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Annals of Oncology Advance Access published online on November 12, 2007
Annals of Oncology, doi:10.1093/annonc/mdm490
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© 2007 European Society for Medical Oncology

Serum HER2 extracellular domain predicts an aggressive clinical outcome and biological PSA response in hormone-independent prostate cancer patients treated with docetaxel

J. Domingo-Domenech1, P. L. Fernandez2, X. Filella3, A. Martinez-Fernandez1, R. Molina3, E. Fernandez2, A. Alcaraz4, J. Codony1, P. Gascon1 and B. Mellado1,*

1 Department of Medical Oncology and Laboratory of Experimental Oncology, Institut Clínic de Malalties Hemato-Oncològiques
2 Department of Pathology
3 Department of Biochemistry, Centre Diagnostic Biomèdic
4 Department of Urology, Institut d' Investigacions Biomèdiques Agust Pi i Sunyer, University of Barcelona, Hospital Clinic, Barcelona, Spain

* Correspondence to: Dr B. Mellado, Hospital Clinic i Provincial—Medical Oncology Villarroel, 130 Barcelona 08901, Spain. Tel: +34-932275400 Fax: +34-934546520; E-mail: bmellado{at}clinic.ub.es


   Abstract
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 Abstract
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 material and methods
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 discussion
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Background: Human epidermal growth factor receptor 2 (HER2) overexpression has been linked to hormone-independent prostate cancer (HIPC) progression. Its clinical value and correlation with therapy is not defined.

Patients and methods: Patients with HIPC treated with docetaxel (Taxotere) were prospectively tested for serum HER2 extracellular domain (ECD) by immunoanalysis. HER2 was determined by immunohistochemistry and FISH in tumor samples.

Results: Sixty-nine patients were included. Twenty-four (34.8%) patients had high HER2 ECD (>15 ng/ml). Prostate-specific antigen (PSA) response was 58% for patients with low HER2 ECD and 36% for patients with high HER2 ECD (P = 0.046). HER2 ECD levels were an independent prognostic factor for time to PSA progression [hazard ratio (HR) 2.82; confidence interval (CI) 95% 1.22–6.50; P = 0.015] and overall survival (HR 3.24; CI 95% 1.38–7.59; P = 0.007). Tissue samples from 17 patients were tested for HER2. Patients with negative HER2 tissue expression had lower HER2 ECD levels (median 10.5 ± 2.7 versus 30.5 ± 24.8 ng/ml; P = 0.016). FISH was negative in all samples.

Conclusions: High HER2 ECD levels in serum are associated with a worst clinical outcome of HIPC patients treated with docetaxel.

docetaxel, HER2, HER2 ECD, hormone-independent prostate cancer


   introduction
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 introduction
material and methods
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Prostate cancer (PC) is the second leading cause of death in men from cancer. Despite the availability of local treatment with radical prostatectomy or radiotherapy, many patients develop disease relapse after primary therapy. The first sign of PC recurrence is often heralded by an increase of serum prostate-specific antigen (PSA) levels and is known as biochemical relapse. Subsequently, patients can develop clinical relapse of the disease typically featuring bone metastases [1]. Initially, the majority of metastatic PC patients respond to antiandrogen therapy, having a hormone-dependent status. PC, however, progresses despite androgen withdrawal, transforming into a hormone-independent status.

Docetaxel-based chemotherapy has recently shown to improve survival of patients with metastatic hormone-independent PC and has become a standard treatment in this clinical situation [2, 3]. Approximately one half of patients do not respond to docetaxel, however, and survival for patients with symptomatic hormone refractory PC is low. For this reason, a better understanding of molecular mechanisms related to hormone-independent progression and mechanisms of response or resistance to docetaxel would be of interest to select those patients more likely to derive a clinical benefit and, also, to rationally design combination strategies that might improve therapeutic results.

The c-erbB-2 gene [human epidermal growth factor receptor 2 (HER2)] is a member of the family of oncogen associated with tyrosine protein kinase activity. HER2 has been proposed as a survival factor for PC cells in the absence of androgens [4–9]. Overexpression of HER2 promotes the activation of the androgen receptor (AR) and enhances the binding of AR to the promoters of androgen-regulated genes [5]. Overexpression of HER2 also causes the activation of the PI3k/AKT pathways and the promotion of cell proliferation and survival [10, 11]. In PC patients, HER2 overexpression is found mainly in those patients who have become resistant to hormonal ablation [6, 7, 12–16]. Moreover HER2 expression in tissue samples of hormone-independent PC patients has been associated to a lower survival [17, 18]. Therefore, HER2 inhibition has become an attractive treatment strategy for hormone-refractory PC patients [19–23]. The efficacy of this strategy, however, has not been clinically proved to date.

