Cisplatin versus carboplatin in combination with paclitaxel as neoadjuvant regimen for triple negative breast cancer

Abstract

Background
Platinum salts have demonstrated sufficient efficacy and safety for consideration of their use in a neoadjuvant setting for triple negative breast cancer (TNBC).

Patients and methods
We retrospectively analyzed 145 TNBC cases to compare the activity and tolerability of cisplatin and carboplatin. Two groups received weekly paclitaxel and platinum salts.

Results
In total, 87% of patients in the cisplatin group and 82% of patients in the carboplatin group experienced a clinical objective response after four cycles (complete response or partial response; P=0.570). Pathological complete response (pCR) occurred similarly in the cisplatin group and the carboplatin group (44% versus 42%, P=0.789). In survival analysis, there was no difference between the two regimens. The most common grade 3/4 adverse events were neutropenia and leukopenia.

Conclusion
There was no significant difference between the groups in terms of adverse events. Both types of platinum salts and weekly paclitaxel are feasible therapies that achieved high pCR rates and tolerability in TNBC patients.

Full text

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OncoTargets and Therapy 2017:10 5739–5744
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ORIGINAL RESEARCH
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Open Access Full Text Article
http://dx.doi.org/10.2147/OTT.S145934
Cisplatin versus carboplatin in combination with
paclitaxel as neoadjuvant regimen for triple
negative breast cancer
Liang Huang1,2,*
Qi Liu2,3,*
Sheng Chen1,2
Zhiming Shao1,2
1Department of Breast Surgery, Fudan
University Shanghai Cancer Center/
Cancer Institute, Shanghai, China;
2Department of Oncology, Shanghai
Medical College, Fudan University,
Shanghai, China; 3Department of
Radiation Oncology, Fudan University
Shanghai Cancer Center/Cancer
Institute, Shanghai, China
*These authors contributed equally
to this work
Background: Platinum salts have demonstrated sufficient efficacy and safety for consideration
of their use in a neoadjuvant setting for triple negative breast cancer (TNBC).
Patients and methods: We retrospectively analyzed 145 TNBC cases to compare the
activity and tolerability of cisplatin and carboplatin. Two groups received weekly paclitaxel
and platinum salts.
Results: In total, 87% of patients in the cisplatin group and 82% of patients in the carboplatin
group experienced a clinical objective response after four cycles (complete response or partial
response; P=0.570). Pathological complete response (pCR) occurred similarly in the cisplatin
group and the carboplatin group (44% versus 42%, P=0.789). In survival analysis, there was
no difference between the two regimens. The most common grade 3/4 adverse events were
neutropenia and leukopenia.
Conclusion: There was no significant difference between the groups in terms of adverse events.
Both types of platinum salts and weekly paclitaxel are feasible therapies that achieved high
pCR rates and tolerability in TNBC patients.
Keywords: neoadjuvant chemotherapy, triple negative breast cancer, carboplatin, cisplatin,
pathological complete response
Introduction
Triple negative breast cancer (TNBC) is defined as tumors that do not express ER, PR,
and HER-2. Treatment options for TNBC have been limited by the lack of traditional
targeted therapies, such as hormonal interventions or trastuzumab. Nearly 15% of
breast cancers are defined as TNBC in Western countries, and the vast majority are
sporadic.1 Most of these tumors are high-grade or poorly differentiated tumors with a
high risk of recurrence and mortality.
Neoadjuvant chemotherapy (NCT) has the potential to convert unresectable tumors
to resectable ones and can reduce the extent of surgery needed to achieve breast conserv-
ing surgery. TNBC shows heterogeneity in response to systemic treatment, which can
be divided into six groups according to gene expression profiles.2 In the neoadjuvant
setting, TNBC can achieve a higher pathological complete response (pCR) rate than
the luminal type.3 The pCR rates of TNBC can also increase from single-agent to
multi-agent neoadjuvant trials.4–6 In a pooled analysis, TNBC was associated with a
pooled pCR of 34%.7 In a previous meta-analysis, TNBC patients who presented with
residual disease after NCT had very poor outcomes.3 New therapies should improve
the pCR rate in TNBC patients. A high pCR rate can benefit survival.
Correspondence: Zhiming Shao
Department of Breast Surgery, Fudan
University Shanghai Cancer Center/
Cancer Institute, 399 Ling-Ling Road,
Shanghai, 200032, China
Fax +86 21 6443 4556
Email zhimingshao@outlook.com
Journal name: OncoTargets and Therapy
Article Designation: Original Research
Year: 2017
Volume: 10
Running head verso: Huang et al
Running head recto: Cisplatin vs carboplatin in combination with paclitaxel as NCT for TNBC
DOI: http://dx.doi.org/10.2147/OTT.S145934
This article was published in the following Dove Press journal:
OncoTargets and Therapy

