Journal of Cancer Therapy, 2012, 3, 777-781
http://dx.doi.org/10.4236/jct.2012.325097 Published Online October 2012 (http://www.SciRP.org/journal/jct) 777
Triple Negative Breast Cancer Treatment: Use of Platinum
and Platinum Analogs
Manuela Fantini1*, Carlotta Santelmo1, Fabrizio Drudi1*, Claudio Ridolfi1, Eleonora Barzotti1,
Lorenzo Gianni1, Valentina Arcangeli1, Alessandra Affatato1, Alberto Ravai o li2
1Oncology Department, Infermi Hospital, Rimini, Italy; 2IRST (Cancer Center of Romagna), Meldola, Italy.
[e-mail], [e-mail], aaffa [e-mail], ara v aioli@au slrn.net
Received July 24th, 2012; revised August 27th, 2012; accepted September 9th, 2012
ABSTRACT
Triple negative br east cancer (TNBC) is characterized by a high sensitivity to antiblastic drugs and a high pathological
complete remission rate after neoadjuvant therapy. In patients showing complete re mission, the probabilit y of develop-
ing metastatic disease would seem to be reduced. Nonetheless, this cancer has a high percentage of relapse. Anthracy-
clines, taxanes and platinum compounds are the most effective drugs for the treatment of TNBC. There is substantial
evidence to support the efficacy of platinum-based chemotherapy, probably attributable to the mechanism of action of
such drugs, which react with the DNA repair system. PARP inhibitors would also seem to be very interesting. Despite
promising results, TNBC remains a disease with a poor prognosis due to the lack of targeted therapy. The discov ery of
new targets and new agents is thus a high prio rity issue for this typ e of breast cancer. In this respect, lipoplatin has been
identified as a potentially interesting treatment option to evaluate in both neoadjuvant and advanced settings.
Keywords: Breast Cancer; Triple Negative; Treatment; Platinum; Platinum Analogs
1. Introduction
Breast cancer is the most common malignancy and lead-
ing cause of cancer death in women, both worldwide and
in many developed countries, including Italy.
It is a heterogeneous disease whose prognosis is re-
lated mainly to stage and biological characterization,
which defines a variety of conditions ranging from a low
risk of relapse and indolent clinical course to a high re-
lapse risk and rapid clinical progression, despite aggres-
sive therapies [1]. Routine pathological reports, in addi-
tion to defining tumor stage and grade, include an as-
sessment of proliferation index (Ki-67/MIB-1 immu-
nostaining), expression of estrogen (ER) and progestin
receptors (PR), and HER-2/neu status (evaluated through
protein immunostaining or the study of gene amplifica-
tion). Whilst these biological features have some prog-
nostic value, they are principally considered as predictors
of response to different treatments, especially targeted
therapies. Breast cancer can be classified into three large
subgroups: hormone receptor-positive, HER-2-positive
(which is also hormone-receptor positive in less than half
of cases), and the so-called “triple negative” (TN) tumors,
where ER and PR are negative and there is no amplifica-
tion or overex p ressi o n of HER-2 [2].
Studies of gene expression profiling have confirmed
the existence of breast cancer subtypes, leading to a more
accurate definition: luminal tumors are typically ER-
positive but with different expression of ER-related
genes and proliferative genes; HER-2 positive tumors are
characterized by the overexpression and/or amplification
of HER-2 and other genes; the normal breast-like sub-
type and basal-like subtype are usually TN at immu-
nostaining studies [3]. This classification has biological
and clinical relevance, defining how tumor growth is
driven by different pathways, as best exemplified by the
luminal and HER2/neu subtypes, and with different
prognoses. TN tumors merit special attention because
they have a poor prognosis and also because no targeted
therapy has been approved as yet for clinical use [4]. TN
tumors defined by immunostaining differ somewhat from
the basal-like subtype defined by gene profiling, but the
latter subtype is the most frequent and most important
form of triple negative breast cancer (TNBC) [5]. The
most important features of TN/basal-like tumors include
a strong expression of basal cytokeratins CK5/6 and
CK17 (high molecular weight cytokeratins, found in the
basal layer of stratified epithelia), expression of prolif-
eration related genes, high tumor grade, frequent p53
mutations and p63 gene amplification, low expression of
BRCA1, frequent expression of EGFR, KIT, v imentin, p-
*Corresponding authors

Triple Negative Breast Cancer Treatment: Use of Platinum and Platinum Analogs
778
cadherin, fascin, caveolins 1 and 2, alpha-B-crystallin, and
genes involved in matrix rem odeling and angi ogenesis.
