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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 8  |  Page : 90-96

Circulating gelatinases are not prognostic of treatment response and survival in locally advanced rectal cancer patients undergoing preoperative chemoradiotherapy


1 Department of Radiation Oncology, Gazi University Hospital, Ankara, Turkey
2 Department of Radiation Oncology, Kartal Training and Research Hospital, Istanbul, Turkey
3 Department of Biochemistry, Gazi University Hospital, Ankara, Turkey

Date of Web Publication26-Mar-2018

Correspondence Address:
Sukran Ulger
Department of Radiation Oncology, Gazi University Hospital, 06500 Besevler, Ankara
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.165862

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 > Abstract 


Purpose: To investigate whether the serum levels of matrix metalloproteinases (MMPs) are predictive on treatment response and survival in locally advanced rectal cancer (LARC) patients undergoing preoperative chemoradiotherapy.
Patients and Methods: Serum MMP-2 and MMP-9 was analyzed by enzyme-linked immunosorbent assay and obtained before, midway, and 1-month after the end of preoperative radiotherapy treatment. The prognostic significance of serum MMP-2 and MMP-9 levels and their association with other pathological findings for LARC patients were evaluated.
Results: Serum levels of MMP-2 or MMP-9 were found to decrease with increasing clinical stage and negative correlation was statistically significant (P < 0.05). There was no statistically significant difference in tumor response and survival between the low and high MMP-2 and MMP-9 groups. MMP-2 and MMP-9 were not correlated with local-regional recurrence.
Conclusions: We propose that serum levels of MMP-2 and MMP-9 are not predictive on treatment response and survival in LARC patients.

Keywords: Metalloproteinase-2, metalloproteinase-9, prognosis, rectal cancer


How to cite this article:
Ulger S, Kilic D, Demircioglu F, Demirtas CY, Pasaoglu OT. Circulating gelatinases are not prognostic of treatment response and survival in locally advanced rectal cancer patients undergoing preoperative chemoradiotherapy. J Can Res Ther 2018;14:90-6

How to cite this URL:
Ulger S, Kilic D, Demircioglu F, Demirtas CY, Pasaoglu OT. Circulating gelatinases are not prognostic of treatment response and survival in locally advanced rectal cancer patients undergoing preoperative chemoradiotherapy. J Can Res Ther [serial online] 2018 [cited 2018 May 22];14:90-6. Available from: http://www.cancerjournal.net/text.asp?2018/14/8/90/165862




 > Introduction Top


The annual incidence of colorectal cancer (CRC) has now reached more than 1 million cases worldwide. Although surgery is the main treatment strategy for CRC, a multidisciplinary approach including surgery, radiotherapy (RT), and chemotherapy is necessary in locally advanced rectal cancer (LARC).[1],[2] Nevertheless, despite early diagnosis and the advancement of multi-modality therapies, many CRCs remain incurable.[3]

In LARC, the most important prognostic factor is tumor stage; there is a direct correlation between clinical outcome and the extent of tumor invasion and metastasis.[4] However, considerable heterogeneity exists among CRC patients presenting with the same performance status and tumor stage. Therefore, new useful prognostic indicators are needed to develop individual risk-adapted treatment strategies. These prognostic indicators should be available through noninvasive procedures in a routine clinical setting and would be of special interest for LARC patients in whom real pathological staging is impossible at the time of treatment planning.

Matrix metalloproteinases (MMPs) are a group of proteases well-known to have important roles in normal physiological processes. However, their key roles in cancer pathogenesis are currently being addressed.[5] Their function in various cancer types, and in particular CRC, with regards to tumor growth, progression, and metastasis, has been studied in recent years.[6],[7] MMPs are classified into five subgroups, namely collagenases (MMP-1, -8, and -13), gelatinases (MMP-2 and -9), stromelysins (MMP-3 and -10), membrane-type MMPs, and other MMPs, according to their substrate specificity and composition.[8],[9] Gelatinase A (MMP-2) and gelatinase B (MMP-9) are the most studied enzymes and are known as invasion-promoting MMPs.[10]

Gelatinases have been reported to be overexpressed in CRC, and some studies have shown an association between survival and immunohistochemical staining.[11],[12] Further, we have previously shown that MMP-9 is a poor prognostic factor on treatment response in LARC patients undergoing preoperative chemoradiotherapy (CRT).[13] However, the real prognostic role of these proteolytic enzymes in CRC remains unclear, given the contradictory results of many studies. Nevertheless, reviewed studies mainly examined the prognostic significance of MMP-2 and MMP-9 in CRC patients undergoing primary surgery. In LARC patients who are managed with multi-modality therapy, there is insufficient data about the prognostic role of these enzymes. Further, most studies, including our previous study, showing the prognostic value of MMP-2 and MMP-9 are immunohistochemical studies.[3],[11],[12],[13] Therefore, in this study, we decided to examine MMP-2 and MMP-9 plasma protein expression as an easy, practical, and suitable method for LARC patients. Herein, the prognostic significance of serum MMP-2 and MMP-9 levels and their association with other pathological findings for LARC patients were evaluated.


