The early onset of peripheral neuropathy might be a robust predictor for time to treatment failure in patients with metastatic breast cancer receiving chemotherapy containing paclitaxel
The early onset of peripheral neuropathy might be a robust predictor for time to treatment failure in patients with metastatic breast cancer receiving chemotherapy containing paclitaxel
Ippei Fukada 0 1
Yoshinori Ito 0 1
Kokoro Kobayashi 0 1
Tomoko Shibayama 0 1
Shunji Takahashi 1
Rie Horii 1
Futoshi Akiyama 1 2
Takuji Iwase 1
Shinji Ohno 1
0 Department of Breast Medical Oncology, Breast Oncology Center, the Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan, 2 Department of Medical Oncology, the Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan, 3 Department of Pathology, the Cancer Institute Hospital of the Japanese Foundation for Cancer Research , Tokyo , Japan
1 Editor: William B. Coleman, University of North Carolina at Chapel Hill School of Medicine , UNITED STATES
2 Department of Pathology, the Cancer Institute of the Japanese Foundation for Cancer Research, Tokyo, Japan, 5 Department of Breast Surgical Oncology, Breast Oncology Center, the Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan, 6 Breast Oncology Center, the Cancer Institute Hospital of the Japanese Foundation for Cancer Research , Tokyo , Japan
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
Funding: The authors received no specific funding
for this work.
Competing interests: The authors have declared
that no competing interests exist.
Paclitaxel plays a central role in chemotherapy for breast cancer. Peripheral neuropathy, a
well-known toxicity with paclitaxel, may be of interest in predicting the efficacy of paclitaxel
therapy for patients with metastatic breast cancer. We performed a retrospective analysis
assessing whether the early occurrence of peripheral neuropathy (EPN) was a predictive
marker for better efficacy in patients with metastatic breast cancer receiving chemotherapy
Patients and methods
Between January 2000 and August 2008, we examined the records of 168 patients with metastatic breast cancer treated with paclitaxel in our hospital. EPN was defined as a symptom of Grade 2 or more during first three months of treatment. The overall response rate (ORR) and time to treatment failure (TTF) in each group were analyzed retrospectively.
Of 168 patients with metastatic breast cancer who were treated with paclitaxel, EPN was
documented in 101 patients (60.1%). The clinical benefit rate (CR, PR, and SD
was 72.3% in the EPN group and 49.3% in the non-EPN group (p = 0.002). The TTF of the
EPN group (median 11.2 months, 95% CI: 9.5±12.9) was significantly longer than that of
the non-EPN group (5.7 months, 95% CI: 4.6±6.8) (p<0.001). Multivariate analysis
demonstrated that EPN (p<0.001), dose intensity of less than 70% (p<0.001), and the
history of microtubule agents (p = 0.001) were the significant favorable prognostic factors for
The early onset of peripheral neuropathy might be a robust predictor for TTF in patients with metastatic breast cancer treated with paclitaxel.
Taxane drugs binds to β-tubulin, promotes microtubule polymerization, and prevents
depolymerization, thereby arresting cell division and inducing apoptosis. In Japan, paclitaxel was
approved for breast cancer in 1999. Currently, paclitaxel plays a central role in chemotherapy
for breast cancer. Although with this treatment, neuropathy is a common toxicity, there have
been many reports of the therapeutic effects of paclitaxel for metastatic breast cancer. For
instance, a randomized phase III trial compared the effects of docetaxel and paclitaxel on
metastatic breast cancer, reporting that the overall response rate (ORR) and median time to
progression (TTP) for paclitaxel were 25.0% and 3.6 months, respectively [
]. The incidence of all
grade and grade 3/4 neurosensory toxicities were 59.0% and 4.1% in the paclitaxel groups.
