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ORIGINAL ARTICLE
Year : 2016  |  Volume : 53  |  Issue : 1  |  Page : 39-42
 

Leptin, insulin and body composition changes during adjuvant taxane based chemotherapy in patients with breast cancer, preliminary study


1 Department of Medical Oncology, Izmir Bozyaka Research and Training Hospital, Turkey
2 Department of Endocrinology, Faculty of Medicine, Konya Selcuk University, Turkey
3 Department of Internal Medicine, Izmir Bozyaka Research and Training Hospital, Turkey
4 Department of Radiology, Izmir Bozyaka Research and Training Hospital, Turkey
5 Department of Biochemistry, Izmir Bozyaka Research and Training Hospital, Turkey
6 Department of Medical Oncology, Izmir Ataturk Research and Training Hospital, Turkey
7 Izmir Dokuz Eylul University, Institute of Oncology, Turkey
8 Department of Rheumatology, Faculty of Medicine, Izmir Dokuz Eylul University, Turkey

Date of Web Publication28-Apr-2016

Correspondence Address:
A Alacacioglu
Department of Medical Oncology, Izmir Bozyaka Research and Training Hospital
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.180836

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 » Abstract 

Background: The objectives of the present study were to compare the effect of adjuvant chemotherapy for breast cancer on serum insulin levels, serum leptin levels, and body composition in early stage breast cancer patients.Materials and Methods: 17 breast cancer patients underwent 6 cycles of docetaxel (75 mg), epirubicine (100 mg) and cyclophosphamide (500 mg) (TEC). Anthropometrical and foot-to-foot body fat analyzer BIA, serum glucose, insulin, lipids, HOMA-IR and leptin were compared pre- and post-treatment. Results: There was no statistically significant weight gain after treatment; however, there was an overall trend toward weight gain (69.7 ± 9.8 kg vs 71.03 ± 9.8; P= 0.05). From baseline to the end of the study, percentage of body fat and body fat mass showed an upward trend at the end of chemotherapy (1%; 2 kg P> 0.05). Pre and post-treatment period, leptin was strongly correlated with insulin and HOMA-IR (Spearman's pre-T; r = 0.74; P <0.001, r = 0.66; P = 0.004 post-T; r = 0.549; P =0.022, r = 0.51; P =0.036, respectively). Insulin levels were significantly increased in the post-treatment period (P < 0.05). On correlation analysis, post-T insulin levels were correlated with leptin, weight, fat-mass and fat percentage (Spearman's r = 0.549; P=.022, r = 0.567; P= 0.018, r = 0.498, P= 0.042, r = 0.502; P= 0.040, respectively). DISCUSSION: High insulin and leptin levels, important factors that were previously shown to be related to breast cancer outcome, and insulin resistance may be increased in taxane based chemotherapy regimen. These data may have broad implications for diet and lifestyle strategies for the prevention and treatment of cancers.


Keywords: Breast cancer, chemotherapy, insulin, leptin, taxane


How to cite this article:
Alacacioglu A, Kebapcilar L, Gokgoz Z, Oztekin O, Bozkaya G, Tarhan O, Somali I, Yuksel A, Sop G, Sari I. Leptin, insulin and body composition changes during adjuvant taxane based chemotherapy in patients with breast cancer, preliminary study. Indian J Cancer 2016;53:39-42

How to cite this URL:
Alacacioglu A, Kebapcilar L, Gokgoz Z, Oztekin O, Bozkaya G, Tarhan O, Somali I, Yuksel A, Sop G, Sari I. Leptin, insulin and body composition changes during adjuvant taxane based chemotherapy in patients with breast cancer, preliminary study. Indian J Cancer [serial online] 2016 [cited 2020 Jul 12];53:39-42. Available from: http://www.indianjcancer.com/text.asp?2016/53/1/39/180836