 > Patients and Methods Top


This prospective study was conducted in the Departments of Radiation Oncology and Biochemistry, Gazi University School of Medicine. The study design was approved by the Local Ethics Committee. Signed informed consents were obtained from all study participants.

A homogenous population of 26 patients who were undergoing preoperative CRT with the diagnosis of LARC were included in the study. The protocol of preoperative CRT included; histopathologically proven adenocarcinoma of the rectum, transmural extension and/or lymph node-positive disease. Histopathological diagnosis with biopsy, rectoscopy, pelvic magnetic resonance imaging, and abdominal-pelvic computed tomography were performed for all patients. Patients received 1.8 Gy daily RT to a total dose of 50.4 Gy in 28 fractions to the whole pelvis. The entire rectum, sacrum, and the regional lymph nodes were delineated as the clinical target volume.

For each patient, conformal radiation treatment planning was created to cover the target volume. Concomitant chemotherapy including 5-fluorouracil (5-FU), 400 mg/m 2 intravenous (IV) infusion before RT on the first 4 days of the 1st-week and the last 3 days of the 5th week of RT; and leucovorin calcium, 25 mg/m 2 IV bolus before each dose of 5-FU was applied to all patients. Preoperative CRT protocol was completed by all patient cohort.

Twenty-four patients underwent surgery 6–8 weeks after completion of the preoperative CRT. The median period between the 1st-day of the preoperative treatment and surgery was 89 days (minimum 65, maximum 120 days). Two patients underwent surgery after more than 120 days according to the comorbid diseases. Twenty-one patients underwent low anterior resection (80.8%) and five underwent abdominoperineal resection (19.2%). Total mesorectal excision was the routine surgical procedure. Twenty patients received postoperative maintenance chemotherapy, including 5-FU (425 mg/m 2 IV bolus on 5 consecutive days) and leucovorin calcium (25 mg/m 2 IV bolus before each 5-FU administration).

A complete response was determined by no histologic evidence of residual viable carcinoma; a partial response was defined as the presence of microfoci of residual tumor with marked regressive changes, and no response was characterized by large areas of residual carcinoma by evaluating the surgical specimen.[14]

To observe MMP-2 and MMP-9 levels, serum samples were obtained before, midway, and 1-month after the end of RT treatment. Peripheral venous blood samples were collected in sterile plastic tubes containing 3.8% trisodium citrate dihydrate. Serum samples were obtained from 10 cc venous blood after centrifugation at 3000 rpm for 5 min. The samples were stored at − 80°C until the assays were performed.

Serum MMP-2 and MMP-9 levels were analyzed by enzyme-linked immunosorbent assay (ELISA). Serum MMP-2 levels were measured using RayBio human MMP-2 (total) (RayBiotech, Norcross, GA, USA) and MMP-9 levels were measured using human MMP-9 Platinum (Bender MedSystems, Vienna, Austria) by ELISA with a quantitative enzyme immunoassay kit following the manufacturer's instructions. MMP-2 and MMP-9 were assayed consecutively.

For the prognostic analysis of patients, pathology reports of biopsy and surgical specimens including pathological differentiation grade, lymphatic vascular invasion, T-stage, N-stage, and the imaging modalities initially applied to determine the location and size of the tumor and lymph node metastasis, were all collected.

Patients were followed-up for 3 months after the end of therapy. The local control, disease free survival, and overall survival were evaluated as the endpoints of the prognostic analysis. Disease-free survival was defined as the time elapsed from the 1st-day of CRT to the first recurrence of CRC, distant metastasis or local-regional recurrence, and overall survival was defined as the time elapsed from the 1st-day of CRT to death of patients. The relation between serum levels of MMP-2 and MMP-9 and patients' clinical stage, pathological stage, and response to treatment were evaluated. The prognostic impact of MMP-2 and MMP-9 on local control and survival were also evaluated and the statistical significance was examined.

Statistical analysis

The relation between biochemical variables and clinicopathological features was analyzed by Pearson correlation coefficient test. The difference between the patient, clinical and pathological factors, and serum gelatinases levels were analyzed with nonparametric tests: Mann–Whitney U-test, Kruskal–Wallis and variance tests. To determine the independent factors predicting recurrence and poor survival, multivariate analysis, and logistic regression analysis were used. Survival curves were estimated using the Kaplan–Meier method (SPSS software package, Chicago, IL, USA). Differences in survival distributions were evaluated by the log-rank test. Differences with P < 0.05 were considered to be statistically significant.


