International Journal of Women's Health Dovepress

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REVIEW

Triple-negative breast cancer: current perspective

on the evolving therapeutic landscape
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International Journal of Women's Health

Joe Mehanna 1 Abstract: Triple-negative breast cancer (TNBC) is known to have a poor prognosis and
Fady GH Haddad 1 limited treatment options, namely chemotherapy. Different molecular studies have recently
Roland Eid 1 classified TNBC into different subtypes opening the door to potential new-targeted treatment
Matteo Lambertini 2,3 options. In this review, we discuss the current standard of care in the treatment of TNBC in
the neoadjuvant, adjuvant and metastatic settings. In addition, we summarize the ongoing
Hampig Raphael Kourie 1
phase III clinical trials evaluating different associations between the 3 pillars of anticancer
1
Oncology Department, Faculty of
For personal use only.

treatment: chemotherapy, targeted therapy and immunotherapy.

Medicine, Saint Joseph University of
Beirut, Beirut, Lebanon; 2Department of Keywords: breast cancer, triple-negative, immunotherapy, PARP inhibitors
Medical Oncology, U.O.C. Clinica Di
Oncologia Medica, IRCCS Ospedale
Policlinico San Martino, Genova, Italy;
3
Department of Internal Medicine and
Medical Specialties (DiMI), School of Introduction
Medicine, University of Genova, Genova, Breast cancer continues to be the second cause of death in women worldwide.1
Italy
Triple-negative breast cancer (TNBC) is defined by the lack of expression of
estrogen (ER), progesterone (PR) and HER2 receptors. TNBC represents approxi-
mately 10–15% of all diagnosed breast cancers.2 The pattern of metastatic spread in
TNBC is different from the other breast cancer subtypes with a higher likelihood of
brain and lung involvement and less frequent bone lesions; in addition, this is the
tumor subtype with the poorest prognosis between all breast cancer subtypes.3
In the current era, more in-depth studies have divided TNBC into different
subtypes, according to their molecular characteristics. By analyzing gene-expres-
sion profile of TNBC, Lehman et al showed the existence of 6 different subtypes:
basal-like 1 and 2, immunomodulatory, mesenchymal, mesenchymal stem-like and
luminal androgen receptors.4 In a more recent study, the same authors re-classified
these tumors into 4 groups: basal-like 1, basal-like 2, mesenchymal and luminal
androgen receptor.5 Another classification for TNBC was suggested by Burstein et
al describing four subtypes: luminal androgen receptor, mesenchymal, basal-like
immune-suppressed and basal-like immune-activated.6 In the same study, the basal-
like immune-activated subtype showed to be associated with good prognosis, which
is compatible with the results of other studies showing better outcomes for TNBC
having lymphocytic infiltration.7,8
TNBC is more often associated with hereditary conditions as compared to other
Correspondence: Matteo Lambertini breast cancer subtypes. For instance, among newly diagnosed breast cancer
IRCCS Ospedale Policlinico San Martino, patients, <10% have BRCA1 or BRCA2 mutated genes but this percentage is higher
University of Genova, Largo Rosanna
Benzi 10 16132, Genova, Italy among patients with TNBC with around 35% of BRCA1 and 8% of BRCA2
Tel +39 010 555 4254 mutations in this population. Among BRCA1 mutation carriers, more than one-
Fax +39 010 555 6536
Email matteo.lambertini@unige.it third have TNBC.9 TNBC diagnosed in women at the age of 60 years or less is