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Huang et al
The previous reports demonstrated that some DNA
damaging agents may be more effective in TNBC tumors.8
Therefore, there is interest in utilizing DNA-damaging
agents, such as platinum drugs (cisplatin and carboplatin)
to treat TNBC. Few trials have been designed to compare
the efficacy and safety between carboplatin and cisplatin.
In a neoadjuvant setting, the addition or lack of platinum
versus the same chemotherapy is the most common design.
Due to a lack of clinical evidence, the best platinum salt to
be added to NCT is still unknown. Here, we retrospectively
analyzed 145 patients with locally advanced breast cancer
who received a neoadjuvant combination of weekly paclitaxel
with cisplatin or carboplatin, to compare the efficacy and
safety of the two types of platinum therapy.
Method and treatment
Study population
The cohort in the present study was selected consecutively
from patients with locally advanced breast cancer who
received NCT followed by surgery at Shanghai Cancer Centre
from 2011 to 2015. The major eligibility criteria included:
1) women aged 18–75 years; 2) ECOG score 0–1; 3) core
needle biopsy-diagnosed invasive breast cancer; 4) hormone
receptor-negative (ER and PR negative defined as ,1% tumor
staining by immunohistochemistry [IHC]) and HER-2 nega-
tive (IHC: 0 or 1; or IHC: 2 and FISH negative); 5) clinical
stage IIA-IIIC with NAC indication and measurable lesions;
and 6) normal cardiac, hepatic, and marrow function. Patients
were excluded if they had a history of invasive cancer or
prior exposure to chemotherapy/radiotherapy. The study
was conducted according to the principles expressed in the
Declaration of Helsinki and approved by the Institutional
Review Board of Fudan University Shanghai Cancer Center/
Cancer Institute. All patients enrolled in this study signed an
informed consent voluntarily.
Response and toxicity evaluation
A pCR was defined as the absence of an invasive tumor in the
final surgical breast and axillary lymph node (ALN) sample.
Residual ductal carcinoma in situ was included in the pCR
category. Standard RECIST guidelines were used to evaluate
the clinical and pathological response. No clinical evidence
of palpable tumor in the breast and ALNs was defined as a
clinical complete response (CR). Reduction in the greatest
tumor diameter of $30% was graded as a partial response
(PR). An increase in greatest tumor diameter of .20% or
the appearance of new disease was considered as progres-
sive disease (PD). Tumors that did not meet the criteria for
objective PR or PD were considered as stable disease (SD).
The Miller-Payne (MP) grading system was employed to
evaluate the decrease in cancer cellularity.9 Toxicity was
evaluated at every period of chemotherapy treatment and
based on the NCI-CTCAE v3.0.
Treatment
In this retrospective study, patients received four cycles of
weekly carboplatin (AUC =2 calculated using the Calvert
formula, d1, d8, d15) and paclitaxel (80 mg/m2, d1, d8, d15)
or four cycles of cisplatin (25 mg/m2, d1, d8, d15) treatment
and paclitaxel (80 mg/m2, d1, d8, d15, d22). Breast surgery
was performed 2–4 weeks after the last chemotherapy dose.
The surgery type was at the surgeon’s discretion. Adjuvant
chemotherapy began within 4 weeks postoperatively. An addi-
tional two cycles of the same regimen treatment were admin-
istered to patients who achieved pCR; otherwise, four cycles
of epirubicin and cyclophosphamide were administered.
Statistical analysis
Descriptive statistics were calculated to summarize the patient
characteristics, tumor size, and biomarker levels according to
the core needle biopsies. Toxicity rates in the two cohorts were
presented using frequency tabulations with the corresponding
percentages. Disease free survival (DFS) was calculated from
the date of first diagnosis to the date of disease relapse or metas-
tasis. Overall survival (OS) was calculated from the date of first
diagnosis to the date of death or last follow-up. Patients without
relapse events or death were censored at the last follow-up. Sur-
vival curves were estimated using the Kaplan–Meier method,
and the log-rank test was used to determine significance. The
Chi-squared test was used to evaluate the relationship between
patient characteristics and clinical response. A multivariate
logistic regression model for predicting the response to NCT
was used when combining a series of variables. All P-values
reported are two-sided and were calculated at a significance
level of 0.05. All statistical procedures were performed using
SPSS (version 13.0) and Stata (version 11.0).
Results
Patient characteristics
Overall, 145 consecutive patients with breast cancer were
enrolled from January 2011 to December 2015 to receive
NCT at Fudan University Shanghai Cancer Center. Of these
patients, 52 cases were assigned to receive weekly cisplatin
and paclitaxel, and 93 cases were assigned to receive weekly
carboplatin and paclitaxel. Table 1 summarizes the main
clinical and pathological characteristics. These factors were
well balanced in the two groups, including age, menopausal
status, clinical stage, Ki67 index, and body mass index

