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ORIGINAL ARTICLE
Year : 2019  |  Volume : 15  |  Issue : 1  |  Page : 48-53

The prognostic and predictive significance of plasma type 1 plasminogen activator inhibitor and endoglin in metastatic colorectal cancer patients treated with bevacizumab-containing chemotherapy


1 Department of Medical Oncology, Ankara Numune Training and Research Hospital, Ankara, Turkey
2 Department of Medical Oncology, Ankara Oncology Training and Research Hospital, Ankara, Turkey
3 Department of Biochemistry, Ankara Oncology Training and Research Hospital, Ankara, Turkey
4 Department of Epidemiology, Gülhane Military Medical Academy, Ankara, Turkey

Date of Web Publication13-Mar-2019

Correspondence Address:
Dr. Oznur Bal
Department of Medical Oncology, Ankara Numune Training and Research Hospital, 06200 Ankara
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_1253_16

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 > Abstract 


Aim: This study aims to evaluate the prognostic and predictive value of plasma plasminogen activator inhibitor-1 (PAI-1) and endoglin in metastatic colorectal cancer (mCRC) patients receiving chemotherapy with bevacizumab.
Materials and Methods: Between April 2012 and September 2013, 47 mCRC patients with a mean age of 58.5 ± 9.6 years were included in the study. Male-to-female ratio was 29/18. The baseline and posttreatment plasma PAI-1 and serum endoglin levels after 3 cycles of bevacizumab-containing chemotherapy were evaluated. The percent change between baseline and posttreatment levels after treatment was also recorded.
Results: The median follow-up duration was 26.6 months (range 1.8–70.2 months). The clinical benefit rate was 70% (partial response [32%], stable disease [38%]). Overall survival was 20.8 ± 1.5 months. The patients with progressive disease had statistically significantly higher baseline PAI-1 level (57.9 pg/mL vs. 29.9 pg/mL, P = 0.036). The percent change of the plasma PAI-1 level after the third cycle of treatment was also statistically significantly lower in those with clinical benefit (P = 0.035). However, there was no statistically significant difference in endoglin level and its change after therapy with respect to the response to treatment (P = 0.771 and P = 0.776, respectively). Plasma PAI-1 level had no statistically significant effect on survival (P = 0.709).
Conclusion: Baseline plasma PAI-1 level and its percent change with bevacizumab were shown to have statistically significant predictive value for the response to therapy whereas serum endoglin had no statistically significant predictive value for the response to therapy. However, neither PAI-1 nor endoglin had prognostic significance in mCRC.

Keywords: Bevacizumab, colorectal cancer, endoglin, plasminogen activator inhibitor-1


How to cite this article:
Bal O, Ekinci AS, Dogan M, Atay C, Demirci A, Oksuzoglu B, Kilic S. The prognostic and predictive significance of plasma type 1 plasminogen activator inhibitor and endoglin in metastatic colorectal cancer patients treated with bevacizumab-containing chemotherapy. J Can Res Ther 2019;15:48-53

How to cite this URL:
Bal O, Ekinci AS, Dogan M, Atay C, Demirci A, Oksuzoglu B, Kilic S. The prognostic and predictive significance of plasma type 1 plasminogen activator inhibitor and endoglin in metastatic colorectal cancer patients treated with bevacizumab-containing chemotherapy. J Can Res Ther [serial online] 2019 [cited 2019 Aug 20];15:48-53. Available from: http://www.cancerjournal.net/text.asp?2019/15/1/48/243477




 > Introduction Top


Colorectal cancer is the leading cause of cancer death worldwide.[1] Angiogenesis plays an important role in the tumor growth, progression, and metastasis in colorectal cancer.[2] Angiogenesis is a complex process, in which proangiogenic factors are activated and/or antiangiogenic factors are inactivated. Vascular endothelial growth factor (VEGF) is one of the most critical mediators in angiogenesis.[3],[4] Targeted therapy including anti-VEGF agents in metastatic colorectal cancer (mCRC) is a novel treatment modality in the last decade. Anti-VEGF agents such as bevacizumab, a monoclonal antibody against VEGF, are known to have potent effects in mCRC.[3],[5],[6] Bevacizumab is a recombinant humanized monoclonal antibody that inhibits angiogenesis through binding VEGF-A. Cytotoxic chemotherapy with bevacizumab (CB) has been shown to increase survival in mCRC.[4],[5],[6],[7] However, the most appropriate candidates for bevacizumab-containing chemotherapy are not well defined because of the lack of predictive markers with higher sensitivity and specificity.[8] Hence, we need predictive markers for CB to have the most effective therapy with higher response rates and less toxicity.

