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ORIGINAL ARTICLE
Year : 2017  |  Volume : 13  |  Issue : 2  |  Page : 204-207

The significance of serum leptin level in patients with early stage nonsmall cell lung cancer


1 Department of Medical Oncology, Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey
2 Department of Medical Oncology, Yildirim Beyazit University, Faculty of Medicine, Ankara, Turkey
3 Department of Medical Oncology, Faculty of Medicine, Ankara University, Ankara, Turkey

Date of Web Publication23-Jun-2017

Correspondence Address:
Fatih Karatas
Department of Medical Oncology, Diskapi Yildirim Beyazit Training and Research Hospital, 06100 Altindag, Ankara
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.196859

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 > Abstract 

Backgrounds: The serum leptin level (SLL) has been shown to increase in patients with nonsmall cell lung cancer (NSCLC). However, available data regarding the relation between SLL and tumor subtypes, survival, cachexia, and tumor respectability in NSCLC are still under debate. The aim of this study is to evaluate SLL in NSCLC patients with and without cachexia.
Materials and Methods: A total of 71 patients with early stage NSCLC were enrolled in this prospective study. SLL was measured by enzyme-linked immunosorbent assay. The relationship between SLL and clinicopathological factors including histopathological subtypes, weight loss, overall survival, and tumor resectability were evaluated.
Results: Of the 71 patients, 57 (81%) were male with a mean age of 63.3 ± 8.2 years. The rates of histological subtypes of NSCLC were as follows: Squamous cell carcinoma 60.5%, adenocarcinoma 32%, and others 7.2%. Mean SLL was 12.9 ± 38.4 pmol/mL. There was no distinctive difference between SLL, weight loss, and survival. However, when stratifying the groups according to the lung cancer histological subtypes, mean SLL was significantly higher in patients with adenocarcinoma than those with squamous cell subtype (26.9 ± 6.2 pmol/mL vs. 5.1 ± 9.1 pmol/mL, P = 0.004).
Conclusions: SLL might be beneficial as a useful biomarker in preclinical setting of NSCLC to guide detecting the lung cancer subtypes as well as monitoring the patients.

Keywords: Adenocarcinoma subtype, cachexia, leptin, nonsmall cell lung cancer, operability, significance


How to cite this article:
Karatas F, Yalcin B, Sahin S, Akbulut H, Utkan G, Demirkazik A, Icli F. The significance of serum leptin level in patients with early stage nonsmall cell lung cancer. J Can Res Ther 2017;13:204-7

How to cite this URL:
Karatas F, Yalcin B, Sahin S, Akbulut H, Utkan G, Demirkazik A, Icli F. The significance of serum leptin level in patients with early stage nonsmall cell lung cancer. J Can Res Ther [serial online] 2017 [cited 2021 Sep 24];13:204-7. Available from: https://www.cancerjournal.net/text.asp?2017/13/2/204/196859


 > Introduction Top


Lung cancer is the most leading cause of cancer-related death worldwide. Despite new advances in diagnostic methods, vast majority of the patients with lung cancer present with advanced-stage disease with a 5-year survival rate of 15.9%, leading to approximately 160.000 deaths annually in the United States.[1] According to the histological characteristics, lung cancers, also known as bronchogenic carcinomas, are classified into two major groups as small cell (oat cell) and nonsmall cell lung cancer (NSCLC).[2] Despite the fact that lung cancer was rare during the first decade of 20th century, as of today, its incidence has increased since cigarette smoking has become increasingly popular in both women and men, thus has become one of the most common cancer types worldwide.

Preclinical biochemical parameters to predict the disease stage and operability in patients with NSCLC have remained unexplored. It has been reported that an increase in serum leptin level (SLL) due to cancer-related cachexia may lead to poor clinical outcomes by causing weight loss.[3],[4] Leptin, the “satiety hormone,” is produced by adipose cells that have a role in regulating the energy by inhibiting hunger, thus is opposed to the actions of ghrelin hormone which is known as the “hunger hormone.” Moreover, leptin has proangiogenic, pro-inflammatory, and mitogenic effects which are strengthened by cross talk with interleukin-1 family cytokines in cancer. In cancer patients, SLL may decrease due to high levels of inflammatory cytokines. This condition slows down the decrease in appetite and in weight loss in patients and also keeps the weight loss at optimum level.[5],[6]

Although not all, most of the studies regarding the effect of leptin hormone have included patients with adenocarcinoma subtype of different organs, hence have not specifically assessed the impact of leptin in lung adenocarcinoma.[7],[8],[9] Herein, we aimed to investigate the clinical significance of leptin hormone, specifically in NSCLC subtypes.

