Diagnostic Utility of Selected Matrix Metalloproteinases (MMP-2, MMP-3, MMP-11, MMP-26), HE4, CA125 and ROMA Algorithm in Diagnosis of Ovarian Cancer.

Ovarian cancer (OC) has an unfavorable prognosis. Due to the lack of effective screening tests, new diagnostic methods are being sought to detect OC earlier. The aim of this study was to evaluate the concentration and diagnostic utility of selected matrix metalloproteinases (MMPs) as OC markers in comparison with HE4, CA125 and the ROMA algorithm. The study group consisted of 120 patients with OC; the comparison group consisted of 70 patients with benign lesions and 50 healthy women. MMPs were determined via the ELISA method, HE4 and CA125 by CMIA. Patients with OC had elevated levels of MMP-3 and MMP-11, similar to HE4, CA125 and ROMA values. The highest SE, SP, NPV and PPV values were found for MMP-26, CA125 and ROMA in OC patients. Performing combined analyses of ROMA with selected MMPs increased the values of diagnostic parameters. The topmost diagnostic power of the test was obtained for MMP-26, CA125, HE4 and ROMA and performing combined analyses of MMPs and ROMA enhanced the diagnostic power of the test. The obtained results indicate that the tested MMPs do not show potential as stand-alone OC biomarkers, but can be considered as additional tests to raise the diagnostic utility of the ROMA algorithm.

CXCL12 and CXCR4 as Potential Early Biomarkers for Luminal A and Luminal B Subtypes of Breast Cancer.

Purpose: Breast cancer is the most common type of malignancy in women. Factors that increase the risk of occurrence include chronic inflammation, with chemokines as its mediators. Therefore, the purpose of the present study was to determine the diagnostic utility of CXCL12 and CXCR4 as modern tumor markers in patients with early-stage luminal A and luminal B subtype of breast cancer and also to compare the results with the routinely used marker - CA 15-3. Patients and Methods: The study included 100 patients with early breast cancer of luminal A and B subtypes, 50 women with benign breast lesion and 50 healthy women. The levels of CXCL12 and CXCR4 concentrations were determined by enzyme-linked immunosorbent assay (ELISA), comparative marker CA 15-3 - by electrochemiluminescence method (ECLIA). Results: Concentrations of CXCL12 were significantly lower, while CXCR4 and CA 15-3 - significantly higher among patients with early-stage breast cancer than healthy women. CXCL12 also showed lower concentrations among fibroadenoma patients in comparison to healthy women, while CXCR4 - lower concentrations among fibroadenoma patients than cancer group. CXCL12 showed significantly higher values of sensitivity (79%), specificity (82%), positive predictive value (89.72%), negative predictive value (80%), diagnostic accuracy (80%) and diagnostic power (AUC = 0.8196) in the whole breast cancer group compared to the CA 15-3 marker (58%; 72%; 80.56%; 46.15%, 62.67%, 0.6434, resp.). Analysis of combined parameters resulted in increased sensitivity, negative predictive value and power of the test with a slight decrease in positive predictive value and a more significant decrease in specificity, reaching the best values for the three-parameter test CXCL12+CXCR4+CA15-3 (96%; 85.71%; AUC = 0.8812; 78.69%; 48%, resp.). Conclusion: The results indicate the preliminary usefulness of CXCL12 and CXCR4 as early biomarkers in the diagnosis of breast cancer, especially in the combined panel with CA 15-3.

Plasma Levels of Metalloproteinase 3 (MMP-3) and Metalloproteinase 7 (MMP-7) as New Candidates for Tumor Biomarkers in Diagnostic of Breast Cancer Patients.

