriched subtypes. As a mon-
otherapy, only modest effects on survival were
seen in heavily pretreated metastatic TNBC using
the PD-1 inhibitor pembrolizumab;79 however,
numerous clinical trials combining checkpoint
inhibitors with chemotherapy or PARP inhibitors
earlier in metastatic disease management are
ongoing.80–82 A recently completed phase III
study, IMpassion130, combined nab-paclitaxel
chemotherapy with the anti-PD-L1 antibody ate-
zolizumab, in the first-line therapy of advanced
TNBC. Atezolizumab plus nab-paclitaxel led to
PFS of 7.2 months, significantly longer than
5.5 months with nab-paclitaxel alone. The benefit
was enhanced among patients with PD-L1-
positive tumours, with median PFS of 7.5 months
and 5.0 months, respectively. Interim OS analysis
showed a numerically longer survival in both the
intention-to-treat (ITT) and PD-L1 positive
A Fitzpatrick and A Tutt
journals.sagepub.com/home/tam 9
subgroups at 21.3 versus 17.6 months (ITT) 25
versus 15.5 months (PD-L1 positive). These
results have led to atezolizumab gaining FDA
approval for first-line treatment of locally
advanced or metastatic TNBC, combined with
nab-paclitaxel. This is the first immune-check-
point inhibitor therapy approval in breast cancer.
Durable responses in advanced disease with
immunotherapy have spawned an attractive con-
cept for neoadjuvant treatment, where release of
immune checkpoints while macroscopic tumour is
present and subjected to chemotherapy induced
cytotoxicity may both improve tumour response
and long-term eradication of minimal residual dis-
ease. A trial arm within the I-SPY 2 phase II plat-
form trial evaluated the addition of pembrolizumab,
a PD-1 inhibitor, to NACT in HER2-negative
breast cancer with high-risk features on prede-
fined molecular profiling. The initial results from
this study involving 69 patients demonstrated an
increase in pCR rate from 22.3% to 62.4% with
the addition of pembrolizumab to standard AC–
paclitaxel therapy.83 Neoadjuvant pembrolizumab
is also being investigated in the phase II neoadju-
vant study KEYNOTE-173, and preliminary
results were presented at the San Antonio Breast
Cancer Symposium in 2018. This six-cohort study
assesses the safety and efficacy of the combination
of PD-1 inhibitor pembrolizumab (Keytruda)
with platinum/taxane chemotherapy at varying
doses. Pembrolizumab was administered in each
cohort. The pCR rate across all cohorts was 60%,
and the highest rates were reported in the cohorts
administered nab-paclitaxel and carboplatin with
pembrolizumab. Less encouraging results were
seen with durvalumab, a PD-L1 antibody, which
was investigated as a neoadjuvant therapy in the
phase II placebo-controlled study GeparNuevo.
This study included a window period where
patients received durvalumab or placebo alone
2 weeks prior to commencement of durvalumab/
placebo plus chemotherapy, which comprised
nab-paclitaxel followed by epirubicin and cyclo-
phosphamide.84 There was a nonsignificant
increase in pCR with the addition of durvalumab
(53% versus 44%, p = 0.287). However, the sub-
group that received durvalumab in the window
period displayed significant increase in pCR (61%
versus 41%, p = 0.035), raising the question of
appropriate sequencing of immune-checkpoint
inhibition when combined with chemotherapy.85
Preliminary data was also reported at ASCO 2019,
suggesting higher NACT response associated with
higher levels of tumour mutational burden but no
interaction with durvalumab effect.86
Both pembrolizumab and atezolizumab are now
being investigated in placebo-controlled phase III
neoadjuvant studies, combined with taxane, plati-
num and anthracycline, in the KEYNOTE-522
trial [ClinicalTrials.gov identifier: NCT0303648]87
and IMpassion131 trial [ClinicalTrials.gov identi-
fier: NCT03125902].88 These large multicentre
trials are expected to establish the role of neoadju-
vant PD-1/PD-L1 inhibitor therapy in TNBC.
What is the role of second adjuvant therapy
in patients with TNBC who don’t achieve
pCR?
A major advantage of NACT, and consequent
ability to quantify chemotherapy-resistant resid-
ual disease burden, is the identification of patients
who have a higher risk of relapse and may benefit
from second adjuvant systemic therapy following
surgery. The CREATE-X study was the first
phase III trial conducted in this setting, rand-
omizing patients with HER2-negative breast can-
cer and residual disease at surgery to six to eight
cycles of adjuvant capecitabine.89 The study met
the primary outcome of improvement in disease-
free survival, both for HR-positive and TNBC
populations. The benefit was most prominent in
the TNBC subgroup (30% of patients), where
5-year disease-free survival was 70% with capecit-
abine versus 56% without. Overall capecitabine
was well tolerated, with hand–foot syndrome
being the most common grade 3/4 toxicity (11%
of patients), followed by neutropenia (6.3%) and
diarrhoea (2.9%). Relative dose intensity was
maintained in 80% of patients despite having
recently completed 4–5 months of NACT. The
results of this study are encouraging of the use of
further systemic chemotherapy for residual dis-
ease, particularly in TNBC; however, as yet, this
approach has not been widely adopted. A chal-
lenge to the generalization of the result of this sin-
gle trial is that the study population was exclusively
Japanese and Korean, therefore, the result should
ideally be further verified in other populations.
