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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 9  |  Page : 362-367

Serum paraoxonase and arylesterase can be useful markers to predict neoadjuvant chemotherapy requirement in patients with breast cancer


1 Department of Internal Medicine, Bakirkoy Dr. Sadi Konuk Education and Research Hospital, Istanbul, Turkey
2 Department of Medical Oncology, Bakirkoy Dr. Sadi Konuk Education and Research Hospital, Istanbul, Turkey
3 Department of Biochemistry, Bakirkoy Dr. Sadi Konuk Education and Research Hospital, Istanbul, Turkey

Date of Web Publication29-Jun-2018

Correspondence Address:
Hakan Kocoglu
Department of Internal Medicine, Bakirkoy Dr. Sadi Konuk Education and Research Hospital, Istanbul
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.235355

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 > Abstract 

Aim: The aims of this study are to evaluate the serum levels of paraoxonase (PON) and arylesterase (ARE) in breast cancer (BC) patients; to determine their relationship with chemotherapy requirements in BC; and to find a cut-off value to assess subjects with a higher risk of BC.
Subjects and Methods: A total of 40 BC patients and 33 age-matched healthy women were included in this study. Beside other biochemical parameters, participants' serum PON and ARE levels were determined and analyzed.
Results: Serum PON and ARE levels were found decreased in sera of the patients (96.44 ± 21 and 159.75 ± 15.75 U/L, respectively)compared to controls (158.39 ± 23.04 and 239.33 ± 32.98 U/L, respectively) (P = 0.001 for both). Subgroup analysis of the BC patients revealed that both serum PON and ARE levels were lower in patients who needed neoadjuvant chemotherapy (NAC), compared to those who did not (P = 0.024 and 0.02, respectively). We determined a cut-off value of PON according to the receiver operating characteristic curve analysis as 131.2 U/L (sensitivity 97.5% and specificity 93.9%).
Conclusion: BC patients have lower serum PON and ARE levels than healthy controls. Also, serum ARE levels (but not PON) were negatively correlated with body mass index in BC patients. Both serum PON and ARE levels were lower in patients who needed NAC than in patients who did not need such therapy.

Keywords: Arylesterase, breast cancer, cancer risk, cut-off value, neoadjuvant, paraoxonase, screening


How to cite this article:
Okuturlar Y, Gunaldi M, Kocoglu H, Hursitoglu M, Gedikbasi A, Acarer D, Harmankaya O, Kumbasar A. Serum paraoxonase and arylesterase can be useful markers to predict neoadjuvant chemotherapy requirement in patients with breast cancer. J Can Res Ther 2018;14, Suppl S2:362-7

How to cite this URL:
Okuturlar Y, Gunaldi M, Kocoglu H, Hursitoglu M, Gedikbasi A, Acarer D, Harmankaya O, Kumbasar A. Serum paraoxonase and arylesterase can be useful markers to predict neoadjuvant chemotherapy requirement in patients with breast cancer. J Can Res Ther [serial online] 2018 [cited 2019 Sep 15];14:362-7. Available from: http://www.cancerjournal.net/text.asp?2018/14/9/362/235355


 > Introduction Top


The most common cause of cancer death among women is breast cancer (BC) in the world.[1],[2] It is estimated that about 500,000 women in the world died in 2011 because of BC. Family history of BC, obesity, age, menstruation status, genetics, radiation to the chest before age 30, race/ethnicity, pregnancy/breastfeeding, alcohol consumption, lack of exercise, and smoking are the most important determinant factors of BC.[1],[3]

Elevated oxidative stress, as in the various types of cancer, also has a role in BC by causing metabolic malfunction and damage to biological molecules such as DNA. Oxygen radicals can oxidize DNA bases and activate chemical carcinogens into highly reactive compounds.[4],[5],[6] Oxidative DNA damage may contribute to cancer risk and the antioxidant paraoxonase (PON) is one endogenous free radical scavenger in the human body which could, therefore, exert influence.[7]