Matrix metalloproteinases (MMPs) are a group of enzymes that mediate both physiological and pathological processes such as carcinogenesis. The role of matrix metalloproteinase-3 (MMP-3) and (MMP-7) in the pathogenesis of breast cancer (BC) has been demonstrated, suggesting that they may be considered as potential markers of this condition. The aim of this study was to assess plasma concentrations and diagnostic utility of MMP-3 and MMP-7 in 100 patients with early-stage breast cancer with Luminal A subtype or Luminal B HER-negative subtype, before and after surgical treatment, and in the following control groups: patients with a benign tumor (fibroadenoma) and healthy subjects. The concentrations of MMP-3 and MMP-7 were referenced to the levels of the widely recognized marker for BC diagnosis CA 15-3. MMP-3 and MMP-7 was measured by ELISA method and CA 15-3 by CMIA. Plasma levels of MMP-7 were significantly higher in Luminal A and Luminal B HER2-negative subtype breast cancer patients as compared to the healthy group. MMP-7 demonstrated comparable but mostly higher to CA 15-3 or MMP-3 values of diagnostic sensitivity, specificity, positive and negative predictive values and AUC (0.6888 for Luminal A subtype; 0.7612 for Luminal B HER2-negative; 0.7250 for BC total group, respectively) in the groups tested. The combined use of the tested parameters resulted in a further increase in diagnostic criteria and AUC. These results suggest the usefulness of combining MMP-7 with CA 15-3 in the diagnostics of breast cancer, especially in Luminal B HER2-negative subtypes patients, as a new candidate for tumor markers.

Plasma Levels of CXC Motif Chemokine 1 (CXCL1) and Chemokine 8 (CXCL8) as Diagnostic Biomarkers in Luminal A and B Breast Cancer.

Chemokines are involved in the regulation of immune balance and in triggering an immune response. CXCL1 and CXCL8 belong to the ELR-motif-containing group of CXC chemokines, which, in breast cancer (BC), stimulate angiogenesis and increase migration and invasiveness of tumor cells. The aim of this study was to evaluate CXCL1, CXCL8 and comparative marker CA 15-3 plasma concentrations in BC patients with luminal subtypes A and B. The study group consisted of 100 patients with BC, and the control group of 50 subjects with benign breast lesions and 50 healthy women. Chemokines concentrations were determined by ELISA method; CA15-3-by CMIA. Concentrations of CXCL8 and CA15-3 were significantly higher in BC total group and luminal B (for CA15-3 also in luminal A) subtype of BC than in healthy controls and subjects with benign lesions. In the total BC group, the highest SE, PPV and NPV were observed for CXCL8 (70%, 77.78%, 50%, resp.). A combined analysis of tested chemokines with CA 15-3 increased SE and NPV values (96%, 69.23%, resp.). The diagnostic power of the test (measured by area under ROC curve (AUC)) showed the highest value for CXCL8 in the total BC group (0.6410), luminal A (0.6120) and B subgroup of BC (0.6700). For the combined parameter, the AUC was increasing and reached the highest value for CXCL1 + CXCL8 + CA15-3 combination (0.7024). In light of these results, we suggest that CXCL8 could be used as an additional diagnostic marker that would positively influence the diagnostic utility of CA 15-3, especially in luminal B subtype of BC.

Plasma Levels and Diagnostic Utility of VEGF in a Three-Year Follow-Up of Patients with Breast Cancer.

Breast cancer is the most common malignancy in women globally. The increasing worldwide incidence of this type of cancer illustrates the challenge it represents for healthcare providers. Therefore, new tumor markers are constantly being sought. The aim of this study was to assess plasma concentrations and the diagnostic power of VEGF in 100 patients with early-stage breast cancer, both before and after surgical treatment and during a three-year follow-up. The control groups included 50 subjects with benign breast tumors (fibroadenoma) and 50 healthy women. The VEGF concentration was determined using enzyme-linked immunosorbent assay (ELISA) and the CA 15-3 concentration was determined by chemiluminescent microparticle immunoassay (CMIA). We observed significantly higher preoperative plasma concentrations of VEGF and CA 15-3 in patients with breast cancer. VEGF, similar to CA 15-3, demonstrated high diagnostic utility in the assessment of the long-term efficacy of surgical removal of the tumor. Determinations of VEGF had the highest diagnostic usefulness in the detection of breast cancer recurrence (SE 40%, SP 92%, PPV 67%, NPV 79%). Additionally, the highest values of SE, NPV and AUC were observed during the combined analysis with CA 15-3 (60%; 84%; 0.7074, respectively). Our study suggests a promising diagnostic utility of VEGF in the early stages of breast cancer and in the evaluation of the efficacy of the surgical treatment of breast cancer as well as the detection of breast cancer recurrence, particularly in a combined analysis with CA 15-3 as a new diagnostic panel.