Endoglin (CD105) is a coreceptor for transforming growth factor beta which has a critical role in angiogenesis.[9] Endoglin is expressed in tumor vessels excessively and affects metastatic process.[10] Plasminogen activator inhibitor-1 (PAI-1) is a serine protease inhibitor that was shown to play an important role in the metastasis and neovascularization.[11] Some studies demonstrated that higher PAI-1 levels were associated with large tumor size, advanced stage, and poor prognosis.[12],[13] However, neither endoglin nor PAI-1 has been evaluated for prediction of response to bevacizumab.

In this study, we aimed to evaluate the prognostic and predictive significance of plasma PAI-1 and endoglin levels for mCRC patients receiving bevacizumab with chemotherapy since predictive biomarkers are needed for the most effective “tailored therapy” with bevacizumab.


 > Materials and Methods Top


Patients and method

This was a prospective follow-up study performed in clinics of medical oncology of Ankara Oncology Training and Research Hospital between November 2012 and September 2013. The study was approved by the Institutional Ethics Committee of Ankara Oncology Training and Research Hospital (14.11.2012-2012/350) and conducted in accordance to latest version of Helsinki Declaration.

All of the patients had the chemotherapy containing bevacizumab (CB) at any line. The patients aged >18 years, Eastern Cooperative Oncology Group (ECOG-PS) <2 were included. The demographical, clinicopathological, and surgical data of the participants were recorded. The KRAS mutation status and treatment details were also noted. Blood samples for analysis of PAI-1 and endoglin levels were collected from the patients before chemotherapy (baseline) and 2 weeks after three cycles of chemotherapy. All of the patients signed inform consent. The median follow-up duration was 26.6 months (range 1.8–70.2 months).

Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) criteria were used to evaluate response to the treatment. According to the RECIST criteria, complete response (CR) was disappearance of all target lesions and reduction in the short-axis measurement of all pathologic lymph nodes to ≤10 mm, partial response (PR) was defined as ≥30% decrease in tumor size, progressive disease (PD) was defined as ≥20% increase in tumor size, and stable disease (SD) is neither PR nor PD criteria met.[14],[15] Clinical benefit rate was defined as the sum of CR, PR, and SD. Overall survival (OS) was defined as the duration between diagnosis and death/date of last known alive.

Blood sample analysis

The blood samples collected were centrifuged at 2400 g for 15 min and upper layer plasma samples transferred to another tube were stored at −20°C until analysis.

PAI-1 levels were measured in citrated plasma by an enzyme-linked immune sorbent assay (ELISA) kits (eBiosience Instant ELISA, Vienna, Austria). The minimum detectable level was 29.0 pg/mL. Intra-assay variability was 4.7%. Inter-assay variability was 5.0%.

Serum endoglin levels were determined using commercially available ELISA kits (eBiosience Instant ELISA, Vienna, Austria). The minimum detectable level was 2.60 pg/mL. The intra-assay and inter-assay variabilities were 4.6% and 3.3%, respectively.

The plasma levels of PAI-1 and endoglin were estimated using the standard curve.

Statistical analysis

The statistical analysis was performed using SPSS 15.0 (Statistical Package for the Social Science, SPSS Inc., Chicago, IL, USA) software for Windows. Descriptive statistics were presented as mean, standard deviation, min-max, frequency, and percentages. A receiver-operator characteristic (ROC) curve analysis was performed to identify the optimal cutoff plasma levels of PAI-1 and endoglin and percent change in these levels with chemotherapy to predict response to therapy. The area under the ROC curve (AUC) values were calculated as a measure of the accuracy of the test. Kaplan–Meier analysis was utilized to estimate the overall and progression-free survival (PFS) rates and Kaplan–Meier curves were presented. Multivariate step-wise Cox proportional hazard regression analysis was used to determine the independent predictor clinical variables on response to therapy. Hazard ratios (HRs) were given with 95% confidence interval (CI). Log-rank test was used to evaluate the effects of plasma levels of PAI-1 and endoglin on the OS. P ≤ 0.05 was considered to be statistically significant.