Human serum PON and arylesterase (ARE) are both esterase enzymes that have lipophilic antioxidant characteristics.[8],[9] Serum PON acts in conjunction with ARE to function as a single enzyme.[10] All PON proteins (PON1, PON2, and PON3) possess antioxidant properties and are implicated in the pathogenesis of several inflammatory diseases including atherosclerosis, Alzheimer's and Parkinson's diseases, diabetes mellitus and cancer. PON1 is found exclusively extracellular and associated solely with high-density lipoprotein (HDL) particles in the circulation, and, in part, confers the antioxidant and anti-inflammatory properties associated with HDL.[11] It binds to HDL and contributes to the detoxification of organophosphorus compounds, such as paradoxes and carcinogenic lipid-soluble radicals from lipid peroxidation.[12],[13] PON1 plays an important role in the HDL – mediated prevention of low-density lipoprotein (LDL) oxidation and the metabolism of lipid-soluble radicals. Although oxidative stress and inflammation are believed to be important in carcinogenesis, there has been a little investigation of changes in PON1 activity in cancer. Previous studies have been shown that serum levels of PON were lower in patients with colorectal, pancreatic, or ovarian cancer than in healthy controls.[7],[14],[15],[16]

The aims of this study are to evaluate the serum levels of PON and ARE in BC patients; to determine their relationship with chemotherapy requirements in BC, and to find a cut-off value to assess subjects with a higher risk of BC.


 > Subjects and Methods Top


This prospective study was conducted between June 2014 and January 2015 and included 50 patients older than 18 years with newly diagnosed BC who consecutively (selected regardless of type and stage of the disease) admitted to our oncology clinic. The diagnosis was established based on clinical, radiological, and histopathological features. Ten patients were excluded because of fulfilling exclusion criteria mentioned below. A total number of 40 patients with BC and 33 age-matched healthy women were enrolled in this study. Forty patients with BC were compared with controls.

Exclusion criteria were as follows: Having another tumor diagnosis, taking systemic chemotherapy, surgical intervention for BC before referral to our oncology clinic, male patients with BC, dysregulated diabetes mellitus, kidney disease, cardiovascular disease, rheumatological diseases, alcohol consumption, taking anti-hyperlipidemic or antioxidant drugs, and undergoing treatment for BC.

Patients' history and physical examination were recorded and clinicopathological features (age, weight, height, menopausal status, smoking, histopathological type, grade, tumor size, lymph node metastasis, stage according to the American Joint Committee on Cancer staging system, estrogen receptor [ER] and progesterone receptor [PR] and human epidermal growth factor receptor 2 [HER2], lymphovascular invasion, perineural invasion status) were evaluated. The study was approved by our hospital's Local Ethical Committee and written informed consent was provided from all subjects before the assessment.

Biologic sub-classification using ER, PR, HER2 were performed. Luminal A was defined as ER +, PR +, HER2; luminal B was defined as ER +, PR , HER2 or ER +, PR +, HER2+; HER2 like tumor was defined as ER , PR +, HER2+; and triple negative tumor was defined as ER , PR , HER2.[17] The pathological tumor stage was defined according to the sixth edition of the tumor-node-metastasis classification of the International Union against Cancer. Tumor differentiation was defined according to the World Health Organization classification of tumors.[18] Tumor size was classified as T1 (2 cm), T2 (2–5 cm), or T3 (>5 cm); both tumor size and lymph node metastasis status were evaluated separately.

Blood sample collection

Blood samples of patients were drawn before initiating chemo/radiotherapy and/or surgical resection of tumor. After 12-h overnight fasting period, venous blood was drawn from the antecubital vein. The tubes were centrifuged at 4000 rpm (10 min) to remove the plasma and serum. The plasma and serum samples were kept at −80°C until analysis of PON and ARE activities.

Measurement of paraoxonase and arylesterase activities

PON and ARE activities were determined using a novel automated measurement method developed by Erel (Rel Assay ®, Turkey). Briefly, the rate of paraoxon hydrolysis was measured by the increased absorbance at 412 nm at 25°C. The PON activity is expressed as U/L serum. The coefficient of variation (CV) for individual samples was 1.8%. ARE activity was measured spectrophotometrically using phenylacetate. The reaction was started by the addition of the serum; the increase in absorbance was read at 270 nm. Enzymatic activity was calculated from the molar absorptivity coefficient of the produced phenol. One unit of ARE activity was defined as 1 μmol phenol generated/min under the defined assay conditions and expressed as U/L serum. The CV for individual serum samples was 3.3%.

