Clinical Benefits of and Recent
Progress in Eribulin Mesylate Therapy for Breast Cancer Patients
Youngjin
Park, Tomoaki Kitahara, Kengo Kadoya, Ryoji Kato
Youngjin Park, Tomoaki Kitahara, Kengo Kadoya, Ryoji
Kato, Department of
Surgery, Sakura Medical Center, School of Medicine, Faculty of Medicine, Toho
University, 564-1, Shimshizu, Sakura, Chiba, 285-8741, Japan
Correspondence to: Youngjin Park, MD, PhD, Associate Professor (Breast Surgery),
Sakura Medical Center, School of Medicine, Faculty of Medicine, Toho
University, 564-1, Shimshizu, Sakura, Chiba, 285-8741, Japan.
Email: youngjinpark@sakura.med.toho-u.ac.jp
Telephone: +81-43-462-8811
Fax: +81-43-462-8820
Received: December 5, 2013
Revised: February 15, 2014
Accepted: February 21, 2014
Published online: April 18, 2014
ABSTRACT
Metastatic breast cancer is difficult to completely cure with currently
available drug therapy, and the main treatment goals are prolongation of
survival and improvement of the quality of life (QOL). Eribulin mesylate
(eribulin) is a synthetic analogue of halichondrin B. Because eribulin
selectively binds with highly affinity to only microtubule plus ends, a small
number of molecules can exert antitumor effect through microtubule inhibition.
A phase ¢ó randomized clinical trial (Study 305) was
performed in 762 women with locally recurrent or metastatic breast cancer who
had previously received 2 to 5 regimens of chemotherapy, including an
anthracycline and a taxane. On independent review of the results, the median OS
was found to be significantly longer in patients who received eribulin than in
those who received treatment of physician¡¯s choice. To our knowledge, no single
anticancer agent has been demonstrated to significantly prolong OS in patients
with metastatic breast cancer who previously received chemotherapeutic regimens
including anthracyclines and taxanes. In addition, new randomized clinical
trials are ongoing to evaluate eribulin monotherapy and eribulin in combination
with other anticancer agents and to compare eribulin monotherapy with
monotherapy with other anticancer agents. New clinical trials of eribulin
monotherapy and combined therapy are expected to further clarify the clinical
benefits of eribulin in patients with metastatic and primary breast cancer. We
expect that eribulin will be shown to be clinically beneficial, thereby
contributing to further progress in the treatment of breast cancer.
© 2014 ACT. All rights reserved.
Key words: Eribulin; Monotherapy; Combined
therapy; Metastatic breast cancer; OS; PFS
Park Y, Kitahara
T, Kadoya K, Kato R. Clinical Benefits of and Recent Progress in Eribulin
Mesylate Therapy for Breast Cancer Patients. Journal of Tumor 2014;
2(4): 113-121 Available from: URL:
http://www.ghrnet.org/index.php/JT/article/view/651
INTRODUCTION
Breast
cancer is the most common cancer among women and has high risks of metastasis
and recurrence. Many anticancer drugs have been developed for the management of
metastatic breast cancer, but complete cure is difficult to attain with
currently available drug therapy. The main treatment goals are therefore the
prolongation of survival and improvement of patients¡¯ quality of life (QOL). The
development of novel agents that prolong overall survival (OS) and
progression-free survival (PFS) and have well-tolerated toxicity that does not
negatively affect patients¡¯ QOL is eagerly awaited. In the diagnostic algorithm
for recurrent or metastatic breast cancer reported by Hortobagyi in 1998[1],
hormone therapy is indicated for the treatment of hormone receptor (HR)-positive
and non-life-threatening disease, while chemotherapy is indicated for
HR-negative or life-threatening disease (or both). On the decision to
administer chemotherapy, whether patients should receive single agents
sequentially or combined chemotherapy must be carefully considered. Prolonging
survival without negatively affecting patients¡¯ QOL is an important treatment
goal. However, many patients with metastatic breast cancer have previously
received multiple regimens of chemotherapy. Therefore, new effective treatments
are required for the management of breast cancer refractory to prior therapy.