Can VEGFR-3 be a better tumor marker for breast cancer than CA 15-3?

Vascular Endothelial Growth Factor Receptor 3 (VEGFR-3) is a very important factor which promotes lymphangiogenesis not only in physiological but also in pathological processes in which we can include neoplasia. The aim of this study was to analyze the plasma concentrations and diagnostic utility of this parameter in comparison and in combination with CA 15-3 in breast cancer (BC) patients and in relation to the control groups. The study included 120 breast cancer and 60 control patients (28 with benign breast tumors and 32 healthy women). Plasma levels of VEGFR-3 were determined by an Enzyme-Linked Immunosorbent Assay (ELISA), and those of CA 15-3 by a Chemiluminescent Microparticle Immuno Assay (CMIA). Differences in concentrations of both of the tested parameters were statistically significant when breast cancer patients were compared to the control groups. VEGFR-3 had higher values of sensitivity (SE), specificity (SP), predictive value of a positive (PPV) and negative test result (NPV) in the whole BC group (90%; 98.33%; 99.08%; 83.10%, respectively) and, more importantly, in the early stages of BC, than CA 15-3. VEGFR-3 was also a better parameter in terms of statistically significant Area Under Curve (0.9656) in the whole group and at all BC stages (I-IV), but a maximum range was obtained for the combination of VEGFR-3 and CA 15-3 (0.9710). The combined analysis of VEGFR-3 and CA 15-3 provides hope that a new BC diagnostic panel may be developed in the future.

Diagnostic Power of Cytokine M-CSF, Metalloproteinase 2 (MMP-2) and Tissue Inhibitor-2 (TIMP-2) in Cervical Cancer Patients Based on ROC Analysis.

Macrophage colony-stimulating factor (M-CSF), matrix metalloproteinase-2 (MMP-2) and its specific tissue inhibitor (TIMP-2) may play an important role in the pathogenesis of cancer disease. We investigated the plasma levels and diagnostic power (ROC curve analysis) of M-CSF, MMP-2, TIMP-2 and tumor markers CA 125 and SCC-Ag in cervical cancer (CC) patients as compared to control group. The study included 89 patients with cervical cancer. The control group consisted of 50 healthy, untreated women. The plasma levels of M-CSF, MMP-2 and TIMP-2 were determined using ELISA, CA 125 and SCC-Ag - by CMIA method. The median levels of M-CSF, TIMP-2, SCC-Ag and CA 125 in the entire group of CC were significantly different than compared to the healthy women group. MMP-2 showed the highest value of sensitivity from all examined parameters (in stage I of CC - 93.10%, II - 82.76%, III and IV - 96.88%, total group - 92.05%). The highest specificity was obtained by M-CSF (86%). The area under the ROC curve (AUC) of M-CSF (0.8051) was the largest of all the tested parameters (even higher than commonly used tumor markers) in the group of cervical cancer. The combination of M-CSF, MMP-2 or TIMP-2 with SCC antigen resulted in an increase AUCs in all cases (0.8760;0.7880;0.8081;respectively). The findings of this study suggest the usefulness of all examined parameters in the diagnostics of CC patients. Out of the tested substances, M-CSF also appears to be the best candidate for cancer diagnostics in all stages of the disease, based on ROC analysis.

Plasma levels of M-CSF and VEGF in laboratory diagnostics and differentiation of selected histological types of cervical cancers.