Furthermore, the incidence of all grade and grade 3/4 neuromotor toxicities were 12.6% and 2.3%
in the paclitaxel groups. It was also reported that the RR and median TTP for paclitaxel 175
mg/m2 intravenously as the first-line therapy were 19% and 16.9 weeks, respectively [
Treatment-related grade 3 sensory neuropathy occurred in 2% of the paclitaxel arm. Seidman et al.
reported the final results of randomized phase III trial of weekly compared with every-3-weeks
paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and
random assignment to trastuzumab or not in HER-2 nonoverexpressors (Cancer and Leukemia
Group B protocol 9840). In their study, the incidence of grade 2 and grade 3 neurosensory
toxicity were 33% in patients who received constant dosing of paclitaxel at 175 mg/m2 q3w, 45%
in 80 mg/m2 weekly arm, and 51% in 100 mg/m2 weekly arm, respectively [
peripheral neuropathy is managed by dose reduction and treatment delays. There have been
no reports as to whether peripheral neuropathy may be predictive of the efficacy of paclitaxel
therapy for patients with metastatic breast cancer.
We performed a retrospective analysis assessing whether the early occurrence of peripheral
neuropathy constituted a predictive marker for improved efficacy in patients with metastatic
breast cancer who had received chemotherapy containing paclitaxel.
Material and methods
Patients and methods
Of 527 patients with metastatic breast cancer treated in our hospital between January 2000 and
August 2008, 168 who were treated with paclitaxel were included. Comprehensive consent for
the use of specimen materials was obtained by written informed consent from all patients
participating as subjects in this study. The retrospective study was approved by the Institutional
Review Board of the Cancer Institute Hospital of the Japanese Foundation for Cancer Research
(2013±1136), and data were collected in compliance with the ethical requirements of our
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Immunohistochemical subtypes were determined by biopsy of the primary lesion at stage IV
or surgical materials of primary tumor in patients with recurrent breast cancer. They were
stained with hematoxylin-eosin (HE) and were immunohistochemically examined for ER, PgR,
and HER2. Immunohistochemical assessment of ER and PgR expression was performed using
antibodies for ER, clone 1D5 (Dako Japan Inc., Tokyo, Japan) and for PgR, clone PgR636 (Dako
Japan Inc.). Positive reactions for ER and PgR were defined as nuclear staining in 10% or more
of cancer cells, and negative reactions were defined as staining in less than 10%. Hormone
receptor positivity was defined as showing positivity in ER and/or PgR.
Immunohistochemical detection of HER2 protein was performed using the Hercep Test
(Dako Japan Inc.). Expression of HER2 protein was classified into four groups: 0, 1+, 2+, and
3+. In those cases that were 2+, HER2 genetic testing by FISH was performed using a
PathVysion HER2-DNA Probe Kit (Abbott Molecular Inc., Des Plaines, IL). Both protein and genetic
status were estimated based on the guidelines for HER2 testing in breast cancer, as edited by
the American Society of Clinical Oncology/College of American Pathologists [
positivity was defined as HER2 protein 3+ or HER2 gene amplification.
After combining ER, PgR, and HER2, patients were classified into four subtypes, defined as
follows: luminal subtype, ER+ and/or PgR+, HER2-; luminal HER2 subtype, ER+ and/or PgR+,
HER2+; HER2 subtype, ER-, PgR-, HER2+; and triple negative subtype, ER-, PgR-, HER2-.
The chemotherapy regimens given to patients in this study included a weekly paclitaxel
(wPAC) regimen at a dose of 80 mg/m2. Concurrent trastuzumab was used for all patients of
the luminal-HER2 type and HER2 type (loading dose of 4 mg of intravenous trastuzumab per
kilogram of body weight, followed by 2 mg per kilogram weekly).
The intensity of the paclitaxel dose was analyzed at the standard regimen of paclitaxel, 80 mg/
m2 once a week. Relative dose intensity (RDI) was the ratio of actual total dose intensity
(ATDI) and planned total dose intensity (PTDI), expressed as a percentage and calculated as
PTDI was the dose intensity planned for the entire treatment duration, averaged across the
chemotherapy agents used. ATDI was defined as the actual average dose intensity over real
treatment duration. Cumulative dose was the same as the actual dose.