The therapeutic usefulness
of eribulin mesylate was confirmed in Study 305, an open-label, randomized,
multicenter, international trial of 762 women with advanced breast cancer who
had received 2 to 5 prior chemotherapeutic regimens, including anthracycline-
and taxane-based chemotherapy. The results of this study led to the approval of
eribulin in the United States in November 2010, followed by the European Union
and Japan. The objective of this article is to comprehensively review the
clinical benefits of eribulin in patients with breast cancer. This review is
based on the following recent findings: the results of clinical trials in women
with heavily pretreated metastatic breast cancer (Study 305); the updated
results of Study 305; the outcomes of combination therapy with eribulin and
other anticancer agents as postoperative adjuvant, preoperative chemotherapy,
or treatment for recurrence; the results of previously unreported studies in
women with less heavily pretreated metastatic breast cancer (Study 301); and
the results of clinical trials of eribulin as first-line treatment for
metastatic breast cancer (Study 206, Study 208). Our ultimate goal is contribute
to the improved treatment of patients with breast cancer.
DEVELOPMENT OF ERIBULIN
Eribulin is a
synthetic analogue of halichondrin B, a natural anticancer agent that was first
isolated from the marine sponge Halichondria okadai by Hirata et al in
1986[2]. H. okadai is a rare species that was collected at Aburatubo
beach, located on Miura Peninsula, Kanagawa Prefecture, Japan. Subsequently,
Bai et al[3] evaluated the antitumor activity of halichondrin
B in vitro. The high antitumor activity of halichondrin B prompted
interest in the development of a new anticancer drug, but the supply of
halichondrin B was limited severely by its complex chemical structure. Clinical
development was thus considered difficult (Figure 1A).
In 1992, however, Aicher et al[4] reported the total
synthesis of halichondrin B, leading to the synthesis of halichondrin B
derivatives to attempt to develop a new anticancer drug. Consequently,
structure-activity relationships were defined for halichondrin B, culminating
in the successful total synthesis of eribulin, a chemically and biologically
optimized derivative[5]. The antitumor activity of halichondrin B
was found to be related to its macrocyclic ketone structure, and eribulin was
created as a derivative (Figure 1B).
INHIBITORY PATTERNS OF VARIOUS MICROTUBULE INHIBITORS
Microtubule
inhibitors such as taxanes and vinca alkaloids have been reported to be highly
effective against breast cancer as well as many other types of cancer. Similar
to these drugs, eribulin is a microtubule inhibitor that induces apoptosis of
cancer cells by stopping mitosis in the G2/M phase of the cell cycle[6-10].
However, recent studies have demonstrated that the mode of inhibitory action of
eribulin differs from mechanisms of conventional microtubule inhibitors.
Taxanes (paclitaxel and
docetaxel) bind to the inner surface of microtubules and promote microtubule
lengthening (polymerization), while inhibiting microtubule shortening
(depolymerization) (Figure 2A). Vinca alkaloids (vincristine, vinblastine,
etc.) bind to microtubule plus ends and the outer surface of microtubules,
inhibiting microtubule lengthening (polymerization) as well as shortening
(depolymerization) (Figure 2B). In contrast, eribulin[10-12] binds
to only microtubule plus ends and inhibits only microtubule lengthening
(polymerization), without affecting shortening (depolymerization) (Figure 2C).
Because eribulin selectively binds
with highly affinity to only microtubule plus ends, a small number of molecules
can exert antitumor effect through microtubule inhibition. Binding of one
molecule of eribulin to two microtubules can inhibit cell proliferation by 50%,
and such binding is reversible[10,11]. A recent analysis showed that
eribulin binds to a site near the guanosine 5'-triphosphate (GTP) binding site
of the subunit[10]. Because eribulin
strongly binds only to this unique site involved in microtubule polymerization,
eribulin produces antitumor activity at much lower drug concentrations than
conventional microtubule inhibitors.
PHASE¢ñCLINICAL
TRIALS FOR SOLID TUMORS (STUDIES 101, 102, 105)
To clarify the
dose-limiting toxicity (DLT), maximum tolerated dose (MTD), safety, and
antitumor activity of eribulin in patients with solid tumors, three phase¢ñclinical trials (Studies 101, 102, 105) were performed[13-15].
The DLT was neutropenia, and
the MTD was 1.4 mg/m2 when given intravenously on days 1 and 8 of
3-week cycles, which was designated as the recommended dose (RD) for the next phase
of clinical development (Table 1).