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considered a criterion to test for BRCA mutations.9 Tumors mesenchymal stem-like subtype is characterized by having
missing the germline mutations in BRCA1/2 but keeping components interfering with the EGFR, calcium signaling,
the same characteristics are classified as “BRCAness.”10 G-protein receptors.11
In this review, we discuss the standard of care in the
treatment of TNBC in the neoadjuvant, adjuvant and meta- Immunomodulatory subtype
static settings. In addition, we summarize the ongoing In the classification of Burstein et al,6 immunomodula-
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phase III clinical trials evaluating different associations tory subtype is considered as another type of basal-like
between the 3 pillars of anticancer treatments: chemother- subtype, ie, the basal-like immune-activated subtype. It
apy, targeted therapy and immunotherapy. has a favorable prognosis. It is characterized by an
upregulation in genes responsible for T-cell, B-cell
Different subtypes of TNBC and natural killer, by having a high expression of
STAT genes.
Basal-like 1 and 2 subtypes
It is estimated that 75% of TNBC belong to the basal-like
subtypes, and TNBC forms the largest part of the basal-
Standard of care in TNBC
The standard of care in patients with TNBC defined by the
like subtypes11 (Figure 1).
guidelines of the European Society of Medical Oncology
Basal-like 1 is associated with an elevated DNA
(ESMO) and the American Society of Clinical Oncology
damage response and Ki67 levels.4 Burstein et al showed
(ASCO) is reported in this section.
that basal-like immune-suppressed subtypes of TNBC
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have downregulation of B cell, T cell and natural killer

in both cytokines and immune pathways, which results in
Neoadjuvant treatment
The addition of carboplatin in the neoadjuvant setting
worse prognosis for these subtypes.6 Mostly, all cell lines
showed to increase the rate of pathological complete
harboring mutations in BRCA1 and BRCA2 have correla-
response in TNBC from 37.0% to 52.1% (OR 1.96, 95%
tion with the gene patterns of the basal-like subtype.12
CI 1.46–2.62). Consequently, it can be considered a pos-
sible option in patients with TNBC at the cost of more
Luminal androgen receptor subtype frequent hematological toxicities.13
The luminal androgen receptor subtype contains pathways
For patients with TNBC treated in the neoadjuvant
that regulate steroid synthesis, porphyrin metabolism and
setting but with residual disease post-chemotherapy at
androgen/estrogen metabolism.6 In this subtype, the andro-
the time of surgery, the CREATE-X trial demonstrated
gen receptor is heavily expressed, with an expression 10-
improved outcomes when administering capecitabine for
fold greater than the other subtypes.4
six to eight cycles as adjuvant treatment. Disease-free
survival rate at 5 years was improved with capecitabine
Mesenchymal and mesenchymal stem-like by around 14% (69.8% vs 56.1%; HR 0.58; 95% CI 0.39–
subtypes 0.87) and overall survival (OS) at 5 years was improved
In addition to the mesenchymal subtypes having pathways by around 8% (78.8% vs 70.3%; HR 0.52; 95% CI 0.30–
included in the motility and cell differentiation, the 0.90).14 The post-neoadjuvant setting has gained great
attention after the publication of the CREATE-X trial and
several studies are currently investigating new treatment
options for patients with residual disease at the time of
surgery.15

Basal-like Triple-negative Triple-negative

20 to 40% are and 20 to 30% are
Adjuvant treatment
not triple negative basal-like not basal-like The vast majority of TNBC benefit from adjuvant che-
motherapy with the possible exception of some low-risk
histologic subtypes (secretory juvenile, apocrine, or ade-
noid cystic carcinomas). When adjuvant chemotherapy is
indicated, anthracycline- and taxane-based regimens are
Figure 1 Basal-like subtype and triple-negative breast cancer. considered the optimal strategy.16