 » Introduction Top


The most commonly used treatments for patients with breast cancer are surgery, radiotherapy, hormon replacement therapy and chemotherapy. Chemotherapy has many side effects such as nausea, womiting, diarrhea, loss of functional capacities, decreased range of motion, muscle weakness, fatigue, dry mouth, anorexia, emotional/psychological disturbances. Weight gain is a common side effect in women receiving chemotherapy for breast cancer. The most frequently reported incidence ranges from 50 to 96% of all early stage breast cancer patients during treatment with adjuvant chemotherapy.[1] The median gain in weight ranges from 2.5 to 6.2 kg. These side effects can contribute to marked changes in body composition.[2] Weight gain may negatively affect quality of life and it may predispose women to weight-related disorders such as hypertension, cardiovascular and gallbladder disease, orthopedic disturbances, and diabetes.[3],[4] Furthermore, it has been suggested that weight gain during the year following diagnosis may be associated with an increased risk of recurrence and poorer survival. Mechanisms proposed to explain the association between obesity and poorer survival include adipose tissue-induced increased concentrations of insulin, leptin, and cytokines.[5],[6] Goodwin et al.[7] found that in both premenopausal and postmenopausal women, high fasting plasma insulin concentrations correlated with the presence of high tumour grade and axillary lymph node involvement, and with an increased risk of recurrence and shortened survival. On the other hand, elevated leptin levels also have been associated with increased breast cancer risk and poor prognosis in breast cancer. Leptin is, however, associated with insulin resistance, breast cancer cell proliferation.[8]

The objectives of the present study were to compare the effect of adjuvant chemotherapy for breast cancer on serum insulin levels, serum leptin levels, and body composition in early stage breast cancer patients.


 » Materials and Methods Top


Nineteen women with node positive breast cancer who applied hospital between January 2008-November 2008 were included in this study. The study was approved by the local ethical committee of Hospital. Written informed consent was obtained from every patient.

Women were included in this study, if they had histologically confirmed operable stage II or III breast adenocarcinoma and had primary surgical resection within one month of beginning chemotherapy and were older than18 years and were beginning adjuvant chemotherapy regimens. Women with breast cancer were excluded from the study if they were already receiving neoadjuvant chemotherapy. Other exclusions included patients receiving alternative therapies alone, women participating in or planning to participate in dietary and/or exercise weight loss programs, and patients with a history of diabetes mellitus or untreated hypo- or hyperthyroidism, hypertension, obesity and hyperlipidemia or smokers or patients who've began use of antidepressants or other medications known to promote weight gain or loss.

The adjuvant CT regimens included in the study were docetaxel (75 mg/day), epirubicine (100 mg/day) and cyclophosphamide (500 mg/day) (TEC). The TEC regimen is administered intravenously every 3 weeks for 6 treatment cycles. The treatment course included administration of 80 mg/day steroid for 3 days. In addition, 5 mg/kg filgrastim was administered for prophylaxis of neutropenia on Days 2-7.

Patients with breast cancer were evaluated on two occasions: At baseline (on day-1 of the chemotherapy cycle 1), at one week after their chemotherapy cycle 6.

All anthropometric measurements were made by same observer using the same equipment for each subject. Height, weight, and waist circumference (WC) were measured.

Foot-to-foot body fat analyzer (Tanita TBF 300, Tanita, Tokyo, Japan) was used. Total body water (TBW), FFM, fat mass (FM), and fat percent were recorded.

Blood samples were obtained from antecubital vein into citrated tubes (trisodium m-citrate 0.129 mol/l, whole blood ratio 1:9) and centrifuged 2000/g for 15 min. Then, all plasma samples were divided into aliquots and frozen and preserved at −70°C until the test time. At the same time when blood samples were obtained, whole blood count, lipids, liver function tests, renal function tests were also studied. This treatment protocol was given for 3 months, and pre- and post-treatment variables were compared.