Leptin receptor has been shown to be expressed in several cancer types including lung, breast, gastric, prostate, and endometrial carcinomas.[7],[9],[10],[11],[12] Terzidis et al. reported that SLL may lead to a malignant transformation in lung cells, suggesting that high SLL may be associated with increased risk of lung cancer.[13] By contrast, Jean Paul et al., who investigated the relation between SLL and cachexia in NSCLC patients, did not find any significant difference in SLL between cachectic versus noncachectic patients, suggesting that leptin did not increase in cancer-related cachexia. In another study comparing SLL in cachectic, noncachectic lung cancer patients and healthy controls, SLL was found to be significantly lower in cachectic NSCLC patients compared to noncachectic counterparts and healthy control group. In addition, weight loss ≥5% in the total body was found to be associated with lower SLL.[4] Similarly, Jamieson et al. found a significant low cachexia rate in NSCLC patients with high SLL.[5]


 > Materials and Methods Top


Medical records of 71 NSCLC patients were enrolled in this prospective study. Patients with histopathologically confirmed early stage NSCLC (clinical stage I–III) and Eastern Cooperative Oncology Group performance score <4 were included in the study. The following parameters were the exclusion criteria: patients who do not have an adequate oral intake, presence of any active infection, patients with diabetes mellitus, previous or active treatment for NSCLC including surgery, chemotherapy, or radiotherapy, patients using megestrol acetate or additional nutritional support, and history of a secondary primary malignancy. Staging was performed based on the radiological and histopathological findings. Stage IIIb and unresectable Stage IIIa disease were the inoperability criteria. Significant weight loss was defined as the loss of more than 5% of usual body weight over the 6 months.

Laboratory studies and statistical analysis

Fasting blood samples were collected from all patients 12 h before the beginning of the oncologic treatment. Blood samples were centrifuged for 5 min with a 5000 rev/min, and then the serums were separated. Serum samples were settled to Eppendorf tubes with a sufficient volume of minimal 1.0 mL and then were stored at −80°C up to 18 months. Samples were studied through Rayton ©-automated ELISA equipment and Rayton © ELISA washer equipment. SLL was measured by the human ELISA BioVendor © kit. Normal ranges of SLL were determined according to the values identified by the kit provider.

Statistical analysis

SPSS software version 16.0.0 (SPSS Inc., Chicago, IL, USA) was used for all statistical analysis. Data were expressed as mean (standard deviation) and percentage where appropriate. Comparisons were performed using Chi-square test for categorical variables. ANOVA method and Student's t-test were used for parametric continuous variables; Kruskal–Wallis and Mann–Whitney U-tests for nonparametric continuous variables. Survival rates (with their 95% confidence intervals [CIs]) were calculated with Kaplan–Meier survival method with differences tested using Log-rank test. P value ≤0.05 was considered statistically significant.

Ethics committee approval

The study was submitted to the Clinical Research Chairman of the Ethics Committee in Ankara and was approved on January 4, 2010. Informed consent form was obtained from all patients.


 > Results Top


Mean age was 63.3 ± 8.22 years and was similar in both operable and inoperable groups (63.3 ± 8.8 vs. 63.5 ± 9.13, P= 0.936). Of the 71 patients, 14 (19%) were females and 57 were (81%) males. The mean body mass index of patients for operable and inoperable groups was 22.5 ± 3.6 kg/m 2 and 22.1 ± 3.1 kg/m 2, respectively, however, there was not a significant difference between the groups. [Table 1] shown the all patients characteristics.
Table 1: Patients characteristics (n=71)

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The data regarding the weight loss were available in 61 patients. The rate of weight loss in inoperable group was significantly higher than those in operable group (35.5% vs. 20%, respectively, P= 0.001). Besides, the rate of average weight loss in operable group was significantly lower than those in inoperable group (3.0% vs. 8.9%, P= 0.001). Mean SLL was found similar in both operable and inoperable groups (15.3 ± 50.1 pmol/mL vs. 9.2 ± 15.2 pmol/mL, respectively, P= 0.855). [Table 2] shown the relationship between the operability and variables. There was no significant relation between weight loss and SLL [Table 3]. However, when stratifying the groups according to tumor histology, the mean SLL was found significantly higher in patients with adenocarcinoma subtype than those with squamous cell subtype (26.9 ± 6.2 pmol/mL vs. 5.10 ± 9.1 pmol/mL, P= 0.004) [Table 4].
Table 2: The relationship between the operability and variables

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Table 3: The significance between weight loss and leptin levels

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Table 4: The relationship between histopathological subtype and leptin levels