HER2 oncoprotein is a 185-kDa transmembrane receptor (p185), with intracellular, transmembrane and extracellular domains (ECDs). The tyrosine kinase activity is associated with the intracellular domain. The ECD of the HER2 oncoprotein can be proteolytically cleaved from the intact receptor and released as a soluble molecule with a molecular mass of 105 kDa [24–26]. The ECD can be detected in the serum of patients with PC and its increase has been associated to metastatic hormone-independent disease stage [27].

In this study, we show that circulating serum HER2 ECD levels are associated with the extension of the disease and a poor clinical outcome in patients with hormone-independent PC treated with docetaxel-based chemotherapy. Moreover, elevated levels of HER2 ECD correlate with 2+/3+ HER2 expression in hormone-independent PC tumor biopsies and may be useful to select patients for HER2-targeted therapy.


   material and methods
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 Abstract
 introduction
 material and methods
results
 discussion
 funding
 References
 
patients
Patients with metastatic hormone-independent PC receiving first-line docetaxel-based chemotherapy were included in the study and were prospectively tested for HER2 ECD in serum before and during treatment. Hormone-independent progression was defined as evidence of disease progression (PSA increase on two consecutive measurements 2 weeks apart in addition to either new lesions on bone scan or increase in the size of measurable lesions) in presence of castrate levels of testosterone (<50 ng/ml) after previous therapy with androgen suppression and progression to antiandrogen withdrawal. A histologically proven adenocarcinoma of the prostate and a patient Eastern Cooperative Group performance status (PS) of zero to two were required for the inclusion in the study. Patients who received antiandrogen therapy with flutamide or biclutamide had to demonstrate rising PSA levels 6 weeks after antiandrogen withdrawal. Patients who had not undergone orchiectomy were required to continue gonadal ablation with luteinizing hormone-releasing hormone analogue.

Pretreatment evaluation included a complete medical history, physical examination, bone scan, computed tomography of the abdomen and pelvis, and laboratory studies, including PSA, testosterone, cell blood count and biochemistry. Follow-up included physical examination and laboratory studies [complete blood count, PSA, alkaline phosphatase (AP) and lactate dehydrogenase (LDH)], before each cycle of chemotherapy and every 3–4 weeks after treatment was stopped. Bone scan and computed tomography (if measurable disease) were carried out after the third and sixth cycle of therapy or when clinically indicated.

Patient recruitment began in August 2002. Based on docetaxel (Taxotere; Sanofi-Aventis) phase II reported studies in hormone-independent prostate cancer (HIPC) [28–31], patients were initially treated with docetaxel 70 mg/m2 i.v. on day 2 plus estramustine 280 mg/day p.o., days 1–5, every 21 days or docetaxel 36 mg/m2 three consecutive weeks, every 28 days. Once randomized trials were published [2, 3], all patients included in the study received docetaxel 75 mg/m2 i.v. on day 1 plus prednisone 5 mg/day p.o. twice daily every 21 days. Patients received a maximum of six cycles of chemotherapy, unless disease progression or unacceptable toxicity. Patients were evaluated for PSA response, time to PSA progression and survival. The criteria for PSA response were based on the guidelines from the PSA Working Group. Time to biochemical disease progression was considered from the time treatment started until PSA progression was detected. Overall survival (OS) was defined as the time from treatment start to patient death. For HER2 ECD determination, aliquots of serum samples were obtained before the start of docetaxel and every 3–4 weeks during therapy. Samples were assayed the same day they were obtained. The institutional review board of Hospital Clinic Barcelona approved this research project, and all patients provided informed consent before inclusion in this study.

serum HER2 ECD levels
Measurement of serum HER2 ECD levels was determined using the automated Advia Centaur HER-2 assay (Siemens Medical Solutions Diagnostics, Tarrytown, NY). This test was performed by a two-sandwich chemoiluminometric assay using two monoclonal antibodies: acridinium ester-labeled mouse TA-1 and fluorescein-labeled mouse NB-3. These two monoclonal antibodies are specific for unique epitopes on the ECD of HER2. The chemiluminometric reaction is initiated after the addition of acid and base reactive. The relative light units are directly proportional to the quantity of HER2 antigen in serum.