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Cisplatin vs carboplatin in combination with paclitaxel as NCT for TNBC
(BMI). The median age was 43 years (range 26–65 years)
in the cisplatin group and 47 years (range 27–68 years) in
the carboplatin group. A total of 58 patients (46.9%) were
initially diagnosed with stage III disease, and 88 patients
(60.7%) were premenopausal.
Treatment compliance and surgery
One hundred and thirty (90%) patients completed all four
cycles of weekly paclitaxel and carboplatin/cisplatin treat-
ment. Because of adverse events, disease progression, with-
drawal of consent or immediate surgery, five patients in the
cisplatin group and ten patients in the carboplatin group did
not finish four cycles. Among these 145 cases, 27 patients
received breast conserving surgery, 118 patients had mas-
tectomy, and only two patients received immediate breast
reconstruction with the latissimus dorsi muscle flap. Sentinel
lymph biopsy was not a common choice for locally advanced
breast cancer. Only eight patients received this operation,
while nearly 95% of patients received ALN dissection.
Treatment response
After two cycles, 132 patients (91%) had a clinical response
(CR or PR). After four cycles, 86% patients had a clinical
response. Two patients in the cisplatin group and five in the
carboplatin group received anthracycline, capecitabine or
radiotherapy before surgery. The MP scores for responses
to four cycles of platinum are listed in Table 2. The pCR in
the carboplatin group was 53% (ypT0/isNxM0) and 42%
(ypT0/isN0M0) while the pCR in the cisplatin group was
52% (ypT0/isNxM0) and 44% (ypT0/isN0M0). In addition,
80 patients who were clinically positive for ALNs had a nega-
tive result after NCT. Table 3 lists the distribution of various
clinical and pathological characteristics according to the
response outcomes. In univariate and multivariate analysis,
tumor size, age, ALN status, Ki67 index, and neoadjuvant
regimen were not significantly related to pCR. The median
follow-up time was 33 months (6–61 months). Survival anal-
yses revealed no significant relationship between regimens
and DFS (P=0.877, Figure 1A). Similarly, different kinds
of platinum were not significantly related to OS (P=0.663,
Figure 1B). The Kaplan–Meier curves also demonstrated that
age, BMI, tumor size, and lymph node involvement were not
prognostic factors; non-pCR was the only significant poor
prognostic factor for DFS (P=0.016).
Toxicity
During the four cycles of NCT, only one patient in the cisplatin
group and two patients in the carboplatin group could not
Table 1 Patient characteristics and clinical evaluation at baseline
Characteristics Cisplatin
group (N=52)
Carboplatin
group (N=93)
P-value
Median age (range), years 43 (26–65) 47 (27–68) 0.478
Menopausal status 0.222
Premenopausal 35 (67%) 53 (57%)
Postmenopausal 17 (33%) 40 (43%)
Clinical tumor stage 0.192
cT1 1 (2%) 9 (10%)
cT2 32 (62%) 52 (55%)
cT3 17 (33%) 24 (26%)
cT4 2 (3%) 8 (9%)
Clinical lymph node stage 0.231
cN0 3 (6%) 13 (14%)
cN1 39 (75%) 55 (59%)
cN2 6 (11%) 13 (14%)
cN3 4 (8%) 12 (13%)
Clinical TNM stage 0.831
II 27 (52%) 50 (54%)
III 25 (48%) 43 (46%)
Ki67 index 0.192
$20% 11 (21%) 12 (13%)
,20% 41 (79%) 81 (87%)
Body mass index 0.295
$25 kg/m213 (25%) 31 (33%)
,25 kg/m239 (75%) 62 (67%)
Table 2 Clinical and pathological evaluation
Variables Cisplatin
group
Carboplatin
group
OR (95% CI) P-value
ypT0/is, ypN0 0.911 (0.459–1.806) 0.789
No 29 (56%) 54 (58%)
Yes 23 (44%) 39 (42%)
ypT0/is, ypN0/+1.031 (0.523–2.034) 0.930
No 25 (48%) 44 (47%)
Yes 27 (52%) 49 (53%)
MP grade for breast NA 0.448
MP 5 27 (52%) 49 (53%)
MP 4 8 (15%) 8 (9%)
MP 3 14 (27%) 24 (26%)
MP 2 3 (6%) 9 (10%)
MP 1 0 (0%) 3 (3%)
Clinical response after two cycles NA 0.352
CR 3 (6%) 2 (2%)
PR 43 (82%) 84 (90%)
Overall
(CR or PR)
46 (88%) 86 (92%)
SD or PD 6 (12%) 7 (8%)
Clinical response after four cycles NA 0.570
CR 8 (15%) 11 (12%)
PR 37 (72%) 65 (70%)
Overall
(CR or PR)
45 (87%) 76 (82%)
SD or PD 2 (4%) 7 (8%)
Notes: ypT0/is, ypN0: the absence of invasive carcinoma in both the breast and
axilla. ypT0/is, ypN0/+: the absence of invasive carcinoma in the breast.
Abbreviations: CI, condence interval; CR, complete response; MP, Miller-Payne;
NA, not available; OR, odds ratio; PD, progressive disease; PR, partial response;
SD, stable disease.