BACKGROUND: The search of useful serum biomarkers for the early detection of cervical cancers has been of a high priority. The activation of Macrophage-Colony Stimulating Factor (M-CSF) and Vascular Endothelial Growth Factor (VEGF) is likely involved in the pathogenesis and spread of cancer. We compared the plasma levels of M-CSF and VEGF to the ones of commonly accepted tumor markers CA 125and SCC-Ag in three groups of patients: 1. the cervical cancer group (patients with either squamous cell carcinoma or adenocarcinoma); 2. the cervical dysplasia group; 3. the control group. METHODS: This cohort study included 100 patients with cervical cancer and 55 patients with cervical dysplasia. The control group consisted of 50 healthy volunteers. The plasma levels of VEGF and M-CSF were determined using ELISA, while CA 125 and SCC-Ag concentrations were obtained by the chemiluminescent microparticle immunoassay (CMIA). RESULTS: The median levels of M-CSF and VEGF as well as CA 125 and SCC-Ag in the entire group of cervical cancer patients, were significantly different compared to the healthy women group. In case of both the squamous cell carcinoma and the adenocarcinoma groups, plasma levels of M-CSF and VEGF were higher compared to the control group. No significant differences in the studied parameters between the squamous cell carcinoma and the adenocarcinoma group were observed. The highest sensitivity and specificity were obtained for VEGF (81.18 and 76.00%, respectively) and SCC-Ag (81.18%; 74.00%) in the squamous cell carcinoma group and for VEGF (86.67%; 76.00%) in the adenocarcinoma group. The area under the ROC curve for VEGF was the largest in the adenocarcinoma group followed by the squamous cell carcinoma group (0.9082 and 0.8566 respectively). CONCLUSIONS: Obtained results indicate a possible clinical applicability and a high diagnostic power for the combination of MSC-F, VEGF, CA 125 and SCC-Ag in the diagnosis of both studied types of cervical cancer.

Diagnostic Power of Selected Cytokines, MMPs and TIMPs in Ovarian Cancer Patients - ROC Analysis.

BACKGROUND/AIM: The aim of the study was to identify new non-invasive ovarian cancer (OC) tumor markers. MATERIALS AND METHODS: In postmenopausal ovarian cancer patients and in a control group (benign ovarian lesions and healthy subjects), preoperative plasma levels of cytokines, metalloproteinases and their tissue inhibitors were determined using ELISA while those of CA125 and HE4 by chemiluminescent microparticle immunoassay methods. RESULTS: The diagnostic sensitivity (SE) value was the highest for HE4 and MMP-7 (78.0%). The diagnostic specificity (SP) for M-CSF, VEGF and MMP-9 was 95.2%, 95.2% and 95.7%, respectively. The highest positive predictive value (PPV) for M-CSF and MMP-9 was ~84.6% and negative predictive value (NPV) for MMP-7 and HE4 was ~87.6%. The biggest areas under the ROC curve were obtained for the combination of VEGF, MMP-7 or MMP-9 with HE4+CA125 (0.9130-0.9234), but not for CA125+HE4 (0.8260). CONCLUSION: Our research confirms the validity of combining classic markers with new markers to improve the diagnostic power of CA125 and HE4.

Diagnostic power of VEGF, MMP-9 and TIMP-1 in patients with breast cancer. A multivariate statistical analysis with ROC curve.

PURPOSE: Vascular endothelial growth factor is an important factor in promoting angiogenesis in malignant processes, matrix metalloproteinase-9 in the degradation of extracellular matrix, which enhances metastasis, and tissue inhibitor of metalloproteinase-1 is its inhibitor. The aim of this study was to investigate the diagnostic power of these parameters in comparison to CA15-3 in breast cancer patients and in relation to the control group. MATERIALS/METHODS: The study included 120 breast cancer patients, 60 patients with benign breast tumors and 60 healthy women. Plasma levels of tested parameters were determined by enzyme-linked immunosorbent assay, CA15-3 by chemiluminescent microparticle immuno assay. RESULTS: Tissue inhibitor of metalloproteinase-1 showed the highest value of sensitivity in breast cancer group (86.25%) and, more importantly, highest value in breast cancer stage I (85%). Vascular endothelial growth factor also showed high sensitivity (stage I and II-75%, III-85%, IV-70% and 76.25% in total breast cancer group) and the highest specificity (85%) from all tested parameters. It was also the only parameter which had statistically significant area under curve in all stages. In the total breast cancer group all tested parameters showed statistically significant area under curve, but the maximum range was obtained for combination: 'vascular endothelial growth factor + CA15-3'. Vascular endothelial growth factor seems to be the best candidate for diagnosing breast cancer stage I and for differentiating between breast cancer and non-carcinoma cases. CONCLUSIONS: The combined analysis of tested parameters and CA15-3 resulted in an increase in sensitivity and area under curve values, which provides hope for developing new panel of biomarkers that may be used in diagnosing breast cancer in the future.

Plasma levels and diagnostic utility of macrophage-colony stimulating factor, matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 as tumor markers in cervical cancer patients.