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 Dovepress Mehanna et al

Dose-dense chemotherapy is of special interest in these vinorelbine in 21-day cycles) in BRCA-mutated breast
aggressive tumors. In fact, efficacy may be enhanced when cancer patients. Among the 302 patients that underwent
increasing the intensity of treatment by giving individual randomization, 205 received olaparib and 97 received
drugs sequentially at full dose rather than in lower-dose standard chemotherapy. Response rate was 59.9% in
concurrently, or by shortening the intervals between patients receiving olaparib and 28.8% in patients receiving
cycles. This was evaluated in an individual patient-level standard chemotherapy. The rate of adverse events was
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meta-analysis of trials comparing 2-weekly versus stan- higher (50.6%) in the chemotherapy group versus the
dard 3-weekly schedules and of trials comparing sequen- olaparib group (36.6%). Median progression-free survival
tial versus concurrent administration of anthracycline and (PFS) was 7.0 months with olaparib and 4.2 months with
taxane chemotherapy. Data were provided for 26 trials chemotherapy (HR 0.58; 95% CI 0.43–0.80). However, no
including 37,298 patients, most aged younger than 70 significant difference was observed in OS that was 19.3
years. It showed that fewer breast cancer recurrences months with olaparib and 17.1 months with standard ther-
were seen with dose-intense than with standard-schedule apy (HR 0.90; 95% CI 0.66–1.23).23,24
chemotherapy (10-year recurrence 28.0% vs 31.4%; RR
0.86; 95% CI 0.82–0.89). Similarly, 10-year breast cancer Talazoparib FDA-approved targeted therapy
mortality was reduced (18.9% vs 21.3%; RR 0.87, 95% CI With a similar design as the OlympiAD study, the
0.83–0.92), as was all-cause mortality (22.1% vs 24.8%; EMBRACA trial showed important activity for talazoparib
RR 0.87, 95% CI 0.83–0.91).17 in the treatment of metastatic breast cancer patients har-
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The role of platinum agents in the early setting is boring a germline BRCA mutation including women with
currently being evaluated. The US trial EA1131 is an TNBC.25 This was a randomized open-label phase III
ongoing randomized phase III post-operative trial compar- study that included 431 patients divided into two groups:
ing single-agent platinum-based chemotherapy to capeci- 287 patients received talazoparib and 144 received stan-
tabine in patients with residual TNBC with residual dard chemotherapy (capecitabine, eribulin, gemcitabine
disease after standard neoadjuvant chemotherapy. The pri- and vinorelbine). A significantly longer median PFS, the
mary objective consists in comparing the invasive disease- primary outcome of the study, was observed with the
free survival.18 group receiving talazoparib (8.6 months vs 5.6 months;
HR 0.54; 95% CI 0.41–0.71). The objective response rate
Treatment of advanced disease was also higher in the talazoparib group than in the che-
Chemotherapy motherapy group (62.6% vs 27.2%; OR, 5.0; 95% CI, 2.9–
In patients with advanced TNBC treated with an anthracy- 8.8). Median OS was 22.3 months (95% CI 18.1–26.2) in
cline with or without a taxane in the neoadjuvant or adju- the talazoparib group and 19.5 months (95% CI 16.3–22.4)
vant setting, carboplatin demonstrated comparable efficacy in the chemotherapy group, with no significant difference
and a more favorable toxicity profile than docetaxel.19 In (HR 0.76; 95% CI 0.55–1.06).
the subgroup of patients with germline BRCA1/2-mutated Respectively, hematologic grades 3–4 adverse events
breast cancer, carboplatin showed to double the objective (primarily anemia) and nonhematologic grade 3 adverse
response rate as compared to docetaxel (68% vs 33%, events occurred in 55% and 32% of the patients who
P=0.01).19 This suggests the importance of characterizing received talazoparib and each in 38% of the patients who
the BRCA1/2 mutation status of patients with advanced received standard therapy.
disease to also help informing on the choices of the best In this trial, quality of life in the two treatment arms
first-line chemotherapy approach. was assessed. In the patient-reported outcomes analysis, a
significant overall improvement was seen in the global
Poly ADP-ribose polymerase (PARP) inhibitors health status/quality of life with the use of talazoparib as
Olaparib FDA- and EMA-approved targeted therapy compared to chemotherapy.26
In metastatic patients harboring a germline BRCA muta-
tion, olaparib has shown important activity in both TNBC Immunotherapy
and luminal-like disease.20–22 The OlympiAD study was Atezolizumab has shown safety and good clinical activity
designed to compare the use of olaparib versus standard in TNBC.27 Chemotherapy, taxanes in particular, may
single-agent chemotherapy (capecitabine, eribulin, or enhance tumor antigens release by activating toll-like