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Huang et al
tolerate the adverse events and quit the treatment after two
cycles. Severe toxicity was also uncommon. The most
common grade 3/4 adverse effect was hematological toxicity,
such as neutropenia and leukopenia (Table 4). Grade 3/4
non-hematological toxicity was rare, and only diarrhea and
peripheral neuropathy occurred. There was no significant
difference between the adverse events in the groups.
Discussion
Because of the younger age, poorly differentiated tumors, and
shortened survival, TNBC is a high-risk breast cancer that
lacks the benefit of targeted therapies. In metastatic breast
cancer patients, previous clinical trials have indicated that
the addition of platinum salts to chemotherapy can increase
the response rate or progression free survival (PFS).8,10
The BRCA1/2 mutation is associated with DNA damage,
and platinum can cause DNA damage. In a retrospective
analysis of 6,903 patients, including 102 patients with the
germ-line BRCA1 mutation, the highest pCR rate was reported
in germ-line BRCA1-mutation carriers who received neoadju-
vant cisplatin therapy (83%). In the other treatment subgroups,
such as anthracyclines and taxanes or cyclophosphamide,
methotrexate and fluorouracil, a low rate of pCR was observed
in women with breast cancer and BRCA1 mutation.11 How-
ever, combining the two trials, the pCR in patients with BRCA
mutation and wild-type TNBC was similar.12 BRCA mutated
cancers and some sporadic TNBC have a potentially higher
sensitivity to DNA-damaging agents, such as platinum salts.
In untreated metastatic breast cancer, single platinum
agents have had encouraging overall response rates
(42%–54% for cisplatin, 32% for carboplatin).13 In prospec-
tive clinical trials, the addition of carboplatin increased the
pCR rates from 28% to 42% in stage II–III TNBC.14 The
addition of weekly carboplatin to non-pegylated liposomal
doxorubicin, weekly paclitaxel and bevacizumab boosted the
pCR rate from 38% to 58%.15 In a meta-analysis including
28 studies, the pooled rate of pCR for cisplatin was 41.9%
(95% CI: 32%–51%) while carboplatin was associated with a
pCR rate of 46.3% (95% CI: 40.7%–52.1%).16 In a retrospec-
tive analysis for platinum salt in TNBC, the study found that
cisplatin offered a survival advantage over carboplatin in both
PFS and OS. Cisplatin/docetaxel neoadjuvant therapy was
well tolerated and an effective therapy in locally advanced
TNBC.17 Patients who achieved pCR had a significant ben-
efit in relapse and death compared with non-pCR patients.
However, we lack long-term outcome data from prospective
Table 3 Odds ratios for pathological complete response according to subgroups
Variables Category Univariable Multivariable
Odds ratio (95% CI) P-value Odds ratio (95% CI) P-value
Arm Cisplatin vs carboplatin 0.911 (0.459–1.806) 0.789 0.905 (0.441–1.857) 0.786
Age ,45 y vs $45 y 0.724 (0.371–1.414) 0.344 0.754 (0.376–1.511) 0.425
cT cT1–2 vs cT3–4 0.620 (0.307–1.252) 0.182 0.572 (0.278–1.176) 0.129
cN cN0–1 vs cN2–3 0.530 (0.237–1.187) 0.123 0.487 (0.213–1.112) 0.088
Ki67 index ,20% vs $20% 2.404 (0.887–6.512) 0.084 2.622 (0.945–7.274) 0.064
Abbreviations: CI, condence interval; cN, clinical node stage; cT, clinical tumor stage; y, years.
Figure 1 Kaplan–Meier disease free survival curve (A) and overall survival curve (B) of triple negative breast cancer patients treated with cisplatin or carboplatin.
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Cisplatin vs carboplatin in combination with paclitaxel as NCT for TNBC
neoadjuvant trials to determine if the addition of different
types of platinum salts and the higher pCR rates associated
with its addition significantly impacted DFS or OS. These
results indicate that adding effective agents, such as antian-