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At a median follow-up time of 49 months, forty patients (68.9%) expired. Survival analysis could be evaluated in 58 patients. Median survival time was 28 months (range; 25–30). No significant survival difference was found between patients with normal, low, and high SLL (P > 0.05) [Figure 1].
Figure 1: The relationship between leptin levels and cumulative survive

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 > Discussion Top


So far, there have been many studies investigating the association between SLL and NSCLC; however, the relation has remained unclear. In a study by Kerenidi et al., SLL was found significantly low in eighty patients with NSCLC compared to healthy control group, suggesting a significantly shorter survival in NSCLC.[14] However, although not statistically significant, NSCLC patients with low SLL in our study, experienced higher survival rate. In another study by Song et al., SLL and leptin expression in tumor tissue were detected significantly high in 126 NSCLC patients compared to healthy control group. However, these findings regarding the relation between SLL and NSCLC have remained controversial and confounding.[15] In one study, increased SLL in lung tissue was found to be associated with impairment in lung tissue, along with increased risk of NSCLC. In addition, the same authors found that LEP-2548G > A polymorphism was found significantly high in 162 NCSLC patients compared to healthy control group (P = 0.007), suggesting LEP-2548G > A polymorphism as an important factor in the development of NSCLC.[16] In a retrospective study investigating the leptin role in lung cancer, biopsy specimens of lung in NSCLC patients versus healthy control group were evaluated and the authors reported that leptin and OB-Rb expressions were significantly higher in NSCLC patients than healthy control group (P < 0.05), suggesting leptin as an independent prognostic factor for NSCLC (heart rate 1.69, 95% CI: 1.01–2.80, P= 0.044).[17] Despite the lack of a similar study comparing the SLL in operable versus inoperable group, there have been several studies demonstrating a significant increase in SLL in patients with advanced NSCLC compared to healthy control group.[6],[13] Herein, we investigated whether or not this significance has a clinical importance in NSCLC patients. However, the mean SLL in our study was found similar in both operable and inoperable groups.

One of the most crucial results in our study was that the mean SLL was found significantly higher in patients with adenocarcinoma than those with squamous cell subtype. It is well known that leptin hormone is secreted from many adenomatous structures in the body, particularly from adipose tissue.[9],[18],[19] Therefore, it should not be disregarded that leptin secretion may be induced by paraneoplastic events or cytokine effects in lung adenocarcinoma. More studies on this issue are required to show SLL as a useful biomarker in preclinical setting of NSCLC to guide detecting the lung cancer subtype as well as monitoring the NSCLC patients. On the other hand, studies investigating the association between SLL and histopathological subtypes of NSCLC have been limited.[20]

Leptin, the “satiety hormone,” is produced by adipose cells that have a role in regulating the energy by inhibiting hunger, thus is opposed to the actions of ghrelin hormone which is known as the “hunger hormone.” Briefly, leptin is known as a hormone which prevents weight gain.[19] On the basis of this findings, it can be hypothesized that SLL may decrease as a compensatory mechanism in case of cachexia, which is mainly caused by “cancer-related cytokines.”[5] However, in most studies investigating the relation between cachexia and leptin, SLL has been found to be high. Therefore, some theories have been suggested regarding the role of leptin antagonists in the treatment of cancer-related cachexia. In one study, amino acids 39–42 (Leu-Asp-Phe-Ile), also known as “LDFI,” was shown to significantly decrease the tumor growth in xenograft breast models. The unmodified LDFI peptide, which acts as a full leptin antagonist, might become a favorable treatment option in breast cancer treatment, particularly in obese women.[21]

In our study, no significant difference in SLL was found between patients with and without weight loss. As previously mentioned, leptin was detected high in our patients, particularly in patients with adenocarcinoma; however, leptin alone was not significantly correlated with weight loss. This might explain why there was no significant difference in SLL despite the weight loss in patients.

The major limitation of our study was the lack of a control group. In addition, most of the information such as weight loss of patients could be collected by medical history. One another important limitation was the relatively small sample size.

Overall, study results regarding the SLL in NSCLC have remained controversial. This may be due in part to the diversity in the proportion of adenocarcinoma patients enrolled in the previous studies. Herein, our study, it is important to note that SLL may show variability according to the NSCLC subtypes.


 > Conclusions Top


SLL was significantly higher in NSCLC patients with adenocarcinoma subtype than those with squamous cell carcinoma. Thus, SLL might be beneficial as a useful biomarker to guide detecting the NSCLC subtype in the preclinical setting, particularly for patients in whom biopsy specimens are insufficient to make an accurate pathological examination. Moreover, SLL might help monitor the NSCLC patients in the future. However, more prospective studies including larger number of patients are needed to confirm these results.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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