Using univariate analysis, we can define the differ-
ences between the two main histological subgroups. In
Bertucci and co-workers 2008 study on TNBC, the me-
dian age of patients with basal tumors (50 years) was
lower than that of patients with other TN types (57 years).
Basal tumors exhibited a higher pathological grade: 88%
were grade III ver sus only 51% in non basal tumors. The
pathological tumor size (pT) was higher in basal tumors:
60% pT2 - pT3 versus 46% in the other group. No corre la-
tion was found with pathological axillary lymph node
status (pN). There were more medullary breast cancers
within the basal tumors, and more lobular breast cancers
within the non basal tumors. Five-year metastasis-free
survival was 65% in the basal group and 75% in the other
group, while 5-year overall survival (OS) was 68% and
78%, respectively. Pathological complete resp onse (p CR)
after primary chemotherapy was observed in 59% of
basal tumors versus 27% in the other group [6].
TNBC represents a heterogeneous group of tumors
that include 70% of basal tumors and 30% of the non
basal kind. TN basal tumors are characterized by ER, PR
and HER-2 negativity, and EGFR and cytokeratin 5/6
and 17 positivity. In contrast, TN non basal tumors are
characterized by ER, PR and HER-2 negativity and
EGFR and cytokeratin 5/6 and 17 negativity. Neverthe-
less, it is impossible to distinguish between basal and non
basal subtypes in the results obtained from the clinical
treatment of TN tumors in neoadjuvant, adjuvant and
metastatic settings because they are not considered sepa-
rately in either clinical practice or in the majority of pub-
lished pa p ers.
2. Treatment of TNBC
TNBC is characterized by a high sen sitivity to antib lastic
drugs. Although an elevated percentage of pCR is ob-
served in the neoadjuvant setting and a high remission
rate in metastatic disease, this breast cancer subtype
shows a high percentage of relapse. Numerous drugs
have been evaluated for the treatment of this tumor, the
most efficacious being anthracyclines, taxanes (paclitaxel
and docetaxel) and platinum compounds. Among the
new drugs, PARP-inhibitors would seem to be of par-
ticular interest. However, because of the biological het-
erogeneity within TNBC, many patients show an excel-
lent outcome while others obtain much poorer results,
despite the administration of systemic treatments consid-
ered effective.
2.1. The Experience in Neoadjuvant Settings
In the neoadjuvant treatment of TNBC, the paradox of
high sensitivity to anthracyclines and a high percentage
of relapse in this poor prognostic subgroup is attributable
to the elevated recurrence rate in patients who have re-
sidual disease at the time of surgery. Those who achieve
pCR in basal-like, HER-2 positive and ER negative tu-
mors would seem to show a higher rate of survival, in
contrast to patients who do not achieve pCR and appear
more likely to experience early relapse and early death.
One of the most important studies published to date is by
Carey and coworkers who examined the response rate to
neoadjuvant anthracycline-based chemotherapy in 34 TN
patients, reporting 85% clinical response (complete or
partial), more than the value reached in luminal subtypes
[7]. pCR to chemotherapy was significantly better among
basal-like subtypes (27%) than among other subtypes
(7%). Furthermore, the percentage of patients with
minimal residual disease after chemotherapy was higher
in basal-like (58%) than in luminal A subtypes (21%).
Despite sensitivity of basal like-TNBC in Carey’s study,
his group still showed very poor prognosis, for the high
relapse rates observed among those who do not achieve
pCR.
In another study by Liedtke and coworkers, response
to neoadjuvant chemotherapy and survival was compared
in TNBC and non-TNBC patients [8]. 1118 patients at
M.D. Anderson Cancer Center received neoadjuvant che-
motherapy for stage I-III breast cancer from 1985 to
2004. Although patients with TNBC (23%) had higher
pCR rates than those with non-TNBC (22% versus 11%),
they showed poorer 3-year progression-free (PFS) and
overall survival (p < 0.0001 and p < 0.0001, respectively).