Macrophage-colony stimulating factor, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinase-1 may play an important role in malignant processes. The aim of this study was to investigate the diagnostic power of those parameters (serological biomarkers) in comparison to cancer antigen 125 and squamous cell carcinoma antigen in cervical cancer patients and in relation to the control groups. The study included 100 cervical cancer patients, 50 patients with cervical ectropion and 50 healthy women. Plasma levels of tested parameters were determined by enzyme-linked immunosorbent assay, cancer antigen 125, and squamous cell carcinoma antigen by chemiluminescent microparticle immunoassay. Plasma levels of all parameters in the total cancer group showed statistical significance (in all cases p < 0.05). In stage I of cancer only medial supraclavicular fossa and tissue inhibitor of metalloproteinase-1, in stage II all the tested parameters and cancer antigen 125, and in stage III + IV macrophage-colony stimulating factor, matrix metalloproteinase-9, and cancer antigen 125 showed statistical significance when compared to the healthy volunteers group. Macrophage-colony stimulating factor showed the highest value of sensitivity from all tested parameters (I: 56.25%, II: 72.73%, III + IV: 77.14% and 69% in total cervical cancer group). The highest specificity was obtained by matrix metalloproteinase-9 (94%). Positive predictive values were highest also for matrix metalloproteinase-9 (I: 82.35%, II: 84.21%, III + IV: 88% and 94.55% in total cervical cancer group), negative predictive values for macrophage-colony stimulating factor (I: 75.44%, II: 82.69%, III + IV: 87.5% and 58.11% in total cervical cancer group) and tumor markers. In the total cervical cancer group, all tested parameters showed statistically significant areas under receiver operating characteristic curve, but maximum range was obtained for the combination macrophage-colony stimulating factor + squamous cell carcinoma antigen (0.8723). The combined analysis of tested parameters and tumor markers resulted in an increase in sensitivity and areas under receiver operating characteristic curve values, which provides hope for developing new panel of biomarkers that may be used in the diagnosis of cervical cancer in the future.

Human Plasma Levels of Vascular Endothelial Growth Factor, Matrix Metalloproteinase 9, and Tissue Inhibitor of Matrix Metalloproteinase 1 and Their Applicability as Tumor Markers in Diagnoses of Cervical Cancer Based on ROC Analysis.

Cervical cancer (CC) remains a major diagnostic problem. The introduction of human papillomavirus vaccination significantly reduced the number of new cases; however, the search for new methods that would earlier indicate the development of cancerous changes is vital. The aim of this study was to investigate the diagnostic power of those parameters in comparison to Cancer Antigen 125 (CA 125) and Squamous Cell Carcinoma Antigen (SCC-Ag) in patients with CC and in relation to the control group. The study included 100 patients with CC and 50 healthy women. Plasma levels of tested parameters were determined by enzyme-linked immunosorbent assay, CA 125, and SCC-Ag by chemiluminescent microparticle immunoassay. Plasma levels of all parameters in the total cancer group showed statistical significance (in all cases P < .05). In stage I cancer, only vascular endothelial growth factor (VEGF) and tissue inhibitors of metalloproteinase 1; in stage II, all the tested parameters and CA 125; and in stage III + IV, VEGF, matrix metalloproteinase 9 (MMP-9), and CA 125 showed statistical significance when compared to the healthy volunteers group. Vascular endothelial growth factor showed the highest value of sensitivity from all tested parameters (I: 75%, II: 76%, III + IV: 94%, and 82% in total CC group). The highest specificity was obtained by MMP-9 (94%). In the total CC, stage I, and stage II groups, all tested parameters showed statistically significant area under the receiver operating characteristics curve (AUC), but maximum range was obtained for the combination VEGF + SCC-Ag (I: 0.9146, II: 0.8941, III + IV: 0.9139, total CC group: 0.9347). The combined analysis of tested parameters and tumor markers resulted in an increase in sensitivity and AUC values, which provides hope for developing new panel of biomarkers that may be used in the diagnosis of CC in the future.

[The plasma levels and diagnostic utility of matrix metalloproteinase-9 and CA 125 in cervical cancer patients]. / Ocena stezenia i przydatnosci diagnostycznej metaloproteinazy-9 i CA 125 w osoczu chorych na raka szyjki macicy.