PHASE¢òCLINICAL TRIALS
FOR METASTATIC BREAST CANCER (STUDIES 201, 211, 221)
To evaluate the
efficacy [overall response rate (ORR), clinical benefit rate (CBR),
progression-free survival (PFS), and overall survival (OS)] and safety of
eribulin in patients with metastatic breast cancer, three phase¢òclinical trials were performed[16-18]. The results for
efficacy are shown in table 2. In Study 221, response was additionally analyzed
according the number of previously received regimens of chemotherapy. The ORR
was 36.0% for 0 to 1 regimen, 14.7% for 2 regimens, and 14.3% for 3 regimens,
indicating that a lower number of previous regimens were associated with a
higher ORR. In addition, two regimens or less were associated with longer PFS
and OS (Table 3).
The main types of
hematologic toxicity were neutropenia, leukopenia, and lymphopenia. The
incidence of febrile neutropenia was low. The main types of nonhematologic
toxicity included alopecia, decreased appetite, fatigue, and nausea.
A PHASE ¢ó RANDOMIZED CLINICAL TRIAL FOR
METASTATIC BREAST CANCER (STUDY
305, EMBRACE)
A total of 135
centers located in 19 countries of 3 regions of the world participated in this
phase III clinical trial[19]. The subjects were 762 patients with
metastatic breast cancer who had previously received 2 to 5 regimens of
chemotherapy including anthracyclines and taxanes. The number of enrolled
patients according to region, the treatment history, the number of previously
received chemotherapeutic regimens, and metastatic sites are shown in table 4.
The investigators decided
the best treatment for each subject (= treatment of physician¡¯s choice, TPC)
before randomization. Overall, 508 patients were assigned to eribulin
monotherapy, and 254 were assigned to TPC. Patients who were assigned to the
TPC group received the designated treatment. In the TPC group (247 patients
after excluding dropouts), TPC included chemotherapy, endocrine therapy,
radiotherapy, biological agents, and best supportive care. Among the 247
eligible patients in the TPC group, 238 (96%) received chemotherapy, including
vinorelbine in 61 patients (25%), gemcitabine in 46 (19%), capecitabine in 44
(18%), taxanes in 38 (15%), anthracyclines in 24 (10%), and other anticancer
drugs in 25 (10%). Nine patients (4%) were given endocrine therapy. No patient
received other types of treatment.
Results for efficacy in the eribulin
group and the TPC group were shown. On an independent review of the results, the
median OS was found to be significantly longer in the eribulin group (13.1
months) than in the TPC group (10.6 months) (Figuer 3). However, the median PFS
was not significantly longer in the eribulin group (3.7 months) than in the TPC
group (2.2 months). The ORR was significantly higher in the eribulin group
(12%) than in the TPC group (5%). The CBR was similar in the eribulin group
(23%) and the TPC group (17%).
Toxic effects were
summarized. The most common hematologic toxicity was neutropenia (eribulin
group 52%, TPC group 30%), and the most common non-hematologic toxicity was
asthenia/fatigue (eribulin group 54%, and TPC group 40%).
NEW PRESENTATIONS IN RECENT YEARS (2010-2013) AFTER
STUDY 305
(1) Updated results of Study 305
San Antonio Breast Cancer Symposium
(SABCS) 2010
A stratified
analysis of Study 305 was presented. OS was analyzed according to the number of
prior chemotherapy regimens in subjects with locally recurrent or metastatic
breast cancer treated with eribulin monotherapy or TPC. The median OS was
significantly longer in the eribulin group than in the TPC group among patients
who received up to 3 regimens (13.3 months vs 10.7 months, hazard ratio
[HR] 0.774, 95% CI 0.606-0.988; p=0.039). OS was not longer in the
eribulin group as compared with the TPC group among patients who received more
than 3 regimens (11.7 months vs 10.7 months, HR 0.899, 95% CI
0.600-1.348; p=0.607)[20].
A subgroup analysis of Study
305 was performed to determine OS among patients in region 1 (North America,
Western Europe, and Australia) who received eribulin during phase ¢ó studies. The median OS was significantly longer in patients who
received eribulin monotherapy than in those who received TPC (13.1 months vs
10.0 months, HR 0.724, 95% CI 0.568-0.924; p=0.009). The median PFS did
not differ significantly (eribulin monotherapy 3.3 months vs TPC 2.2
months, HR 0.843, 95% CI 0.666-1.066; p=0.153)[21].