 > Results Top


Blood samples from 26 patients with LARC who met the inclusion criteria were obtained. There were 17 men (65.4%) and 9 women (34.6). The median age was 52.5 years (minimum 36, maximum 75 years). According to tumor node and metastasis classification, 12 patients were clinical stage IIA (46.2%), 1 patient was clinical stage IIB (3.8%), and 13 patients were clinical stage IIIB (50%). Tumor location and clinical T- and N-stages are described in [Table 1].
Table 1: Clinical characteristics of study population

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Serum levels of MMP-2 and MMP-9 in blood samples collected at different times (78 blood samples were collected from the 26 patients) are shown in [Table 2]. There was a statistically significant positive correlation between pre-RT MMP-2 or mid-RT MMP-2 with mid-RT MMP-9 levels (respectively correlation coefficient: 0.536, 0.638 and P= 0.005, P < 0.001). Serum levels of mid-RT MMP-2 or mid-RT MMP-9 were found to decrease with increasing clinical stage significantly (respectively correlation coefficient: −0.444, −0.399 and P= 0.023, P= 0.043). However, there was no statistically significant correlation between MMP-2 or MMP-9 and pathological stage.
Table 2: Serum MMP-2 and MMP-9 levels of patients and controls

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The median serum levels of MMP-2 and MMP-9 were assigned as cut-off values and statistical evaluation was based on these values (median MMP-2 values: Pre-RT: 5.72; mid-RT: 5.72; post-RT: 5.88; median MMP-9 values: Pre-RT: 77.35; mid-RT: 70.8; post-RT: 74.75). To evaluate the prognostic impact of serum MMP-2 and MMP-9 levels on the local control, disease free survival, and overall survival, patients were divided into two groups according to high and low MMP levels (MMP-2 groups were: Pre-RT low MMP-2 group <5.72; pre-RT high MMP-2 group ≥5.72; mid-RT low MMP-2 group <5.72; mid-RT high MMP-2 group; post-RT low MMP-2 group <5.88; and post-RT high MMP-2 group ≥5.88. MMP-9 groups were: Pre-RT low MMP-9 group <77.35; pre-RT high MMP-9 group ≥77.35; mid-RT low MMP-9 group <70.8; mid-RT high MMP-9 group ≥70.8; post-RT low MMP-9 group <74.75; and post-RT high MMP-9 group ≥74.75). The number of patients in low and high MMP-2 and MMP-9 levels were shown in [Table 3]. The number of patients with complete, partial and no response were shown in [Table 4].
Table 3: Distrubution of number of patients in low and high MMP.2 and MMP.9 groups

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Table 4: The number of patients according to the pathological response rates

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There was no statistically significant difference in survival between the low and high MMP-2 and MMP-9 groups [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]. On the other hand, although not statistically significant, the 5-year overall survival rate was higher in the high pre-RT MMP-2 group (60% and 93% in the low and high MMP-2 groups, respectively) (P = 0.1) [Figure 1]. Similarly, there was no statistically significant difference in local-regional recurrence between the low and high MMP-2 and MMP-9 groups. Five years survival and local control rates in low and high levels of MMP-2 and MMP-9 patients were shown in [Table 5].
Figure 1: The five-year OS rate was higher in the high pre-RT MMP-2 group, 93 % (P=0,1)

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Figure 2: The five-year OS rates in the low and high mid-RT MMP-2 group (91 % and 83%, respectively, P=0.94)

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Figure 3: The five-year OS rates in the low and high post RT MMP-2 group (73 % and 91%, respectively, P=0.31)

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Figure 4: The five-year OS rates in the low and high pre RT MMP-9 group (76 % and 90%, respectively, P=0.28)

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Figure 5: The five-year OS rates in the low and high mid RT MMP-9 group (73 % and 92%, respectively, P=0.13)

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Figure 6: The five-year OS rates in the low and high post RT MMP-9 group (92 % and 79%, respectively, P=0.7)

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Table 5: Five year survival and local control rates in low and high levels of MMP-2 and MMP-9 groups

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 > Discussion Top


The predictive potential of circulating levels of MMP-2 and MMP-9 in LARC patients undergoing preoperative CRT and the alteration of the gelatinase serum levels throughout the preoperative CRT period (pre-, mid-, and post-treatment measurements) were examined prospectively in this study. The data included 26 LARC patients and indicated that serum levels of MMP-2 and MMP-9 have no influence on survival and treatment response and showed a negative correlation between MMP-2 or MMP-9 plasma levels and clinical stage.

In many types of human cancers, tissue levels of gelatinases have been found to be correlated with tumor progression, metastasis, and recurrence.[15],[16] Moreover, there is a large body of data observing the predictive value of tumor tissue gelatinases in CRC.[4],[12],[13],[17],[18] However, data examining the prognostic information of serum levels of MMP-2 and MMP-9 in cancer patients, especially in CRC, is lacking. Further, most studies evaluating the predictive value of both tissue and serum MMPs include patients with early stage rectal cancers undergoing primary surgery. Thus, the current study provides valuable information on the serum levels of MMP-2 and MMP-9 and their clinical correlation in LARC patients in whom complete pathological prognostic classification cannot be applied at the time of treatment planning.