tissue specimens
Hormone-dependent PC tissue was obtained by either prostate fine-needle biopsy or radical prostatectomy. Hormone-independent PC tissue was obtained by transuretral resection (prostate), lymph node biopsy (lymph node metastases) and bone marrow biopsy (bone metastases). The bone marrow specimens used in this study had been fixed with 4% buffered formalin and then decalcified using the chelating agent EDTA. A 10% EDTA solution was used in distilled water (pH 7.4) for a period of 2 weeks. Then the tissues were embedded in paraffin. All tissue specimens (prostate, lymph node and bone marrow) were cut (2–4 µm), mounted in sylanizated slides and then deparaffinized in xylene followed by immersion in ethanol and rehydrated previously to inmunohistochemistry.

HER2 immunohistochemistry
Available hormone-dependent and hormone-independent PC tissue specimens from patients included in this study were stained for HER2 using the HercepTest immunohistochemistry kit (Dako, Carpinteria, CA) according to the manufacturer's procedures. HER2 cell membrane-specific immunostaining was classified as 0 to +3 categories. Score 0 was defined as undetectable staining or membrane staining in <10% of the tumor cells. Score +1 was defined as a weak incomplete membrane staining detected in >10% of the tumor cells. Score +2 was considered as a weak to moderate complete membrane staining observed in >10% of the tumor cells. Finally, score +3 was defined as a moderate to strong complete membrane staining observed in >10% of the tumor cells.

FISH
The Vysis INC (Downers Grove, IL) system was used. This procedure consists of two different probes, one with the centromeric {alpha}-satellite probe specific for chromosome 17 (spectrum green) and a locus-specific probe for HER2 gene (spectrum orange). The Vysis probe was provided in denaturated state as single-strand DNA. Results were analyzed in a fluorescent Nikon (Eclipse 600) microscope. HER2 amplification was calculated dividing both the most frequent and largest values for HER2 spots/nucleus by the most frequent values of chromosome 17 centromere spots/nucleus. A minimum of 60 nuclei were scored, and amplification was considered when the ratio was ≥2.

statistical analysis
Statistical analysis was carried out with SPSS version 13.0 (SPSS, Inc., Chicago, IL). Correlation tests between qualitative variables ({chi}2 test or Fisher's exact test when applicable) and between continuous quantitative variables and qualitative variables (t-test) were used to identify the association between HER2 serum levels and clinicopathologic variables. Time to PSA progression and OS were calculated from the time docetaxel was initiated until PSA increased ≥25% from the nadir or death, respectively. Time to PSA progression and OS were analyzed by the Kaplan–Meier method. Curves were compared with the log-rank test. Multivariate analysis using the Cox proportional hazards model was carried out. All the statistical tests were conducted at the two-sided 0.05 level of significance.


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patients
Sixty-nine patients were included in the study. Patient's characteristics are shown in Table 1. Two patients could not be analyzed for PSA response and time to PSA progression since treatment was stopped after the first dose of docetaxel. One patient died as a consequence of docetaxel administration (neutropenic sepsis) and the other patient decided to withdraw from the study. At the moment of this analysis, the remaining 67 patients had progressed to docetaxel chemotherapy and 54 (78.3%) had died due to PC progression. Median follow-up time was 34.9 months (range 7.7–60.4). PSA response to docetaxel was achieved in 36 (53.7%) patients. Median time to PSA progression was 4.2 months (range 0.6–15.1) and median OS was 12.9 months (range 1.6–47.1).


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  		Table 1. Patients characteristics

 
serum HER2 ECD levels; association with clinicopathologic variables and clinical outcome
Median prechemotherapy HER2 ECD serum levels was 12.4 ng/ml (range 4.6–79.9). Forty-five patients (65.2%) were considered to have low serum HER2 ECD levels (≤15 ng/ml) and 24 patients (34.8%) had high serum HER2 ECD levels (>15 ng/ml). As shown in Table 2, serum HER2 ECD levels were significantly associated with the number of bone metastasis (P = 0.002), PSA (P = 0.016), disease localization (P = 0.04) and LDH (P = 0.001).