Recurrence and death rates were higher for the TNBC
group, but only in the first three years. When pCR was
achieved, patients with TNBC or non-TNBC showed
similar survival while those with residual disease had a
poorer outcome, especially if they had the TNBC subtype,
confirming previous observations in larger groups of
patients.
2.2. The Experience in Adjuvant Settings
Numerous studies have reported on the adjuvant treat-
ment of TNBC basal-like and non basal-like TNBC, the
majority concerning retrospective experiences analyzing
breast cancer treatments in different subsets. Although
locoregional and distant relapse in TNBC occur mainly
during the first three years of follow up after the end of
therapy, we found few reports on long-term follow up
that made a distinction between TN and other kinds of
breast cancers. In Voduc and coworkers’s report of 4033
patients followed up for almost ten years after breast-
conserving surgery and given post-operative radiotherapy
and hormone or antiblastic treatment, regional relapse-
free survival (RRFS) was 86% for basal-like breast can-
cer and 92% for non basal-like TNBC, while the per-
centage of RRFS of luminal A breast cancer was 97% [1].
The observation that TNBCs are especially sensitive to

Triple Negative Breast Cancer Treatment: Use of Platinum and Platinum Analogs 779
antiblastic drugs has been made by numerous authors.
The Cancer and Leukemia Group B reported a benefit
from the addition of a taxane to the adjuv ant treatment of
ER, PR and HER-2 negative tumors, whereas no benefit
was observed in patients with ER positive tumors [9].
Furthermore, the Breast Cancer Intergroup, in their re-
view of 6644 node-positive breast cancer patients, re-
ported more important results in those with ER- negative
tumor given chemotherapy [9]. Patients with a high pro-
liferative index and ER/PR negativity showed very im-
pressive results at ten years with CMF chemotherapy.
More recently, Colleon i and his co llaborators published a
paper on the use of classic CMF in TN node-negative
breast cancer patients [10]. They found that CMF che-
motherapy produced a stronger effect in patients with
TNBC than in those who did not receive the schedule or
whose tumors showed ER positivity.
New approaches to adjuvant therapy are guided by re-
sults from preclinical models, molecular profiling, and
findings from trials on metastatic disease. Numerous
adjuvant clinical trials are currently ongoing to evaluate
the role of ixabepilone, platinum agents and VEGF in
this clinical setting [11]. The PACS 08 adjuvant trial [12],
built on data from PACS 01 [13,14], is a phase III study
of TNBC patients randomized to receive three cycles of
FEC followed by three cycles of docetaxel or ixabepilone
every three weeks. The phase III adjuvant TITAN trial is
evaluating four cycles of standard doxorubicin plus
cyclophosphamide followed by four cycles of ixabepi-
lone or twelve cycles of weekly paclitaxel [15]. The phase
III BEATRICE study is assessing numerous chemother-
apy agents with or without bevacizumab at a dosage of 5
mg/Kg weekly for patients with TNBC [16]. Findings are
expected in the next year.
In conclusion, TN tumors are currently most effect-
tively treated with conventional adjuvant or neoadjuvant
therapies (anthracyclines and taxanes). Although signifi-
cant results have been achieved, TN patients show lower
disease-free survival than those with non TN tumors.
2.3. The Experience in a Metastatic Setting
Results on the treatment of TNBC in a metastatic setting
do not differ from those described in neoadjuvant and
adjuvant situations. These tumors only respond to che-
motherapy, and although a substantial percentage of
complete response (CR) can be achieved, relapse and non
clinical response remain high. Whilst anthracyclines and
taxanes have proven the most effective drugs in this set-
ting, cisplatin also shows very promising results [17].