Updated results of Study 305
were also presented. The median OS was reported to be significantly longer in
the eribulin group than in the TPC group (13.2 months vs 10.5 months, HR
0.805, 95% CI 0.677-0.958; p=0.014[22].
European Society of Medical Oncology
(ESMO) 2011
The results of Study
305 suggested that patients receiving TPC (n=254) may be less likely to
benefit if they receive therapy with a class of agent they had previously
received (¡°re-challenged patients¡±), thereby favoring eribulin. This analysis
compared OS between the eribulin group and two different subgroups of the TPC
group[23]. (a) Non-re-challenged TPC subgroup (n=156):
patients not being re-challenged, i.e., limited to patients whose TPC was a
class of agent not previously received; (b) Re-challenged TPC subgroup (n=98):
patients being re-challenged, i.e., limited to patients whose TPC was a class
of agent previously received.
Median OS was 13.1 months in
the eribulin group as compared with 10.5 months in the non-re-challenged TPC
subgroup (HR 0.74, p=0.014). When the eribulin group was compared with
the re-challenged TPC subgroup, the median OS was 13.1 months and 10.7 months,
respectively (HR 0.92, p=0.556).
American Society of Clinical Oncology
(ASCO) 2011
A subgroup analysis
of OS in patients with visceral disease in Study 305 was presented. A total of
624 patients were classified as having visceral disease; 413 patients were
randomly assigned to eribulin monotherapy and 211 patients were randomly
assigned to TPC. The median OS was found to be significantly longer in the
eribulin group (12.45 months) than in the TPC group (10.12 months)[24].
(2) Outcomes obtained with eribulin
combined with other anticancer agents as treatment for recurrence,
postoperative adjuvant therapy, or preoperative chemotherapy
ASCO 2012
The results of a
phase¢ñb clinical trial (Study 203, dose-escalation study) of
eribulin plus capecitabine as combined therapy for solid cancers (colon cancer
20.6%, lung cancer 17.7%, breast cancer 14.7%) were presented. This combined
therapy was well tolerated, with no unexpected safety findings. The MTD (1.4
mg/m2 on days 1 and 8) was selected for evaluation in ongoing phase ¢ò clinical trials[25].
A phase ¢ò clinical trial (Study 210, NCT01328249) of dose-dense doxorubicin and
cyclophosphamide followed by eribulin monotherapy as adjuvant treatment for
HER2-negative, early-stage breast cancer was performed (Figure 4). Feasibility
was determined by whether the eribulin portion could be completed without
treatment delay or dose reduction[26].
Phase ¢ò clinical trial (NCT01372579) of eribulin plus carboplatin as combined
therapy for neoadjuvant treatment of triple-negative breast cancer was
performed (Figure 5).
Toxicity will be assessed
for the first 10 patients who receive eribulin at a dose of 1.4 mg/m2
(over 2-5 minutes intravenously on day 1 and 8) followed by carboplatin at a
dose calculated to produce an area under the curve of 6 mg/mL/minute (given
over the course of 30 minutes only on day 1). If dose reduction is not
required, further patients will be evaluated. The primary endpoint was to
determine the rate of pathological complete response (pCR). Secondary endpoints
included determination of the clinical response rate, toxicity evaluation, and
measurement of stem cells and TLE3 as a biomarker of response to eribulin
therapy[27].
(3) Therapeutic usefulness of eribulin
for patients with less heavily pretreated metastatic breast cancer
At SABCS 2012, the
results of a phase ¢ó randomized clinical trial (Study 301,
NCT00337103) comparing eribulin monotherapy with capecitabine monotherapy in
patients with locally advanced or metastatic breast cancer previously treated
with anthracyclines and taxanes were presented. Of the 1,102 patients, 554 were
randomly assigned to the eribulin group and 548 to the capecitabine group. The
median number of treatment cycles was 6 in the eribulin group and 5 in the
capecitabine group. The median OS was 15.9 and 14.5 months (HR=0.879, 95% CI
0.932-1.003; p=0.056), and the median PFS was 4.1 and 4.2 months (HR
1.079, p=0.305) in the eribulin group and the capecitabine group,
respectively. Among patients with HER2-negative breast cancer, the median OS
was 15.9 months in the eribulin group and 13.5 months in capecitabine group (HR
0.838, p=0.030). In this study, eribulin monotherapy was associated with
a trend toward better OS than capecitabine monotherapy[28].