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  		Table 2. Association between serum HER2 ECD levels and other clinicopathologic characteristics

 
Serum HER2 ECD levels were also associated to PSA response to docetaxel (Table 3). When serum HER2 ECD levels were grouped (≤15 versus >15 ng/ml) and analyzed as a binarized qualitative variable ({chi}2 test), significant statistical association emerged between HER2 ECD serum levels and PSA response to docetaxel (P = 0.046). Fifty-eight percent of the patients with low HER2 ECD showed a PSA response to docetaxel, while only 36% of the patients with high HER2 levels responded to the same therapy (P = 0.046).


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  		Table 3. Association between serum HER2 ECD and PSA response to docetaxel

 
Furthermore, high (>15 ng/ml) HER2 ECD serum levels were significantly associated to a lower time to PSA progression (Figure 1A) and lower OS (Figure 1B), when compared with patients with low (≤15 ng/ml) serum HER2 ECD levels. Patients with low HER2 ECD had a median time to PSA progression of 5.1 months [confidence interval (CI) 95% 4.2–6.1] and patients with high HER2 ECD had a median time to PSA progression of 2.4 months (CI 95% 1.2–3.6). Patients with low HER2 ECD had a median survival of 19.1 months (CI 95% 10.3–28.0) and patients with high HER2 ECD had a median survival of 8.2 months (CI 95% 6.4–10.0). Similarly, when HER2 ECD levels were analyzed as a continuous quantitative variable, statistical significancy also emerged. For time to PSA progression, HER2 ECD levels had a hazard ratio (HR) of 1.039 (CI 95% 1.011–1.069; P = 0.007) and for OS a HR of 1.056 (CI 95% 1.030–1.083; P < 0.0001).


Figure 1
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  		Figure 1. Kaplan–Meier estimates for time to prostate-specific antigen (PSA) progression (A) and overall survival (B).

 
Besides HER2 ECD serum levels, other variables were associated to PSA disease progression and OS. Hemoglobin (P = 0.016), number of bone metastasis (P = 0.006), time of hormone dependence (P = 0.016) and LDH (P = 0.036) were predictive factors for time to PSA progression. For OS, visceral metastasis versus nonvisceral metastasis (P = 0.002), PS at study entry of one or more versus zero (P = 0.006), number of bone metastasis (P = 0.002), hemoglobin (P < 0.0001), AP levels (P < 0.0001) and LDH serum levels (P = 0.002) emerged as prognostic factors.

We also analyzed if docetaxel treatment administration (once every 3 weeks versus weekly administration) had an impact on the clinical outcome of patients. Patients that received docetaxel once every 3 weeks had a longer median time to PSA progression (4.3 months; CI 95% 3.0–5.5) when compared with patients that received weekly docetaxel (3.5 months; CI 95% 1.9–5.1). Also a longer OS in the group of patients that received docetaxel once every 3 weeks (12.9 months; CI 95% 8.1–17.7) when compared with patients that received weekly docetaxel (9.3 months; CI 95% 7.5–11.4) was detected. These differences, however, were not statistically significant (P = 0.126 and P = 0.104, respectively).

In the multivariate analysis for time to PSA disease progression and OS, HER2 ECD serum levels emerged as an independent prognostic factor for both time to PSA progression (P = 0.015) and OS (P = 0.007). Patients with high HER2 ECD (>15 ng/ml) levels had a HR for PSA progression of 2.82 (CI 95% 1.22–6.50) when compared with patients with low HER2 ECD (≤15 ng/ml) levels. Similarly patients with high HER2 ECD had a HR for death of 3.24 (CI 95% 1.38–7.59) when compared to patients with low HER2 ECD.