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 Mehanna et al Dovepress

receptors and promoting dendritic cell activity.28 Based on Androgen receptor inhibitors
this rationale, a phase III trial randomized patients with In a study by Gucalp et al,34 242 patients with TNBC were
metastatic TNBC to first-line atezolizumab plus nab-pacli- tested for androgen receptors, and 12% of them were
taxel and placebo plus nab-paclitaxel.29 This study had found positive. This phase II study used single-agent bica-
two primary end points: PFS and OS. A total of 451 lutamide showing a 6-month clinical benefit rate of 19%
patients were included in each treatment group. A better (95% CI 7–39%).
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PFS was obtained in the atezolizumab plus nab-paclitaxel Enzalutamide was also studied in a subset of TNBC
group (7.2 months vs 5.5 months; HR 0.80; 95% CI 0.69– tumors with expression of androgen receptors.35 In the
0.92). OS with atezolizumab plus nab-paclitaxel was 21.3 overall population, the study showed a clinical benefit
months as compared to 17.6 months in the chemotherapy rate at 16 weeks of 25% (95% CI 17–33%). In a biomarker
alone group (HR 0.84; 95% CI 0.69–1.02). A predefined exploratory analysis, patients having positive androgen-
subgroup analysis showed a greater benefit with the addi- driven gene signatures showed greater clinical benefit
tion of immunotherapy among patients having PD-L1 rate (39% vs 11%).
positive tumors: median PFS was 7.5 months versus 5.0 Trials are ongoing to assess enzalutamide in this set-
months (HR 0.62; 95% CI 0.49–0.78) and median OS was ting. As an example, the NCT02750358 trial is designed to
25.0 months versus 15.5 months (HR 0.62; 95% CI 0.45– determine the feasibility of adjuvant enzalutamide for the
0.86) favoring the group receiving atezolizumab plus nab- treatment of patients with TNBC.
paclitaxel. Recently, the combination of atezolizumab plus
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nab-paclitaxel has been approved by FDA as first-line

therapy in patients with PD-L1 positive TNBC.30
Antibody–drug conjugates
Sacituzumab govitecan is an antibody–drug conjugate in
The results of several ongoing trials are awaited to
which SN-38 (an active metabolite of the topoisomerase I
further investigate the role of immunotherapy for the treat-
inhibitor, irinotecan) is coupled to a monoclonal antibody
ment of patients with TNBC in all disease settings
targeting anti-trophoblast cell-surface antigen 2 (Trop-2).36
(Table 1).
Trop-2, stimulates cancer-cell growth and is detected in
breast cancer cells, including TNBC.36 This molecule
Promising agents in TNBC allows the delivery of the drug to the tumors both intra-
PARP inhibitors beyond olaparib/talazoparib cellularly and in the tumor microenvironment. The safety
and efficacy of this treatment were evaluated in a phase I/
and the metastatic setting
II trial in patients with TNBC that have received a median
Several other PARP inhibitors beyond olaparib and tala-
of 3 previous therapies.36 Overall response rate was 33.3%
zoparib are currently under investigation for the treat-
and clinical benefit rate was 45.4%. Median PFS was 5.5
ment of patients with BRCA-mutated breast cancer.31
months and median OS was 13.0 months.37
Veliparib has been investigated in breast cancer patients
A randomized phase III trial (ASCENT, NCT02574455)
with metastatic disease in combination with chemother-
is currently comparing sacituzumab govitecan to standard
apy. A significant anti-tumor effect was shown with the
chemotherapy in the treatment of patients with metastatic
combination of veliparib plus temozolomide.32 In the
TNBC with prior exposure to taxane.
BrighTNess phase III randomized trial, the addition of
veliparib to carboplatin and standard neoadjuvant che-
motherapy did not show any advantage related to patho- Additional therapeutic agents
logic complete response compared to carboplatin and TNBC is considered having a high prevalence of PI3K/
standard chemotherapy.33 AKT pathway activation.38 The LOTUS trial was a rando-
To investigate the activity of PARP inhibitors in TNBC mized phase II trial that investigated the addition of ipa-
patients, both in the adjuvant and the post-neoadjuvant tasertib (an orally administered, ATP-competitive,
settings, the phase III OLYMPIA trial (ClinicalTrials.gov selective AKT inhibitor) to paclitaxel as first-line
identifier: NCT02032823) is currently randomizing early treatment.39 Patients were randomized to ipatasertib and
HER2-negative breast cancer patients harboring BRCA paclitaxel vs paclitaxel and placebo. Median PFS was 6.2
germline mutations to 1 year of olaparib or placebo after months in the group receiving ipatasertib vs 4.9 months in
surgery and standard chemotherapy.15 the group receiving paclitaxel and placebo (HR 0.60; 95%