(4) Therapeutic usefulness of eribulin
as first-line treatment for metastatic breast cancer
At SABCS 2012, the
results of a phase ¢ò clinical trial (Study 206, NCT01268150)
of eribulin monotherapy as first-line treatment for locally recurrent or
metastatic HER2 negative breast cancer were presented. Efficacy and safety were
evaluated. Of 56 enrolled patients, 54 had at least 1 post-baseline assessment.
ORR was 31% [complete response (CR) 0%, partial response (PR) 31%, stable
disease (SD) 48%], and CBR was 48%. The median time to response (TTR), duration
of response (DOR), and PFS were 1.4, 5.8, and 6.1 months, respectively. Treatment-related
serious adverse events occurred in 5 patients (9%): neutropenia (4%), and
febrile neutropenia (5%)[29].
At SABCS 2012, the results of a phase ¢ò clinical trial (Study 208, NCT01269346) of eribulin plus trastuzumab
as first-line combined therapy for locally recurrent or metastatic
HER2-positive breast cancer were presented. Efficacy and safety were evaluated.
37 of 52 planned patients have been treated. The ORR was 60% [CR 5%, PR 54%, SD
30%, progressive disease (PD) 22%], and CBR was 70%. Treatment-related serious
adverse events occurred in 4 patients (11%): neutropenia (8%), and febrile
neutropenia (6%)[30].
(5) Others
ASCO 2013
Subgroup analyses of
a phase ASCO 2013 ¢ó randomized clinical trial (Study 301,
NCT00337103) comparing eribulin monotherapy with capecitabine monotherapy for
locally advanced or metastatic breast cancer previously treated with
anthracyclines and taxanes was presented. Prespecified exploratory subgroups
were defined according to age, receptor status, number and setting of prior
chemotherapy regimens, sites of organs involved, and time to progression after
the last course of chemotherapy. An analysis of OS suggested that the following
subgroups appeared to benefit more from eribulin monotherapy than capecitabine
monotherapy (Figure 6): (1) patients with non-visceral disease (HR 0.51, 95% CI
0.33-0.80); (2) patients with >2 organs involved (HR 0.75, 95% CI
0.62-0.90); (3) patients with a time to progression (TTP) of >6 months after
the last course of chemotherapy (HR 0.70, 95% CI 0.52-0.95), and (4) patients
who had received an anthracycline, a taxane, or both for metastatic disease (HR
0.84, 95% CI 0.72-0.98). For OS, a trend favoring capecitabine was not seen in
any subgroup[31].
The results of QOL research
in patients with locally advanced or metastatic breast cancer who were
previously treated with anthracyclines and taxanes and then received eribulin
monotherapy or capecitabine monotherapy (Study 301, NCT00337103) were
presented. QOL, a secondary endpoint, was assessed using the EORTC QLQ-C30 and
QLQ-BR23 questionnaires at baseline, 6 weeks, and 3, 6, 12, 18, and 24 months
after starting treatment (or until PD or treatment change), as well as at
unscheduled visits. The primary endpoint was the change from baseline for Global
Health Status (GHS)/overall QOL; exploratory endpoints were the change from
baseline for each functional domain and signs/symptoms. GHS/QOL scores improved
more in patients who received eribulin monotherapy than in those who received
capecitabine monotherapy (p=0.048)[32].
The results of a Phase ¢ñ b clinical trial (NCT01554371) of eribulin plus cyclophosphamide as
combined therapy for metastatic breast cancer were presented. There was no DLT;
the RD for phase ¢ò was eribulin 1.4 mg/m2 on
days 1 and 8 plus cyclophosphamide 600 mg/m2 on day 1. All grade
adverse events included neutropenia (50%), thrombocytopenia, fatigue, nausea,
peripheral neuropathy, rash, mucositis, alopecia (38% each) and elevated liver
enzymes (17%). Combined therapy with eribulin plus cyclophosphamide was a
well-tolerated regimen with promising activity in metastatic breast cancer[33].
DISCUSSION
Randomized
controlled clinical trials of a new anticancer agent are designed to show the
superiority of a new anticancer agent to control treatment with standard
therapy if such therapy has been established or to demonstrate the
non-inferiority of a new anticancer agent to control treatment if toxicity is
clearly mild. However, if a standard therapy has not been established and
various types of anticancer therapy are used in clinical practice, the trial
design may include a control group assigned to receive TPC.