Furthermore, we analyzed serum HER2 ECD level changes during docetaxel therapy. Of the 22 patients with high baseline levels of HER2 ECD and with HER2 ECD follow-up during therapy, only two patients showed a HER2 ECD decrease ≥50% and three patients a HER2 ECD decrease ≥25% during docetaxel treatment. No statistical association between PSA response to docetaxel and HER2 ECD serum levels behavior under therapy was observed. In patients with low baseline HER2 ECD levels, no significant changes were observed during therapy.

association between HER2 tissue expression and HER2 ECD serum levels
From the 69 patients tested for baseline serum HER2, 19 hormone-independent PC tissue specimens were available from 17 patients. In two patients, hormone-independent PC tissue from two different sites was analyzed: prostatic tissue and supraclavicular lymph node metastatic tissue in one patient and prostatic tissue and brain metastatic tissue in the other. Furthermore, there were eight matched hormone-dependent and hormone-independent PC tissue specimens. Table 4 shows the results of HER2 hormone-dependent/HIPC tissue staining and serum HER2 ECD levels of the screened patients. None of the hormone-dependent PC tissues overexpressed HER2. Of the 17 hormone-independent patients, six (35.3%) overexpressed HER2 (score +2, +3) and the remaining 11 (64.7%) did not (score 0, +1). The two patients with hormone-independent tissue from two different sites concordantly stained negative for HER2. Figure 2 shows two hormone-independent tissue specimens, one positive (Figure 2A) and the other negative (Figure 2B) for HER2 tissue staining.


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  		Table 4. HER2 tissue expression and HER2 ECD serum levels

 

Figure 2
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  		Figure 2. Immunohistochemical human epidermal growth factor receptor 2 (HER2) expression (HercepTest) of hormone-independent prostate cancer tissue specimens. (A) HER2-positive (score +3) staining. (B) HER2-negative (score 0) staining.

 
Overall, there were eight matched pair cases where both hormone-dependent and hormone-independent PC tissue from the same patient was available for HER2 testing. Five (62.5%) matched pairs were concordantly HER2 negative, and in three (37.5%) matched pairs the hormone-dependent tissue was negative and the hormone-independent tissue was HER2 positive. Furthermore, HER2 PC tissue expression was significantly related to HER2 ECD serum expression (t-test). Patients with negative HER2 tissue expression had 10.5 ± 2.7 ng/ml serum HER2 ECD levels and patients with positive HER2 tissue expression had 30.5 ± 24.8 ng/ml serum HER2 ECD levels (P = 0.016). Of note, all the positive HER2 tissue patients had serum HER2 ECD levels >15 ng/ml and all negative HER2 tissue patients had serum HER2 ECD levels ≤15 ng/ml.

We also analyzed the positive (score +2, +3) HER2 immohistochemical hormone-independent tumors for evidence of genomic amplification. In the tissue specimens analyzed by FISH, genomic amplification was not detected in any of them.


   discussion
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 Abstract
 introduction
 material and methods
 results
 discussion
funding
 References
 
In this study, we show that elevated HER2 ECD serum levels are associated with the extension of disease and an aggressive clinical outcome. HER2 ECD levels also correlate with the overexpression of HER2 in patient's biopsies, suggesting that the determination of HER2 ECD in serum translates the HER2 status in the hormone-independent tumor.

The ECD of HER2 is shed into the circulation and can be elevated in the serum of men with PC [27, 32]. Osman et al. [27] reported that HER2 ECD levels increased during the natural history of PC in 279 patients in different stages of disease and hormone sensitivity. In this study, 13.3% of patients reached HER2 ECD levels superior to 14 ng/ml and correlated with risk of death. In the subgroup of patients with metastatic hormone-independent disease (n = 33), this percentage was of 33.3%. In our study, high HER2 ECD (>15 ng/ml) levels were associated with adverse clinical characteristics, a lower PSA response rate, PSA progression-free survival and survival in a specific population of hormone-independent PC patients treated with docetaxel-based chemotherapy.

In PC patients, a cut-off for evaluating HER2 ECD levels is not established. For that reason, we analyzed HER2 ECD as a continuous variable. We also established a cut-off level of 15 ng/ml based on previous published data of our group in HER2 ECD determinations in patients with different tumor types and healthy donors [33]. In the present study, correlation of HER2 ECD with clinical outcome and with HER2 expression in tumor biopsies was observed in both cases. A larger prospective study of PC patients would be needed to, however, establish a cut-off level of HER2 ECD that may have clinical prognostic implications. Different published studies have shown that the expression of HER2 is linked to the transition of the hormone-dependent to the hormone-independent status [6, 7, 12–16]. We observed here that 37.5% of HIPC biopsies overexpress HER2, considered as 2+/3+ staining by immunohistochemistry. Also, consistent with other published studies, we did not observe HER2 gene amplification by FISH in patients that immunohistochemically overexpressed HER2. In this sense, the transcriptional and post-transcriptional mechanisms that might be responsible for increased HER2 transcript and protein in PC cells are not well known [34].