Another reason to seek further verification is that
capecitabine did not add benefit when given con-
currently with other chemotherapy in the adjuvant
setting,90 despite its clear activity in the metastatic
setting.91 The FinXX trial, where capecitabine
was added to the anthracycline–taxane adjuvant
chemotherapy, also showed no improvement in
recurrence-free survival overall; however, both
Therapeutic Advances in Medical Oncology 11
10 journals.sagepub.com/home/tam
the 5- and 10-year survival data demonstrated
increased recurrence-free survival and OS in the
TNBC subgroup. Therefore, there is a rationale to
consider further evaluation of capecitabine in
TNBC as opposed to other subtypes, particularly
in the setting of residual disease. Currently, a
US-based phase III trial (ECOG-ACRIN EA1131)
is underway comparing second adjuvant platinum
with second adjuvant capecitabine in basal-like
TNBC with residual disease following NACT
[ClinicalTrials.gov identifier: NCT02445391]. It
is hoped this study clarifies the role of specific
drugs for second adjuvant therapy, but will not
address the role of either in comparison with pla-
cebo, meaning the use of second adjuvant chemo-
therapy after failure to achieve pCR will likely
remain a controversial issue.
An attractive therapeutic option is the use of
immune therapy in the setting of minimal residual
disease, rather than clinical metastatic disease, in
patients with TNBC and residual tumour in the
breast resection specimen following NACT who
are at high risk of such minimal residual disease.
Researchers of a large phase III trial [ClinicalTrials.
gov identifier: NCT02954874] currently under-
way aim to evaluate the effect of second adjuvant
pembrolizumab in 1000 patients with TNBC
who have completed definitive local treatment.92
This trial has the potential to change the current
adjuvant standard of care for TNBC patients with
residual disease after NACT.
However, not only those with residual tumour
experience future relapse, and the trial design of
studies such as c-TRAK-TN [ClinicalTrials.gov
identifier: NCT 03145961] incorporates the
analysis of circulating tumour DNA (ctDNA) in
plasma to identify those with minimal residual
disease following NACT for TNBC, and tracks
the effect of early intervention with therapies on
clearance of tumour-specific ctDNA. On detec-
tion of tumour ctDNA in plasma, patients will be
randomized to receive immunotherapy with pem-
brolizumab or placebo and continue with the
monitoring of ctDNA and for the occurrence of
clinical metastasis.
Conclusion
Altering the natural history of this generally
poorer prognosis breast cancer subtype will rely
upon reduction of distant metastatic recurrences,
which appears linked to maximizing the response
to therapy at the primary disease setting. pCR to
chemotherapy before surgery is an important
benchmark for the efficacy of new therapies linked
to, but not always associated with, survival bene-
fit, given the lack of survival benefit associated
with primary tumour responses to antiangiogen-
esis inhibitors.29,30
pCR is demonstrated in response to platinum
chemotherapy in unselected higher-stage TNBC
and this is most prominent in two overlapping
groups: gBRCAm carriers and tumours with high
infiltrating lymphocytes.
PARP inhibitors are showing very promising
results in gBRCAm if a potent PARP-trapping
agent used; however, it is not yet clear which
TNBC subgroups the PARP inhibitor benefit will
extend to and if this will be defined by presence of
mutation in HR-deficiency genes such as BRCA1
and BRCA2 or by HRD-mutational signature
analysis.
Immuno-oncology approaches are attractive in
TNBC with a rationale based in part on relatively
higher mutational load and more frequent infil-
tration of lymphocytes than other breast cancer
subtypes. The recent results of adding check-
point inhibition to NACT in I-SPY2, if con-
firmed by definitive phase III studies, may change
treatment paradigms. However, the long-lasting
nature of some immune-related toxicities points
to the need for identification of subgroups who
could achieve maximal response with chemo-
therapy alone.
Lastly, further subdivision of molecular subtypes
by gene expression and integrated mutation and
gene expression profiles, such as PAM50 Intrinsic
and TNBC type 4 subtypes, may better define the
heterogeneity of TNBC and more accurately tar-
get the unique biological phenotypes associated
with response to both standard-of-care chemo-
therapy and additional novel therapies.
Funding
The authors disclose receipt of the following
financial support for the research, authorship,
and/or publication of this article: Professor Tutt
has received academic research cost support asso-
ciated with academically lead and sponsored clin-
ical trials and research costs and reagent provision
preclinical research studies from Astra Zeneca,
Myriad Genetics and Pfizer.
A Fitzpatrick and A Tutt
journals.sagepub.com/home/tam 11
Conflict of interest statement
Professor Tutt discloses that he has been the bene-
ficiary of a Rewards to Inventors scheme at the
Institute of Cancer Research (ICR) associated with
patents on which the ICR is named relevant to
PARP inhibitors in BRCA1/2-associated cancers.
Professor Tutt has advised, on behalf of the
Institute of Cancer Research and King’s College
London, Merck Serono, Vertex, Celgene, Pfizer
and AstraZeneca as a consultant.
ORCID iDs
Amanda Fitzpatrick https://orcid.org/0000-
0001-9201-3797
Andrew Tutt https://orcid.org/0000-0001-
8715-2901
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