Other variables

Serum glucose, urea, creatinine, LDL cholesterol, HDL cholesterol, triglyceride, and other biochemical parameters were determined by Abbott Architect C16200 Integrated System and using commercial kits (Abbott Laboratories, IL, USA). Complete blood count was determined in a Coulter LH 750 auto analyzer (Beckman Coulter, CA, USA). Serum carbohydrate antigen 15-3 (CA 15-3), carcinoembryonic antigen, carbohydrate antigen 125 (CA-125) were determined by Beckman Coulter AU 5800 chemistry auto-analyzer and DXI 800 systems using commercial kits (Beckman Coulter, CA, USA).

Statistical methods

Statistical calculations were performed with Number Cruncher Statistical Systems 2007 software (NCSS, Kaysville, Utah, USA) program for Windows. Besides standard descriptive statistical calculations (mean and standard deviation), unpaired t-test was used in the comparison of groups, paired t-test was used in the assessment of pre- and post-treatment values, and Chi-square test was performed during the evaluation qualitative data. Pearson's correlation test was used for determining relationships between research variables. Linear regressions analysis was performed to determine the independent effect of factors associated with PON. The value of P < 0.05 was considered as significant.


 > Results Top


The demographic features and biochemical parameters of both groups are presented in [Table 1]. There was no statistical significance in mean age between patients and controls (56.15 ± 9.87 vs. 52.85 ± 5.99 years, respectively; P = 0.097). Serum PON and ARE levels were lower in sera of the patients (96.44 ± 21 and 159.75 ± 15.75 U/L, respectively) than controls (158.39 ± 23.04 and 239.33 ± 32.98 U/L, respectively) (P = 0.001 for both). There was no statistical significance in lipid profile between patients and controls (P ≥ 0.05).
Table 1: Statistical analysis of paraoxonase and arylesterase in both groups

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Subgroup analysis of the BC patients (regarding body mass index [BMI], menopausal status, smoking, etc.) revealed that both serum PON and ARE levels were lower in patients who required neoadjuvant chemotherapy (NAC) than those who did not require such therapy (P = 0.024 and 0.02, respectively). PON and ARE levels did not vary in accordance with presence or absence of luminal A, luminal B, triple negative, HER2, lymphovascular or perineural invasion, histopathological subtypes, grade, and stage status [Table 2].
Table 2: Evaluation of paraoxonase and arylesterase according to characteristics of patients with breast cancer

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Further analysis of patients' blood parameters showed that serum PON levels positively correlated with neutrophil count and CA 15-3 and negatively correlated with lymphocyte, total protein, and total cholesterol. On the other hand, serum ARE levels were only negatively correlated with BMI and with CA-125. Correlation analysis in patients group showed a significant positive correlation between neutrophil (r = 0.569, P = 0.0001) and CA 15-3 (r = 0.339, P = 0.046) and also a significant negative correlation between lymphocyte (r = −0.328, P = 0.047), hemoglobin (r = −0.383, P = 0.019), total protein (r = −0.638, P = 0.0001), and cholesterol (r = −0.544, P = 0.024). A positive correlation has been determined between PON and ARE. There was a negative correlation between ARE and BMI, total cholesterol, and LDL-cholesterol. Furthermore, there was a negative correlation between PON and total protein, and total cholesterol [Table 3].
Table 3: Correlation of serum paraoxonase and arylesterase levels with other blood parameters

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As a result, we found a significant difference in serum PON levels between patients and healthy controls. We also tried to find an optimal cut-off value for PON. Receiver operating characteristic (ROC) analysis was used to determine a cut-off value. The area under an ROC curve for PON to detect BC was determined at ≤131.2 U/L. Using the cut-off value of PON ≤131.2 U/L, there was sensitivity at 97.5%, specificity at 93.9%, positive predictive value at 95.1%, and negative predictive value at 96.9% and accuracy at 95.8% (AUC = 0.977; P = 0.0001) [Figure 1].
Figure 1: Receiver operating characteristics (ROC) curve for serum paraoxonase (PON) for the diagnosis of breast cancer. Area under the curve (AUC) for PON is 0.977; P=0.0001

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 > Discussion Top


PON1, an HDL-associated enzyme, is thought to contribute to cancer development by playing a preventive role against oxidative stress. It has been shown that oxidative stress and free radicals increase the risk of various types of cancers.[19],[20] The human body has several endogenous free radical scavenging systems, which maintain the antioxidant/oxidant balance. PON1, an antioxidant enzyme, may cause defects in this antioxidant/oxidant balance.[21] This can trigger oxidative stress and the formation of reactive oxygen species.