Toxicity and definition of early onset of peripheral neuropathy
Patients who received a paclitaxel regimen at a dose of 80 mg/m2 visited our hospital every
week, and physicians recorded their clinical symptoms in detail. The neuropathy information
have been retrospectively collected by first author based on clinic notes, and toxicity was
assessed according to the National Cancer Institute Common Terminology Criteria for
Adverse Events version 4.0 (NCI-CTC-AE v4). Based on this criteria, we carefully checked
clinic notes retrospectively. The moderate symptoms; limiting instrumental ADL, severe
symptoms; limiting self care ADL, and symptoms which needed dose reduction and
administration of neuroprotective agents were defined as the symptoms of Grade 2 or more. Finally,
the early onset of peripheral neuropathy (EPN) was defined as symptoms of Grade 2 or more
during the first three months of treatment.
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Response evaluation and statistical analysis
Radiological tumor assessments were performed by computed tomography every 3±4 months
during treatment. Local lesion (breast, chest wall, and skin) and regional lymph node
metastases were measured by echogram. The response to chemotherapy was assessed according to the
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The overall response rate
(ORR) was defined as the proportion of patients achieving complete response (CR) and partial
response (PR). The clinical benefit rate (CBR) was defined as the proportion of patients with
CR, PR, and stable disease (SD) lasting >6 months. Time to treatment failure (TTF) was used
as the surrogate marker for the efficacy of paclitaxel. TTF was defined as time interval from the
start of paclitaxel treatment to disease progression or cessation of treatment because of adverse
events. SPSS ver. 17.0 was used for statistical analysis in this study. ORR and CBR were
analyzed using the χ2 test. TTF was measured by the log-rank test using the Kaplan-Meier method.
For multivariate analysis, Cox regression analysis was used. A p-value of less than 0.05 was
considered statistically significant.
Characteristics of all 168 patients are listed in Table 1. All evaluated cases had invasive breast
cancer. The median age was 56 years (29±84). Patient numbers according to age group age
were as follows: <39 years old, 20 patients (11.9%); >40 years old, 148 patients (88.1%). The
most common sites of distant metastasis were the lymph nodes, found in 102 patients (60.7%).
The mean number of metastases was three. The number of patients receiving one or more
prior treatment was 132 (78.6%); 72 patients (42.9%) had a history of receiving anthracyclines.
Early onset of peripheral neuropathy and clinicopathological features of each group
In our study, EPN appeared in 101 patients (60.1%). Associations between EPN and the
distribution of clinicopathological features are shown in Table 1. Although there was significant
difference between age among two groups, there was no important differences between subtype
distribution, portions of metastasis, number of prior chemotherapy treatments, or history of
anthracycline and microtubule agents.
Cumulative dose of all 168 patients are shown in Table 2. Median cumulative dose was 1720.0
mg/m2 in all patients. Median cumulative dose was 1120.0 mg/m2 in the non-EPN group and
1920.0 mg/m2 in the EPN group (p <0.001).
Dose intensity and relative dose intensity
In all patients, dose intensity was 52.3 mg/m2 (range 24.2±80.0 mg/m2) and RDI was 66.4%
(30.2±100%). The dose intensity and RDI were 60.1 mg/m2 (range 24.3±80 mg/m2), 76.0%
(30.4±100%) in the non-EPN group and 49.2 mg/m2 (range 24.2±80 mg/m2), 61.5% (30.2±
100%) in the EPN group (p <0.001) (Table 2).
ORR and CBR for each group are shown in Table 2. The ORR was 40.6% in the EPN group
and 35.8% in the non-EPN group. CBR was 72.3% in the EPN group and 49.3% in the
non4 / 11
EPN group. While there was no important difference in ORR within each group, there was a
significant difference in CBR (p = 0.002). For each immunohistochemical subtype, CBR in the
EPN and in the non-EPN groups were 62.7% and 35.5% in the luminal type, 100% and 77.8%
in the luminal-HER2 type, 85.2% and 71.4% in the HER2 type, and 58.3% and 38.5% in the
triple negative type, respectively.