An insulin resistance score using the Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) was computed from the following formula: HOMA-IR = FPG (mg/dL) × immunoreactive insulin (IRI) (µIU/mL)/405.[9]

Leptin levels were measured by enzyme-linked immunosorbent assay from R and D (Abingdon, UK), and insulin levels were assessed by using an electrochemiluminescence immunoassay (Immulite 1000, DPC, USA).

The level of statistical significance for the study was set at P ≤ 0.05. Analysis was carried out with SPSS for Windows statistical software version 12.0. Descriptive statistics (frequencies, means, ranges, and standard deviations) were computed to summarize sociodemographic and clinical variables, including the percentage of the sample that was overweight at baseline. Analysis of variance was used to examine differences in baseline weight, hips and arms and BMI by treatment regimen. Descriptive statistics were also used to address the frequency and magnitude of weight change in the sample. To explore patterns of change in body composition, change scores (baseline to end of the treatment) for weight, BMI, FFM, fat mass, and body water were calculated. Weight and height data were measured directly and were used to calculate BMI. Estimates of change in FFM were obtained from the BIA data, and estimates of change in FM were obtained by subtracting change in FFM from overall weight change. The Wilcoxon signed rank test was used for comparison of the treatment effect on variables. Spearman rank correlation coefficients were used for correlation analysis between the fat mass measurements and parameters concerning insulin resistance in patients with breast cancer patients.


 » Results Top


The characteristics of the 17 female breast cancer patients in the study were shown in [Table 1]. Ten patients (52.6%) had postmenapausal status. All patients were primarily white Caucasian, were married and had non metastatic node positive breast cancer. All patients completed the scheduled 6 courses of adjuvant TEC chemotherapy. One patient had a 1-week delay in treatment due to cytopenia. 3 patients experienced Grade 1-2 nausea-vomiting.
Table 1: Demographic characteristics of breast cancer patients

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The pre-treatment and post-treatment body composition measurements of patients are shown in [Table 2]. The mean patient age was 50.5 ± 8.8 (range: 32-69) years and mean pre-treatment weight was 69.7 ± 9.8 kg with a mean BMI of 28.4 ± 3.3 kg/m 2. All patients received six cycles of systemic adjuvant taxane based anthracycline-containing regimen. Pre-treatment and post-treatment of body compositions are presented in [Table 2]. There was no statistically significant weight gain across treatments; however, there was an overall trend toward weight gain (69.7 ± 9.8 kg vs 71.03 ± 9.8; P = 0.05). Twelve participants gained weight, whereas 3 participants lost weight and 3 parcipitants did not have an alteration in weight over the course of treatment.
Table 2: Pretreatment and posttreatment body composition values of patients

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Among women with breast cancer, mean abdominal waist circumference, BMI and mean hip circumference increased but these were not statistically significant after chemotherapy ([Table 2]; P > 0.05). BIA percentage of body fat showed a upward trend at the end of chemotherapy (1%; P > 0.05). From baseline to the end of the study, however, there was no significant net difference in percentage of body fat and body fat mass by BIA. TBW and FFM derived from BIA were comparable in pre and post treatment period.

The mean leptin level ± standard deviation was 51.9 ± 48.6 ng/mL. In the pre-treatment period, leptin was strongly correlated with insulin and HOMA-IR (Spearman's r = 0.74; P < 0.001, r = 0.66; P = 0.004). After adjuvant anthracycline-taxane containing chemotherapy, leptin levels were found to be increased whereas leptin levels did not show significant change statistically ([Table 3]; 51.9 ± 48.6 vs 63.9 ± 55.9, P > 0.05). After treatment, leptin levels were corraleted with insulin and HOMA-IR values (Spearman's r = 0.549; P = 0.022, r = 0.51; P = 0.036).
Table 3: Pretreatment and posttreatment laboratory values of patients

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Before the start of adjuvant chemotherapy, the mean serum concentration of insulin was 22.5 ± 27.1 µIU/mL. After 6 cycles of chemotherapy, the mean level of insulin was 30.03 ± 28.6 µIU/mL. Insulin levels were significantly increased in the post-treatment period ([Table 3]; P < 0.05). On correlation analysis, insulin levels were correlated with leptin, weight, fat-mass and fat percentage after chemotherapy (Spearman's r = 0.549; P =0.022, r = 0.567; P = 0.018, r = 0.498, P = 0.042, r = 0.502; P = 0.040, respectively).