 > Results Top


Forty-seven patients with mCRC were included in the study. Male-to-female ratio was 29/18. Mean age of the patients was 58.5 ± 9.6 years. Most of the tumors were located at the rectum or sigmoid colon and most (85.1%) of them had adenocarcinoma. Majority (59%) of the patients had moderate-to-well-differentiated tumors. The liver was the most common site for metastasis. KRAS mutation was evaluated in 41 patients of which 24 (58.5%) were KRAS mutant. The clinicopathological characteristics of the patients were summarized in [Table 1].
Table 1: Clinicopathological characteristics of the patients with metastatic colorectal cancer

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Of the 47 patients, 33 (70.2%) received bevacizumab in the first-line treatment and 30 (63.8%) received bevacizumab in combination with FOLFIRI chemotherapy regimen [Table 2]. Surgical resection had been performed in 34 patients (72.3%), as only 9 patients (19.1%) had metastasectomy [Table 2].
Table 2: Treatment modalities in metastatic colorectal cancer

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Plasma endoglin and plasminogen activator inhibitor-1 levels, and response to treatment

Serum endoglin and plasma PAI-1 levels were measured at baseline and after 3 cycles of chemotherapy. Both endoglin and PAI-1 levels were statistically significantly decreased after 3 cycle of CB (for endoglin from 8.98 to 7.90 pg/mL, P = 0.003; for PAI-1 from 46.3 to 27.1 pg/mL, P = 0.033).

The response rates for CB were as 32% for PR, 38% for SD, and 30% for PD. Hence, the clinical benefit rate was 70% [Figure 1].
Figure 1: Distribution of the study patients according to response to treatment

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The patients who had clinical benefit with CB had statistically significantly lower basal PAI-1 level than the others with PD (29.9 pg/mL [range 15.5–126.5 pg/mL] vs. 57.9 pg/mL [range 19.2–202.1 pg/mL], P = 0.036). Hence, the patients with higher basal PAI-1 level tend to less respond to CB, so it seems to have predictive value.

Similarly, percent change in PAI-1 level after 3 cycles of CB was also statistically significantly lower in the patients with clinical benefit (21% vs. 56%, P = 0.035) [Table 3]. In ROC analysis, AUC for baseline and percent change in PAI-1 levels were as 0.676 (95% CI 0.439–0.913, P = 0.036) and 0.756 (95% CI 0.565–0.946, P = 0.035). For predicting response to therapy, the cutoff value for percent change in PAI-1 levels was calculated as 46% (i.e., PAI-1 level decrease <46% with CB, it is likely that response to therapy would be obtained). However, baseline and percent change of endoglin level did not show statistically significant difference with respect to response to treatment [Table 3].
Table 3: Blood plasminogen activator inhibitor-1 and endoglin (CD 105) levels with respect to response to bevacizumab-containing therapy

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In multivariate Cox regression analysis, in addition to plasma levels of PAI-1 and endoglin, the effects of age, gender, tumor localization, and KRAS mutation on response to chemotherapy regimens including bevacizumab were evaluated. Among these variables, only percent change in PAI-1 levels had statistically significant effect on response to therapy (HR = 8.807, 95% CI 1.014–76.528, P = 0.049) [Table 4] Hence, PAI-1 contributes to the prediction of CB response independent from K-RAS mutation status.
Table 4: Multivariate Cox regression analysis for the effect of clinical variables on treatment response

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Survival

On Kaplan–Meier analysis, the OS and PFS durations were calculated as 20.8 ± 1.5 months (95% CI, 17.8–23.7 months) and 17.5 ± 1.3 months (95% CI, 14.9–20.0 months), respectively [Figure 2]. Plasma levels of PAI-1 had no statistically significant effect on OS (log-rank = 0.140, P = 0.709).
Figure 2: Kaplan–Meier curves for overall and progression-free survivals

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 > Discussion Top


In this study, we evaluated the prognostic and predictive significance of plasma PAI-1 and serum endoglin levels in the patients with mCRC receiving CB. We primarily found that percent change in PAI-1 levels with CB had a significant effect on the prediction of response to the therapy, in other words, if PAI-1 level decrease 46% or less with bevacizumab therapy, it is likely that response to therapy would be obtained. However, plasma endoglin level has no association with response to bevacizumab therapy.