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Time to treatment failure according to subtypes
Average follow-up time was 11.8 months. TTF for the EPN group (median 11.2 months, 95%
CI; 9.5±12.9) was significantly better than that of the non-EPN group (5.7 months, 95% CI;
4.6±6.8) in all patients shown in Fig 1. TTF according to subtype was shown in Fig 2.
Univariate and multivariate analyses of prognostic factors
Univariate and multivariate analyses of prognostic factors are shown in Table 3. In univariate
analysis, the significant prognostic factors for TTF were EPN (relative risk [RR], 0.462; 95%
CI, 0.322 to 0.662; p<0.001); dose intensity more than 70% (RR, 2.225; 95% CI, 1.532 to 3.231;
p<0.001), subtype (RR, 1.008; 95% CI, 0.848 to 1.197; p<0.001), and history of microtubule
agents (RR, 2.337; 95% CI, 1.415 to 3.858; p = 0.001). Multivariate analysis demonstrated that
EPN (p<0.001), dose intensity less than 70% (p<0.001), and the history of microtubule agents
(p = 0.001) were the significant favorable prognostic factors for TTF.
We previously reported on our retrospective analysis of the therapeutic effect of taxanes on
metastatic breast cancer in various immunohistochemical subtypes [
]. We found that the
immunohistochemical subtypes were associated with the therapeutic effect of taxanes for
metastatic breast cancer (clinical benefit rate and median TTP, 51.6% and 8.3 months in luminal;
78.6% and 14.1 months in luminal-HER2; 71.9% and 10.6 months in HER2; and 40.8% and 4.2
months in triple negative, p<0.001). However, the TTP in each subtype was distributed over a
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Fig 1. Kaplan-Meier plots for TTF. The TTF of the EPN group (median 11.2 months, 95% CI; 9.15±12.9) was
significantly longer than that of the non-EPN group (5.7 months, 95% CI; 4.6±6.8) in all patients.
wide range. Further investigation was required to identify the predictive markers associated
with taxane therapy for patients with metastatic breast cancer, according to subtype.
In paclitaxel therapy, the main adverse events that disturb treatment include
paclitaxelassociated peripheral neuropathy. The mechanism of taxane-induced peripheral neuropathy is
related to the presence of disrupted microtubules of the mitotic spindle. This disruption
interferes with axonal transport and macrophage activation in both the dorsal root ganglia and
peripheral nerve, as well as with microglial activation within the spinal cord [
6, 7, 8
Moreover, taxane induced a dying-back process starting from distal nerve endings followed by
effects on Schwann cells and other neuronal cells, which is an essential microtubule-based
process that moves cellular components over long distances between neuronal cell bodies and
nerve terminals [
Peripheral neuropathy may be of interest in predicting the efficacy of paclitaxel therapy for
breast cancer patients. In the ECOG 1199 study, the development of neuropathy was found
not to be predictive of survival outcome for patients with early operable breast cancer who had
received adjuvant taxane therapy [
]. There has been no previous report showing the
development of neuropathy to be predictive of survival outcomes in metastatic breast cancer.
However, we revealed in this study that EPN occurred in 101 patients (60.1%) and that the early
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Fig 2. Kaplan-Meier plots for TTF according to subtypes. Among the four subtypes, TTF was 10.0 months in the EPN group and
3.7 months in the non-EPN group in the luminal type (p = <0.001); 31.7 months in the EPN group and 17.5 months in the non-EPN
group in the luminal-HER2 type (p = 0.270); 15.9 months in the EPN group and 9.5 months in the non-EPN group in the HER2 type
(p = 0.029); and 6.1 months in the EPN group and 3.7 months in the non-EPN group of the triple negative type (p = 0.043).