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes, involved in the degradation of extracellular matrix components. The physiological function of MMP-9 is associated with regulation of immune processes, embryogenesis, reproduction and wound healing. MMP-9 also plays a critical role in tumor invasion, degrading the basement membrane, what is observed in different types of cancers: breast, gastrointestinal, and gynecological. AIM: The aim of this study was to investigate the plasma levels and diagnostic utility of MMP-9 and CA 125 in cervical cancer patients. MATERIALS AND METHODS: The study included 72 patients with cervical cancer and 24 healthy women. Plasma levels of the MMP- 9 was determined by enzyme-linked immunosorbent assay (ELISA) and CA 15-3 - by chemiluminescent microparticle immunoassay (CMIA). RESULTS: This studies have shown increase levels of MMP-9 and CA 125 in cervical cancer patients compared to health control group. In addition, the MMP-9 concentration increased with the clinical stage of tumor. The sensitivity and specificity of MMP-9, positive and negative predictive value, were higher or equal than CA 125, but this parameter can not be used as a single marker. Our studies of MMP-9 have shown a high utility to the exclusion of cancer, similarly to CA 125. The combined analysis of MMP-9 and CA 125 significantly increased the ability to diagnose a cervical cancer and the possibility exclusion of cancer. CONCLUSIONS: MMP-9 has shown the usefulness in the diagnosis of cervical cancer, but only in the combined analysis with CA 125, as a new diagnostic panel.

Plasma levels of MMP-7 and TIMP-1 in laboratory diagnostics and differentiation of selected histological types of epithelial ovarian cancers.

BACKGROUND: MMP-7 and TIMP-1 may play a role in the pathogenesis of cancer disease. In this study we investigated plasma levels of selected metalloproteinase and its tissue inhibitor in comparison to plasma levels of the commonly accepted tumor markers (CA 125 and HE4) in selected histological types of epithelial ovarian cancer patients as compared to control groups: patients with a benign ovarian tumor and healthy subjects. Plasma levels of MMP-7 and TIMP-1 were determined using ELISA, CA 125 and HE4 - by CMIA methods. RESULTS: Plasma levels of all biomarkers studied were significantly higher in ovarian cancer patients as compared to both control groups. MMP-7 demonstrated comparable to HE4 or CA125 values of diagnostic sensitivity (SE: 61%; 68%; 58%, respectively), specificity (SP: 95%; 95%; 98%, respectively), positive (PPV: 93%; 96%; 98%, respectively) and negative predictive values (NPV: 61%; 66%; 60%, respectively) in the groups tested. The combined use of the aforementioned biomarkers resulted in a further increase in diagnostic criteria and AUC, especially in the early stages of the disease. CONCLUSIONS: These findings suggest the usefulness of combining MMP-7 with CA 125 and HE4 in the diagnosis of epithelial ovarian cancer as a new tumor marker panel.

M-CSF in a new biomarker panel with HE4 and CA 125 in the diagnostics of epithelial ovarian cancer patients.

BACKGROUND: We investigated plasma levels of M-CSF and conventional tumor markers (HE4 and CA 125) in epithelial ovarian cancer patients as compared to control groups: benign ovarian tumor patients (cysts) and healthy subjects. METHODS: M-CSF levels were determined by ELISA, HE4 and CA 125 levels - by CMIA method. RESULTS: Our results have demonstrated significant differences in the concentration levels of M-CSF, CA 125 and HE4 between the groups of ovarian cancer patients, cysts patients and the healthy controls. In the groups tested M-CSF demonstrated equal to or higher values than both CA 125 and HE4 in diagnostic sensitivity (SE), positive and negative predictive values (PPV, NPV), and in the area under the ROC curve (AUC), particularly in the group with the serous epithelial sub-type of OC. Moreover, CA 125 showed better results of the aforementioned diagnostic criteria than HE4. The combined use of the parameters studied resulted in a further, significant increase in the value of the diagnostic indicators and in the value of the diagnostic power (AUC), especially in the early stages of ovarian cancer. CONCLUSIONS: These findings suggest a high usefulness of M-CSF in diagnosing the serous sub-type of epithelial ovarian cancer and in discriminating between cancer and non-carcinoma lesions, particularly in new diagnostic panels in combination with CA 125 and HE4 for the detection of EOC in the early stages.