 » Discussion Top


The results of our study demonstrate that in breast cancer patients, serum leptin levels and body fat percent and fat mass and BMI were increased but these values did not reach a statistical significance compared to pre-treatment values. However, serum insulin concentrations, and insulin resistance were significantly higher than the pre-treatment values. Post-treatment elevated insulin levels in breast cancer patients might result from chemotherapy regimen and food intake. We already know that docetaxel increases tyrosine phosphorylation of proteins and activates components of the mitogen-activated protein kinase (MAPK) signalling pathways, including extracellular signal-regulated kinases (ERK1/2).[10] On the other hand, insulin has growth-stimulating effects by activating the AMP kinase metabolic pathway.[11] Accoding to this view, we may speculate that docataxel based chemotherapy regimen may increase insulin levels and these may activate MAPK and ERK1/2. In the early stages, β-cells proliferate to keep up with the increasing insulin requirement that accompanies insulin-resistance syndromes. According to our findings, adjuvant chemotherapy may also cause insulin resistance. Insulin resistance is often found in people with visceral adiposity. On correlation analysis, insulin levels were correlated with leptin, weight, fat-mass and fat percentage in our study. Insulin resistance has a major role in the development of impaired glucose tolerance and diabetes, also in breast cancer patients.[12]

Excess body weight has been linked to an increased risk of postmenopausal breast cancer, and growing evidence also suggests that obesity is associated with poor prognosis in women diagnosed with early-stage breast cancer.[13] Obesity and insulin may impact breast cancer through several mechanisms. Obesity is associated with elevated circulating levels of insulin, estrogen, insulinlike growth factor 1 (IGF-1), and leptin and with inflammation (reflected by markers such as Creactive protein). Insulin may bind to insulin receptors (IR) that are overexpressed on most human breast cancer cells.[14]

Leptin is an adipose tissue hormone that plays a key role in metabolism. In recent years, it is considered to play a role in immunity.[15] Leptin stimulates the proinflammatory response and promotes proliferation, differentiation, and activation of hematopoietic cells. In humans, increased leptin levels have been reported in acute inflammatory and neoplastic conditions, suggesting that leptin may have a role in cancer development.[16] High expression of leptin and the long/signaling form of leptin receptor had been found in breast tumors.[17],[18],[19] Leptin and its receptors are overexpressed in breast cancer tissues and correlate with poor prognosis. High levels of leptin in breast tumors have been associated with increased incidence of breast cancer metastasis.[20],[21],[22] Leptin may suppress docetaxel-induced apoptosis by inhibiting caspase activity.[23] Finally, the suggestion that leptin may be a mediator of the association between obesity or BMI and breast cancer requires confirmation.

This is the first report on leptin in patients recieving adjuvant chemotherapy; however, it was not statistically significant and we observed higher leptin levels in breast cancer patients in the post-treatment period. Serum leptin levels correlate with biochemical insulin and indices of insulin resistance in women with breast cancer before and after chemotherapy regimen. Increased leptin in the breast cancer patients might be responsible for the high circulating insulin concentrations. On this basis, Rose et al.[8] hypothesize that leptin, in association with insulin, the plasma concentrations of which correlate with those of leptin, may have an important role in the known adverse effect on breast cancer.

In our study, relatively small number of patients studied and this may be considered as a limitation. The lack of statistical significance in weight and leptin level are probably due to the small sample size.

We have been able to demonstrate a short-term effect of leptin and insulin on outcome in early-stage breast cancer, and plasma leptin levels were strongly correlated with both HOMA-IR and insulin, factors that were previously shown to be related to breast cancer outcome. These data may have broad implications for diet and lifestyle strategies for the prevention and treatment of cancers.