giogenics, poly-ADP ribose polymerase (PARP) inhibitors,
and other small molecule inhibitors, which may increase the
pCR rate, is a potential cure for TNBC patients.18–20
Cisplatin is highly protein bound and leads to high drug
levels in the kidneys, liver, and other organs, slowing renal
excretion and contributing to its side effect profile, most
of which are dose related. On the other hand, carboplatin
remains largely unbound to plasma proteins and the serum
concentration is closely linked to renal clearance. In toxicity
analysis, cisplatin typically causes more nausea and vomiting,
nephrotoxicity, and neurotoxicity, while carboplatin is more
likely to cause myelosuppression.21 However, severe anemia
and thrombocytopenia only occurred in less than 5% of
patients after four cycles of carboplatin in previous studies.6,22
After four cycles of single-agent cisplatin, grade 3/4 hemato-
logical and non-hematological adverse events (AE) occurred
in less than 5% of patients.23 When combination cisplatin
and paclitaxel was used, grade III neutropenia, anemia,
nausea, and vomiting were reported in 8%–9% of Western
patients.24 In our study, the grade 3/4 AE were neutropenia
and leukopenia and were over 50%, while AE of anemia and
thrombocytopenia were less than 10% in both groups. Nau-
sea/vomiting and peripheral neuropathy was slightly higher
in the cisplatin group but did not reach significance.
Both types of platinum salts and weekly paclitaxel are fea-
sible therapies that achieved high pCR rates, similar survival
rate, and tolerability in TNBC patients. We recognize that
the research still has some points of weakness. First, this was
a retrospective study that lacked long-term adverse event
observations and long-term invalid survival improvement.
A further limitation of our study is the small number of
patients from which to draw meaningful conclusions. The best
platinum salt to be added to NAC is still unknown. Further
studies are needed on the comparison of different platinum
combinations and the comparison between carboplatin- and
cisplatin-based combinations. Based on biomarkers identified
by high throughput technology with DNA, RNA or proteins,
researchers will be able to find a subgroup of patients who
will receive the greatest benefit.
Acknowledgment
This research was supported by the National Natural Science
Foundation of China (81502289 and 81302298). The funders
had no role in the study design, data collection and analysis,
decision to publish, or preparation of the manuscript.
Author contributions
All authors contributed toward data analysis, drafting and
critically revising the paper, gave final approval of the version
to be published, and agree to be accountable for all aspects
of the work.
Disclosure
The authors report no conflicts of interest in this work.
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Table 4 Most common adverse events reported as possibly,
probably, or denitely related to treatment
Adverse event Cisplatin group
(N=52)
Carboplatin group
(N=93)
Grade 1/2 Grade 3/4 Grade 1/2 Grade 3/4
Anemia 26 (50%) 5 (10%) 55 (59%) 8 (9%)
Febrile neutropenia 0 (0%) 3 (6%) 0 (0%) 5 (5%)
Neutropenia 21 (40%) 31 (60%) 25 (27%) 68 (73%)
Leukopenia 22 (42%) 26 (50%) 30 (32%) 55 (59%)
Thrombocytopenia 19 (37%) 3 (6%) 31 (33%) 7 (8%)
Bilirubin increased 23 (44%) 3 (6%) 37 (40%) 3 (3%)
AST increased 17 (33%) 2 (4%) 25 (27%) 2 (2%)
ALT increased 13 (25%) 1 (2%) 28 (30%) 0 (0%)
Diarrhea 8 (15%) 1 (2%) 13 (14%) 1 (1%)
Nausea/vomiting 23 (44%) 1 (2%) 38 (41%) 0 (0%)
Arthralgia/myalgia 3 (6%) 0 (0%) 9 (10%) 0 (0%)
Fatigue 26 (50%) 0 (0%) 39 (42%) 1 (1%)
Peripheral neuropathy 7 (13%) 2 (4%) 5 (5%) 0 (0%)
Abbreviations: ASL, aspartate transaminase; ALT, alanine transaminase.

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