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Table 1 Ongoing phase III clinical trials with immunotherapy in patients with triple-negative breast cancer
ClinicalTrials. Number Management Class of Study arms Primary outcome
gov identifier of options treatment
patients

International Journal of Women's Health 2019:11

NCT02954874 1000 Adjuvant Immunotherapy Arm I: no treatments Invasive disease-free survival
Arm II: pembrolizumab

NCT03498716 2300 Adjuvant Immunotherapy Atezolizumab + adjuvant Antracycline/Taxane versus Chemotherapy Invasive disease-free survival
+ chemotherapy alone

NCT03197935 204 Neoadjuvant Immunotherapy Atezolizumab and chemotherapy versus placebo and chemotherapy Percentage of participants with pCR and percentage of
+ chemotherapy participant with pCR in sub-population with PD-L1
positive

NCT03281954 1520 Neoadjuvant Immunotherapy Neoadjuvant chemotherapy + atezolizumab versus placebo and adju- Pathologic complete response in the breast and lymph
and adjuvant + chemotherapy vant atezolizumab versus placebo nodes and event-free survival

NCT03036488 1175 Neoadjuvant Immunotherapy Pembrolizumab plus chemotherapy versus placebo + chemotherapy in pCR and event-free survival
and adjuvant + chemotherapy neoadjuvant setting and pembrolizumab versus placebo in adjuvant
setting

NCT03125902 540 Metastatic Immunotherapy Atezolizumab and paclitaxel versus placebo and paclitaxel Progression-free survival
+ chemotherapy

NCT03371017 350 Metastatic Immunotherapy Atezolizumab versus placebo Overall survival

+ chemotherapy
Abbreviations: pCR, pathologic complete response; PD-L1, programmed death-ligand 1.

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 Mehanna et al Dovepress

CI 0.37–0.98). Further investigations are ongoing in the the submitted work. All remaining authors declared no
NCT03337724 phase III trial evaluating the efficacity of conflicts of interest in this work.
ipatasertib with paclitaxel versus paclitaxel and placebo in
450 participants.
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Piccart M. Post-neoadjuvant treatment and the management of resi-
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16. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG).
Disclosure Comparisons between different polychemotherapy regimens for
early breast cancer: meta-analyses of long-term outcome among
Matteo Lambertini served as a consultant for Teva and 100 000 women in 123 randomised trials. Lancet. 2012;379
received honoraria from Theramex and Takeda outside (9814):432–444. doi:10.1016/S0140-6736(11)61625-5

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17. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). 29. Schmid P, Adams S, Rugo HS, et al. Atezolizumab and Nab-pacli-
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