Among the new products, PARP-inhibitors are consid-
ered to be potentially important drugs. Indeed some re-
ports suggest that TNBC expresses high levels of poly-
merase 1 (PARP-1), a DNA repair enzyme which is the
molecular target of PARP inhibitors. In a randomized
phase II study in patients with metastatic TN disease, the
PARP inhibitor BSI-201 significantly improv ed objective
response rates (48% vs 16%, p = 0.002), PFS (6.9 vs 3.3
months, p < 0.0001) and median OS (9.2 vs 5.7 months,
p = 0.0005) when added to carboplatin and gemcitabine
[11]. However, despite such encouraging findings, prog-
nosis in TNBC patients with advanced disease (apart
from those with accurately verified CR), remains very
poor.
2.4. Platinum and Lipoplatinum Experience
Although cisplatin is one of the oldest and more effective
anticancer drugs, its use may be limited by adverse
events, mainly nephrotoxicity and neurotoxicity.
A number of studies evaluating platinum agents in pa-
tients with metastatic TNBC have been carried out. A
retrospective study by Uhm and coworkers comparing
outcome in patients with TNBC with th at of p atients with
other BC subtypes, all treated with a taxane-platinum
regimen, did not highlight a difference in response rates
between these two groups [18]. A similar experience
from the UK showed that patients with advanced TNBC
treated with platinum-based chemotherapy had ORRs
similar to those with non-TN tumors [17].
Favorable results have also been obtained with cis-
platin in a metastatic setting. A single institution ph ase II
study on weekly cisplatin and metronomic cyclophos-
phamide reported that such a regimen appeared to be safe
and effective, with an ORR of 63% and median time to
progression of 13 months in contrast to 33% and 7
months, respectively, in patients no t treated with cisplatin
[19,20]. The association of carboplatin with paclitaxel
[21] or irinotecan [22] in pretreated metastatic patients
with TN tumours has also shown good response rates
(57% and 30%, respectively). A study conducted at the
Royal Marsden Institute also supported the hypothesis
that patients with TN tumors have a significantly longer
PFS compared with that of other histological subtypes,
with a trend towards an improved OS when treated with
platinum.
Very few studies have been conducted on lipoplatinum
in advanced TNBC. Only recently Farhat and coworkers
reported the results of their phase II trial of lipoplatin and
vinorelbine combination in patients with HER-2 negative
metastatic breast cancer who had not received prior
treatment in an advanced setting [23]. A 53.1% ORR was
reported (CR in 3 patients, 9.4%) and 37.5% patients
showed stable disease. The majority of adverse events
were mild or moderate. For this reason lipoplatin would
seem to be an attractive treatment option for these pa-
tients.
Lipoplatin is a novel liposomal formulation of cis-
platin, designed to increase safety and tolerability by
decreasing toxicity and nephrotoxicity. It decreases the

Triple Negative Breast Cancer Treatment: Use of Platinum and Platinum Analogs
780
exposure of organs to cisplatin, whilst effectively deliv-
ering the drug to the tumor. The formulation comprises
cisplatin and liposomes based on 1,2 dipalmitoyl-sn-
glycero-3-phospho-rac-1-glycerol (sodium salt) (DPPG,
mw 745), soy phosphatidyl choline (SPC-3, mw 790),
cholesterol (CHOL, mw 386.66) and methoxy-polyeth-
ylene glycol-distearoyl phosphatidyl-etha-nolamine lipid
conjugate (mMPEG2000-DSPE, mw 2807). At steady
state, particles have a weight ratio of 8.9% cisplatin to
91.1% lipids (0.9:9 .1). The total lipid to cisplatin ratio in
lipoplatin is 10 mg lipid/mg cisplatin. The cholesterol
content of lipoplatin is 11.6% of the total lipids. It is cal-
culated that 1.3 mg of cholesterol is injected per mg of
cisplatin [24]. There are numerous indications that point
towards the potential usefulness of lipoplatin as treatment
of TNBC. Consequently, our group is currently planning a
new trial on patients with TNBC who have become resis-
tant to anthracyclines and taxanes, offering lipoplatin as
second-line treatment following progression after first-
line therapy.
3. Conclusion
TNBC is a very serious illness and conventional treat-
ments only obtain partial control of the disease, and
normally for a short period of time. The search for new
treatments is urgently needed and lipoplatin could be
potentially useful in advanced disease and could also
represent a new possible treatment in the future in neo-
adjuvant and ad juvant settings.
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