The risk factors for BC, including increased estrogen metabolism and BRCA1 mutations, are known to influence oxidative stress.[22] Since oxidative stress may be involved in cell proliferation and malignant conversion during the development of BC,[23] it is reasonable to expect that PON1, as a part of the lipid peroxidation scavenging systems, may influence BC development.

PON1 Q192R gene polymorphism has been shown to be associated with a reduced risk of the overall cancers.[24] Furthermore, PON1 M and Q alleles have been shown to be associated with a higher risk of BC.[25] Previous studies have revealed that PON1 expression is depressed in human lung cancer,[26] pancreatic,[16] and gastric cancer.[27]

In our study, serum PON and ARE levels were found to be decreased in BC patients. In a study by Bobin-Dubigeon et al.,[19] PON was found to be an independent factor of early death in BC recurrence. In a study by Abdel-Salam et al.,[28] the serum levels of total antioxidant capacity were found to be lower in nonmetastatic and metastatic BC patients than the healthy controls (P < 0.05). Similar to the above two studies, in our study, serum PON and ARE levels were lower in BC patients than healthy controls (P < 0.05 for both). Furthermore, our study results were correlated with the study results of Balci et al. in which they have shown that PON1 and ARE activities were found to be decreased in BC patients compared to controls and no difference in PON1 and ARE activities between metastatic and nonmetastatic BC patients.[29]

In our study, serum ARE levels (but not PON) were negatively correlated with BMI. There are reports of association of obesity with the carcinogenesis process.[3] Furthermore, there are reports of gaining weight in adulthood appears to increase the risk of BC.[30],[31],[32] Thus, further studies are needed in this area, especially in regard to association with serum ARE levels, BMI, and carcinogenesis.

In literature, there are a few cancer studies that determined the cut-off values of serum PON and/or ARE activities. In malignant gliomas, the cut-off value for PON was found to be ≤104.69 U/L.[33] The cut-off point for plasma PON levels in patients with gastroesophageal malignancies was found to be ≤121.9 U/L.[34] To the best of our knowledge, this is the first study that highlights a clear “PON cut-off” between BC patients and healthy controls. In our study, a cut-off value for PON of ≤131.2 U/L has the best sensitivity and specificity.

The use of neoadjuvant therapy offers several clinical advantages in patients with BC. The use of neoadjuvant therapy in patients with large tumors is likely to reduce the tumor size and can make patients candidates for surgical resection. Also, up to half of the patients undergoing neoadjuvant treatment may become suitable for breast conservation rather than mastectomy.[35] Thus, it is important to determine requirement of NAC in patients with BC. One of the interesting point of our study, which has not been shown in previous studies, is that BC patients who needed NAC had both lower serum PON and ARE levels than patients who did not need such therapy (P = 0.24 and 0.26, respectively). This difference could be caused from several reasons, such as difference of primary tumor load because the patients who needed NAC had more primary tumor load than patients who did not needed such therapy. If this finding is supported by future studies, serum PON and ARE can be used as markers to predict NAC requirement in patients with BC.


 > Conclusion Top


This study showed that BC patients have lower serum PON and ARE levels than healthy controls. Furthermore, serum ARE levels (but not PON) were negatively correlated with BMI. Future studies in this field may provide some information about the underlying mechanisms of carcinogenetic processes in overweight/obese subjects. Also in our study, both serum PON and ARE levels were lower in patients who needed NAC than in patients who did not need such therapy. Further studies are needed to determine whether or not these markers can be used as adjunct tests to predict NAC requirement in patients with BC. Also, to the best of our knowledge, this is the first study that determined a cut-off value for PON in BC patients. This information may help to further studies in an attempt to use this promising marker (which can be easily measure in the serum by ELISA technique) as a quantifiable risk factor in patients who have been suspected BC due to either abnormal imaging or physical findings.

Acknowledgments

The authors wish to thank the study participants for their valuable efforts and time, and Mr. Bulent Altundal for English editing.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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