The negative correlation between plasma levels of MMP-2 or MMP-9 and the clinical stage was statistically significant (P < 0.05). Additionally, there was a trend higher 5-year overall survival in the high MMP-2 group (93% vs. 60%, P= 0.1). Similarly, Waas et al. reported that serum MMP-2 levels were lower in 57 CRC patients compared with healthy controls and that there was no correlation between prognosis and MMP-2 levels in CRC patients.[19] Likewise, many studies have reported that MMP-2 levels were not significantly increased in patients with ovarian cancer, lung cancer, breast cancer, or advanced gastrointestinal cancer, as compared to levels in healthy controls.[16],[20] Therefore, the important aspect of MMP-2 production in cancer pathogenesis is the question of whether this proteinase is produced early or late in the disease. Murnane et al. reported that MMP-2 appears early in disease progression suggesting that it is involved in the initiation of malignancy.[21] This finding is in agreement with the negative correlation of MMP-2 levels and cancer stage in our study population.

Another explanation of the negative results for serum MMP-2 levels is the unknown metabolic pathways of MMPs including degradation and excretion of these proteins.[16] Increased stromal secretion and tissue levels of MMP-2 may not translate into the plasma. On the other hand, it is well known that MMPs tend to bind to the connective tissue matrix and, therefore, measured plasma levels of circulating MMPs could be unreliable depending on the measurement methods used.

Only one statistically significant correlation was found between the serum levels of MMP-2 and MMP-9 (pre-RT MMP-2 or mid-RT MMP-2 with mid-RT MMP-9 levels, P < 0.05). On the other hand, there was no correlation between serum levels of MMP-2 or MMP-9 and tumor response, local recurrence, or survival, which would indicate a worse prognosis. Further, there was no significant correlation between MMP-2 or MMP-9 and pathological stage, in our study population. Contrary to MMP-2, there are some encouraging results with the MMP-9 assay. Zucker et al. demonstrated that the serum levels of MMP-9 were significantly increased in breast cancer and gastrointestinal tract cancer as compared to normal subjects.[22] Further, poor survival with high levels of MMP-9 were also reported.[22] In a recent publication, Dragutinovic et al. showed a significant correlation between serum MMP-2 and MMP-9 and clinical outcome in early stage CRC patients by applying serum electrophoresis to detect the overexpression of gelatinase levels.[23] On the other hand, Waas et al. reported that there is no correlation between survival and serum MMP-9 levels in CRC.[19] These contradictory results indicate that a standardized type of serum or plasma MMP measurement must be recognized. The technique currently uses various antibodies and protein standards, which does not allow a consensus on circulating MMPs and their prognostic value to be drawn according to current results. In addition, the levels of serum MMP-9 cannot be equally reliable to those of MMP-2 due to the nature of MMPs metabolism.

The results of our study demonstrate that, in LARC patients undergoing preoperative CRT, serum MMP-2 and MMP-9 levels showed a negative correlation with clinical tumor stage. Although nonsignificant, a trend toward survival in the high MMP-2 group was demonstrated. Similarly to our results, there are contradictory results regarding the prognostic value of serum gelatinases.[16],[19] The role of gelatinases in CRC pathogenesis and where they exert their active role must be clearly defined. In addition, a standardized technique for the analysis of serum or plasma gelatinase measurements needs to be developed.

Most of the studies evaluating tissue MMPs have shown that they are important molecular prognostic markers in human cancers, and specifically in gastrointestinal cancers and CRCs.[12],[13],[15],[18],[24] The data presented in these studies mainly include the results of immunohistochemical staining on surgical specimens in early CRCs. However, circulating levels of MMPs appeared to be nonpredictive on treatment response and survival and, therefore, are unsuitable as tumor markers for tumor burden or as prognostic markers for LARC patients. Nevertheless, the biological behavior of circulating MMPs in CRC should be evaluated in a large prospective study including LARC patients with a long-term follow-up.

It has to be clarified that the present study is not without limitations, namely the small number of patients included and the fact that we did not examine tissue MMP-2 and MMP-9 through immunohistochemical analysis on biopsy specimens on the same study population. However, the prospective design and the long-term follow-up on a homogeneous patient population may overcome these limitations.


 > Conclusions Top


We propose that serum levels of MMP-2 and MMP-9 are not predictive of treatment response and survival in LARC patients. Although there are many immunohistochemical studies showing the prognostic value of MMP-2 and MMP-9 in CRC, we could not find a similar prognostic level of significance in plasma samples.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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