Identification of biological markers of response to chemotherapy or biological therapies is especially difficult in HIPC, especially because metastatic hormone-independent tissue is rarely accessible. In that sense, the strong correlation observed here between serum HER2 ECD levels and HER2 tissue expression may be a result with potential clinical interest. Our data indicate that patients with high levels of HER2 ECD present an adverse clinical outcome. In our series, HER2 ECD level is an independent prognostic factor for PSA progression and survival. In that sense, this marker emerged as a potential new prognostic factor in HIPC patients. Furthermore, HER2 ECD may also have a predictive value of response to docetaxel since an association between HER2 levels and docetaxel response was observed. The outcome of patients with high HER2 is very poor, with only a 36% of responses to docetaxel and a median time to progression and survival of 2.4 and 8.2, respectively. In this group of patients, it would be of interest to investigate different therapeutic strategies. Previous preclinical studies in PC cancer models showed antitumor activity of the anti-HER2 monoclonal antibodies, both transtuzumab and pertuzumab. Trastuzumab [35, 36] increased the antitumor activity of taxanes in hormone-independent xenografts; and that pertuzumab [37] inhibited prostate tumor growth in animal models. Anti-HER2-targeted therapy, however, has not been proved as clinically active in patients to date. Different studies, with a small number of patients, tested the activity of trastuzumab with or without taxanes in PC patients. These trials failed to show significant antitumor activity of trastuzumab. They, however, included unselected patients for HER2 expression, or HER2 was tested in primary hormone-dependent tumors or the studies were prematurely closed due to the low percentage of HER2 overexpression observed [19–21]. More recently, two studies in nonselected patients for HER2 expression tested the activity of the HER dimerization inhibitor, pertuzumab in HIPC patients. One [22] tested two different doses of pertuzumab as a single agent in castrate chemotherapy-naive PC patients and reported absence of PSA responses. A second study [23] tested pertuzumab in HIPC patients after taxane-based therapy. While no PSA responses were observed, this group reported a significant percentage of patients of disease stabilization and a median survival time longer that the expected in this patients population. These authors suggested that even no PSA response was observed, and impact in survival cannot be excluded.

At this moment, predictive and surrogate markers for response to chemotherapy in PC patients are missing. Updated analysis of the TAX 327 trial failed to identify predictive factors for response to docetaxel [38]. In that sense, the correlation between serum HER2 ECD and response to docetaxel is a nonpreviously reported observation and further investigation in this field is warranted.

Our work and previously published data indicate that about one-third of patients with metastatic HIPC overexpress HER2. Clinical trials with anti-HER2-targeted therapies in this specific patient population have not been conducted to date. Moreover, in these studies the activity of the tested drug has been evaluated based on PSA response criteria. It is not clear whether a potential interaction between HER2 signaling, AR activation and PSA transcription exists, and PSA would not be a reliable marker of antitumor activity. Moreover, based on our results, HER2 ECD levels may be a surrogate marker of HER2 overexpression in hormone-independent tumor cells and can be useful as a noninvasive strategy to select patients for these studies. However, a larger number of patients analyzed for serum HER2 ECD and HER2 tissue expression would be needed to confirm these data.

It is important to consider that the strong correlation observed between HER2 expression in tissue and elevation of HER2 ECD in serum may suggest that the predominant form of HER2 in prostate tumor cells would be the truncated form of the protein (p105). It may explain also, at least in part, a low activity of antibody-based therapies in PC, due to the lack of the extracellular ectodomain. Moreover, high levels of HER2 ECD have been associated to resistance to trastuzumab in breast cancer patients [39]. In that sense, the use of tyrosine kinase inhibitors, such as lapatinib, or the specific inhibition of HER2 ECD cleavage in combination with pertuzumab or trastuzumab [24, 26] may be interesting therapeutic strategies to investigate in HER2 overexpressing metastatic hormone-independent PC patients.


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 Abstract
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References
 
Spanish Ministry of Education and Science (SAF-2005-05109-C02-02).

Received for publication June 27, 2007. Revision received August 18, 2007. Accepted for publication September 18, 2007.


   References
Top
 Abstract
 introduction
 material and methods
 results
 discussion
 funding
 References
 
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