In Study 305, the control
group was assigned to TPC. Provided that the TPC was monotherapy, patients
could receive chemotherapy, endocrine therapy, radiotherapy, biological
therapy, or best supportive care. In this study, patients were randomly assigned
to treatment after TPC was decided by the investigator, thereby reducing bias.
The median OS, the primary
endpoint, was significantly longer in the eribulin group than in the TPC group.
On an independent review of the results, the median PFS, a secondary endpoint,
was not significantly longer in the eribulin group. On an investigator review
of the results, however, the PFS was significantly longer in the eribulin group
(3.6 months) than in the TPC group (2.2 months, p=0.002). The difference
between the 2 evaluations is attributed to the fact that data on patients in
whom PD was difficult to evaluate on imaging studies were censored in the
independent review, thereby decreasing the number of patients eligible for
analysis and eliminating the significant difference between the groups.
To our knowledge, no single
anticancer agent has been demonstrated to significantly prolong OS in patients
with metastatic breast cancer who had previously received anticancer therapy
including anthracyclines and taxanes. The fact that eribulin monotherapy
significantly prolonged OS will most likely have a significant impact on the
future management of metastatic breast cancer.
New randomized clinical
trials are now ongoing to evaluate eribulin monotherapy, and eribulin plus
other anticancer agent as combined therapy, and to compare eribulin monotherapy
with monotherapy with other anticancer agents. We outline the objectives of new
clinical trials designed to further define the therapeutic usefulness of eribulin.
Eribulin-based combination chemotherapy
(1) Phase ¢ñ b trial of eribulin plus capecitabine for metastatic breast cancer
(dose escalation study, Study 203): To determine the maximum tolerated dose and
dose-limiting toxicity of eribulin combined with capecitabine in patients with
metastatic breast cancer[25].
(2) Phase ¢ò trial of doxorubicin and cyclophosphamide followed by eribulin for
early breast cancer (adjuvant treatment, Study 210): To clarify the
effectiveness of sequential treatment with doxorubicin, cyclophosphamide, and
eribulin as postoperative adjuvant chemotherapy in patients with HER2-negative
early breast cancer[26].
(3) Phase ¢ò trial of eribulin plus carboplatin for triple-negative breast cancer
(neoadjuvant treatment): To clarify the effectiveness of combination therapy
with eribulin and carboplatin in patients with triple-negative breast cancer[27].
(4) Phase ¢ò trial of eribulin plus trastuzumab for HER2-positive metastatic breast
cancer (Study 208): To clarify the efficacy and safety of eribulin combined
with trastuzumab, used as first-line standard treatment for patients with
HER2-positive metastatic breast cancer[30].
(5) Phase ¢ñ b trial of eribulin plus cyclophosphamide for metastatic breast
cancer: To determine the maximum tolerated dose and dose-limiting toxicity of
eribulin combined with cyclophosphamide in patients with metastatic breast
cancer[33].
Controlled studies of monotherapy
(1) Phase ¢ó randomized clinical trial of eribulin monotherapy vs
capecitabine monotherapy for metastatic breast cancer (Study 301): This phase
III study is designed to compare the therapeutic effectiveness of eribulin
monotherapy with that of capecitabine monotherapy in patients with less heavily
pretreated metastatic breast cancer[28, 31].
(2) Phase ¢ò trial of eribulin monotherapy for HER2-negative metastatic breast
cancer (Study 206): To clarify the efficacy and safety of monotherapy with
eribulin as first-line treatment for HER2-negative metastatic breast cancer[29].
All new clinical trial
results were abstracted from presentations at many meetings (e.g., ASCO, SABCS,
and ESMO) held from 2010 through 2013 and must be interpreted carefully until
they are published in peer-reviewed journals. However, new clinical trials of
eribulin monotherapy and combined therapy are expected to further clarify
clinical benefits in patients with metastatic and primary breast cancer.
CONCLUSIONS
We expect that
eribulin will be shown to be clinically beneficial, thereby contributing to
further progress in the treatment of breast cancer.
CONFLICT
OF INTERESTS
There are no
conflicts of interest with regard to the present study.
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Peer reviewer: Cristiana Lo Nigro,
Laboratory of Cancer Genetics and Translational Oncology, Oncology Department,
S. Croce General Hospital, Via Carle 25, 12100 Cuneo, Italy.
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