 
 » References Top

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Battaglini C, Bottaro M, Dennehy C, Rae L, Shields E, Kirk D, et al. The effects of an individualized exercise intervention on body composition in breast cancer patients undergoing treatment. Sao Paulo Med J 2007;125:22-8.  Back to cited text no. 2
    
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Demark-Wahnefried W, Peterson BL, Winer EP, Marks L, Aziz N, Marcom PK, et al. Changes in weight, body composition, and factors influencing energy balance among premenopausal breast cancer patients receiving adjuvant chemotherapy. J Clin Oncol 2001;19:2381-9.  Back to cited text no. 3
    
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Carmichael AR. Obesity as a risk factor for development and poor prognosis of breast cancer. BJOG 2006;113:1160-6.  Back to cited text no. 5
    
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Kroenke CH, Chen W, Rosner B, Holmes MD. Weight, weight gain, and survival after breast cancer diagnosis. J Clin Oncol 2005;23:1370-8.  Back to cited text no. 6
    
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Goodwin PJ, Ennis M, Pritchard KI, Trudeau ME, Koo J, Madarnas Y, et al. Fasting insulin and outcome in early-stage breast cancer: Results of a prospective cohort study. J Clin Oncol 2002;20:42-51.  Back to cited text no. 7
    
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Rose DP, Gilhooly EM, Nixon DW. Adverse effects of obesity on breast cancer prognosis, and the biological actions of leptin. J Clin Oncol 2005;23:6037-42.  Back to cited text no. 8
    
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Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412-9.  Back to cited text no. 9
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Seidman R, Gitelman I, Sagi O, Horwitz SB, Wolfson M. The role of ERK 1/2 and p38 MAP-kinase pathways in taxol-induced apoptosis in human ovarian carcinoma cells. Exp Cell Res 2001;268:84-92.  Back to cited text no. 10
    
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Pollak MN, Schernhammer ES, Hankinson SE. Insulin-like growth factors and neoplasia. Nat Rev Cancer 2004;4:505-18.  Back to cited text no. 11
    
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Ligibel J. Obesity and breast cancer. Oncology 2011;25:994-1000.  Back to cited text no. 13
    
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Goodwin PJ, Ennis M, Pritchard KI, Trudeau ME, Koo J, Taylor SK, et al. Insulin- and obesity-relatedvariables in early-stage breast cancer: Correlations and time course of prognostic associations. J Clin Oncol 2012;30:164-71.  Back to cited text no. 14
    
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Wu MH, Chou YC, Chou WY, Hsu GC, Chu CH, Yu CP, et al. Circulating levels of leptin, adiposity and breast cancer risk. Br J Cancer 2009;100:578-82.  Back to cited text no. 16
    
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Miyoshi Y, Funahashi T, Tanaka S, Taguchi T, Tamaki Y, Shimomura I, et al. High expression of leptin receptor mRNA in breast cancer tissue predicts poor prognosis for patients with high, but not low, serum leptin levels. Int J Cancer 2006;118:1414-9.  Back to cited text no. 18
    
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Caldefie-Chezet F, Damez M, de Latour M, Konska G, Mishellani F Fusillier C, et al. Leptin: A proliferative factor for breast cancer? Study on human ductal carcinoma. Biochem Biophys Res Commun 2005;334:737-41.  Back to cited text no. 19
    
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Garofalo C, Koda M, Cascio S, Sulkowska M, Kanczuga-Koıda L, Golaszewska J, et al. Increased expression of leptin and the leptin receptor as a marker of breast cancer progression: Possible role of obesity-related stimuli. Clin Cancer Res 2006;12:1447-53.  Back to cited text no. 21
    
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Jiang H, Yu J, Guo H, Song H, Chen S. Upregulation of survivin by leptin/STAT3 signaling in MCF-7 cells. Biochem Biophys Res Commun 2008;368:1-5.  Back to cited text no. 23
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]

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