Bevacizumab is a monoclonal antibody against VEGF with antiangiogenic properties.[16] Clinical trials and current guidelines suggest adding bevacizumab to the other chemotherapeutic agents in the first-line treatment of mCRC.[17] On the other hand, specific side effects and high cost of bevacizumab therapy necessitate definition of the target population that will benefit most from bevacizumab therapy. However, there is no validated available biomarker for prediction of response to bevacizumab therapy yet. In previous studies, some biomarkers such as soluble VEGF receptor or plasma VEGF levels could not have been successful at the prediction of response to bevacizumab.[18] Some angiogenic factors (e.g., fibroblast growth factor, placental growth factor, or hepatocyte growth factor) which had been claimed to be predictive for resistance to bevacizumab therapy have been shown to be only progression-associated markers.[8],[19]

Although PAI-1 has been shown to play an important role in the metastasis, neovascularization and poor prognosis, its role in predicting response to bevacizumab is not so clear.[11],[12],[13] Chen et al. recently reported that PAI-1 plays a role in bevacizumab-associated venous thromboembolism in a tumor model.[20] In the present study, we showed a significant decrease in plasma PAI-1 level with 3 cycles of CB. It decreased from 46.3 to 27.1 pg/mL (P = 0.033). Furthermore, we found that both baseline PAI-1 level and percent change in PAI-1 level after 3 cycles of chemotherapy were significantly lower in the patients with PR or SD than those with PD, indicating an association between both baseline plasma PAI-level and its changing pattern with therapy. ROC analysis also revealed high accuracy of baseline and percent change in PAI-1 for predicting response to therapy (AUC 0.676 and 0.756, respectively). Although age, gender, tumor localization, or KRAS mutation status had no significant predictive value on response to CB in multivariate Cox regression analysis, percent change in PAI-1 level was shown to have significant effect on response to bevacizumab (odds ratio 8.8, 95% CI 1.04–76.28, P = 0.049). However, plasma levels of PAI-1 had no prognostic value in our population of mCRC. OS is around 30 months with bevacizumab or anti-epidermal growth factor receptor (EGFR) containing chemotherapy.[21],[22] “Ras” mutation analysis is recommended for anti-EGFR monoclonal antibodies such as cetuximab or panitumumab since these agents are effective only in “ras” wild-type tumors. “Pan-ras” analysis is preferred to “k-ras” mutation analysis. In FIRE-3 trial, OS, PFS, and overall response rate were reported to be more striking in k-ras wild-type mCRC patients with cetuximab-containing regimens despite no OS benefit in all patients regardless from “k-ras” status.[21] However, there is no predictive marker for bevacizumab. In our study, basal PAI-1 level and percent change were shown to have significance in prediction of response to bevacizumab-containing therapy. Hence, we consider that it should be evaluated as a predictive marker for bevacizumab in prospective further clinical trials with large number of cases.

Endoglin is overexpressed on highly proliferating endothelial cells.[23],[24] This characteristic of endoglin makes it an appropriate marker for angiogenesis and neovascularization. It has a potential role in tumor pathogenesis and prognosis of various solid tumors.[23] Endoglin has also been shown to be an effective biomarker for predicting response to chemotherapy, hormone therapy, and radiotherapy in laryngeal and breast carcinomas.[25],[26],[27] Previous reports indicated that endoglin correlates with microvessel density and predicts risk of metastasis in colorectal cancer leading to poor prognosis.[28],[29],[30] It has been also suggested as a target for antiangiogenic therapies in colorectal cancer.[31] However, its role in predicting response to bevacizumab has not been evaluated anymore. Uronis et al. showed a change in plasma level of endoglin during bevacizumab therapy in the patients with solid tumors.[32] Similarly, in the present study, we showed a significant decrease in plasma endoglin level with 3 cycles of CB (from 8.98 to 7.90 pg/mL (P = 0.033). However, baseline endoglin level and its percent change had no significant association with response to bevacizumab therapy.

The main limitations of the present study were the small sample size that precludes us reaching a definitive conclusion on the study results. Nevertheless, this is the first study eveluating on the predictive and prognostic values of endoglin and PAI-1 levels in the patients with mCRC treated with bevacizumab-containing regimens, indicating the probable predictive value of PAI-1 levels for response to bevacizumab therapy.


 > Conclusion Top


Baseline plasma PAI-1 level and its percent change with bevacizumab therapy, but not endoglin levels, have significant predictive value for the response to bevacizumab therapy. None of them has been shown to have any prognostic value for mCRC. On the basis of our findings, further larger scale studies are needed to be implemented before using plasma PAI-1 level as a predictive biomarker for bevacizumab-containing chemotherapy regimens in mCRC.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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