development of peripheral neuropathy strongly associated with prolongation of TTF in patients
with metastatic breast cancer. The overall incidence of peripheral neuropathy is similar to that
previously reported in phase III studies in patients with MBC and to other published
retrospective studies, which ranges from 18±83% [
Possible causes of the occurrence of peripheral neuropathy of paclitaxel associated with strong
predictor for prolongation of TTF in patients with metastatic breast cancer include the following
factors. Peripheral neuropathy, a dose-dependent adverse event, is a major toxicity associated
with paclitaxel. The predominant risk factor for peripheral neuropathy is the cumulative dose
over time [
]. Moreover, Mielke S et al reported that there is an obvious mechanism for this
association. It is well established that higher drug concentrations, a longer duration of systemic
concentration above a threshold of 0.05 uM, were associated with greater neuropathy [
also revealed that the effects of time above paclitaxel concentrations of 0.05 micromol/l was
associated with response to treatment, and this emphasizes the value of threshold models for the
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investigation of paclitaxel pharmacodynamics [
]. Our results strongly suggested that patients
with higher drug concentrations have greater neuropathy and greater efficacy. The longer the
period of treatment, the more the total dose of paclitaxel increases, resulting in more instances of
severe peripheral neuropathy in patients receiving paclitaxel-containing chemotherapy. It is
crucial to identify prognostic factors other than the total dose. Therefore, in this study, we defined
EPN at Grade 2 or more during first three months of treatment as the key symptom.
Appropriately reducing the dose of paclitaxel when peripheral neuropathy worsens could make it possible
to extend treatment and to gain the maximum therapeutic effect for these patients, and at the
same time prolonging TTF.
In our study, age was not a significant prognostic factor for TTF. Older age has been
definitively the predictors associated with an increased risk of developing taxane-induced
neuropathy. Hershman et al. reported age was independent predictors of the development of
chemotherapy-induced peripheral neuropathy; for each increase in age of one year, the odds
of neuropathy increased 4% (p = .006) [
]. The results of the Eastern Cooperative Oncology
Group (ECOG) 5103 study showed a significant association between neuropathy and age
(12.9% increase with each 10 years; p = 0 .004) [
]. In these studies of women with early-stage
breast cancer treated with weekly paclitaxel in adjuvant therapy, a genome-wide association
study showed that SNPs in two genes, RWDD3 and TECTA, were significantly associated with
time to onset of neuropathy. However, age was not associated with an increased risk of
neuropathy in the ECOG 1199 study [
]. In our study, there was no significant association
between the occurrence of neuropathy and age.
Regarding the pharmacokinetics of paclitaxel, Paclitaxel is metabolized to inactive
compounds by CYP2C8 and CYP3A4 in the liver [
17, 18, 19
]. Hertz et la. Showed that there is a
low-activity variant of the main paclitaxel metabolizing enzyme (CYP2C8 3) that has been
shown to be associated with increased paclitaxel effectiveness [
] and neuropathy [
Although further investigation is required to identify biomarkers, including the
pharmacokinetic mechanism that we have uncovered via clinical samples, for the early onset of peripheral
neuropathy in metastatic breast cancer treated with paclitaxel, our data shows the important
result that the early onset of peripheral neuropathy might help to motivate patients to continue
treatment with paclitaxel in clinical practice.
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In conclusion, the early onset of peripheral neuropathy of paclitaxel might be a robust
predictor for prolonged TTF in patients with metastatic breast cancer.
S1 Table. Clinical information for neoadjuvant chemotherapy dataset.
Conceptualization: Ippei Fukada.
Data curation: Ippei Fukada.
Formal analysis: Ippei Fukada.
Investigation: Ippei Fukada.
Methodology: Ippei Fukada.
Software: Ippei Fukada.
Supervision: Yoshinori Ito.
Visualization: Ippei Fukada.
Writing ± original draft: Ippei Fukada.
Writing ± review & editing: Yoshinori Ito, Kokoro Kobayashi, Tomoko Shibayama, Shunji
Takahashi, Rie Horii, Futoshi Akiyama, Takuji Iwase, Shinji Ohno.
10 / 11
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