RU2521229C1 - Method for prediction of prostate cancer grade - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: prostate cancer grade is predicted by a biochemical analysis of blood serum for a level of matrilysin and a soluble Fas-antigen (sFas). If the total concentration is up to 7.0 ng/ml, a non-malignant process is stated; the total concentration falling within 7.0 to 12.0 ng/ml shows a moderate grade, while a high grade is stated if the total concentration exceeds 12.0 ng/ml.

EFFECT: invention enables predicting the prostate cancer grade exactly on the basis of an integrated assessment of serological risk factors correlated with the Gleason's pattern.

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Description

The invention relates to medicine, namely to laboratory diagnostics for predicting the degree of malignancy of prostate cancer.

Prostate cancer is the most common cancer in men and the second leading cause of cancer death in the Western world (Hanchette CL, Schwartz GG: Geographic patterns of prostate cancer mortality. Evidence for a protective effect of ultraviolet radiation. Cancer 1992, 70: 2861-2869 ) Today, a significantly larger number of patients with prostate cancer are diagnosed at an early stage of the disease than 10 years ago. However, the biological heterogeneity characteristic of prostate cancer requires unique issues to be addressed. Highly differentiated cancer diagnosed at the end of life may not affect quality and longevity. The development of low-grade tumors at a younger age can lead to death within a few years.

In the practice of laboratory diagnostics, there are known methods for predicting the development of prostate cancer, based on the simultaneous determination of Prostate-specific Antigen (PSA) in blood serum and urine, and their ratio increases the specificity of this test when screening and monitoring patients with prostate cancer (Hellenbrand M., Bastian M., Steiner M., Zingler C, Muller M., Wolff J. et al .: Serum to urinary prostate specific antigen ratio in patients with benign prostatic hyperplasia and prostate cancer. Anticancer Res 2000, 20: 4995-4996). However, prognostic models based on preliminary determination of PSA have not proven to be effective in predicting long-term survival, as are assessed on the Glisson scale (Roach M., Lu J., Pilepich MV, Asbell SO, Mohiuddin M., Terry R. et al .: Four prognostic groups predict long-term survival from prostate cancer following radiotherapy alone on Radiation Therapy Oncology Group clinical trials. Int. J. Radiat. Oncol. Biol. Phys. 2010, 1; 47: 609-615; Steuber T., Graefen M ., Haese A. et al. Validation of a nomogram for prediction of side specific extracapsular extension at radical prostatectomy. J. Urol. 2006; 175: 939-44).

Methods are also known for determining other biochemical markers — for example, apoptosis markers. In a multivariate analysis, p53 overexpression was defined as a prognostic parameter for disease-free survival (P = 0.005) (Kuczyk M.A., Serth J., Bokemeyer C., Machtens S., Minssen A., Bathke W. et al .: The prognostic value of p53 for long-term and recurrence-free survival following radical prostatectomy. Eur. J. Cancer 1998, 34: 679-686). Further studies are recommended to confirm the independent prognostic potential of p53 in patients with localized prostate cancer.

Scherr D.S. et al (Scherr DS, Vaughan ED, Wei J., Chung M., Felsen D., Allbright R. et al .: Bcl-2 and p53 expression in clinically localized prostate cancer predicts response to external beam radiotherapy // J. Urol . - 1999, v. 172 - p.12-16) evaluated the value of two key regulators of apoptosis, bcl-2 and p53, by the immunohistochemical reaction of biopsy samples from 54 patients with localized prostate cancer. They found that biopsies with positive bcl-2 and p53 were associated with high Glisson scores. Bcl-2 and p53 may be useful in predicting tumor resistance to treatment. More promising in terms of assessing the progression of tumors are other markers of apoptosis - such as matrilysin (metalloprotein-for-7), which is associated with tumors originating from the reproductive system and in particular the prostate (Cardillo MR, di Silverio F., Gentile V. Quantitative Immunohistochemical and In Situ Hybridization Analysis of Metalloproteinases in Prostate Cancer ANTICANCER RESEARCH - 2006 - 26: 973-982; Xuefeng B. Ling, Tara K. Sigdel, Kenneth Lau, Lihua Ying, Irwin Lau. James Schilling Integrative Urinary Peptidomics in Renal Transplantation Biomarkers for Acute Rejection // J. Am. Soc. Nephrol. 2010. No. 10. p.1681-1689).

All described methods have disadvantages:

- the above methods are based on a histochemical study of biopsy samples, as in the case of p53 and bcl-2;

- the lack of correlation of the PSA level with points on the Glisson scale;

- technical complexity of execution;

- low accuracy of the study and the lack of clear limits for assessing the degree of malignancy.

Closest to the proposed method is a test for determining the level of another apoptosis marker in the blood serum - soluble Fas antigen (sFas), which correlates with an increase in the malignancy of a prostate tumor according to the degree of differentiation and allows predicting prostate cancer in the case of low-grade tumors producing low PSA levels. The authors propose a sFas level of 3.2 ng / ml as the boundary for assessing tumor malignancy (according to clinical signs, metastasis and survival) (Furuya Y., Nagakawa O., Fuse N. Prognostic significance of serum soluble Fas level and its change during regression and progression of advanced prostate cancer. Endocr J. 2003 Oct; 50 (5): 629-33).

However, the disadvantages of this method are:

- fuzzy distinction in the assessment of malignancy;

- lack of communication with the widespread Glisson scale;

- a narrow range of sFas concentrations proposed by the authors for evaluating malignancy.

The invention is aimed at improving the accuracy of the prognosis of prostate cancer based on a comprehensive assessment of serological risk factors that correlate with the morphological picture on the Glisson scale.

The specified technical result is achieved by the fact that to predict the development of prostate cancer, the levels of matrilysin and soluble Fas antigen (sFas) in the blood serum are determined and a non-cancerous process is judged by the sum of their concentrations up to 7.0 ng / ml, by the sum of concentrations from 7, 0 to 12.0 ng / ml are used to judge a moderate degree of malignancy, and a high degree of malignancy is judged by the sum of concentrations above 12.0 ng / ml.

The proposed method was successfully tested on 65 patients undergoing treatment at the Astrakhan Regional Oncology Center and the urology department of the Astrakhan Regional Clinical Hospital No. 1, from 2006 to 2011.

The method is illustrated by the following clinical examples of its implementation.

Clinical example No. 1:

Patient A., 57 years old (medical history No. 4329). Received February 21, 2006. Blood was taken for the study of markers on February 22, 2006. Matrilizin concentrations were 8.9 ng / ml, sFas 3.6 ng / ml, which totaled 12.5 ng / ml. The prognosis is a high degree of malignancy. For prostate cancer T2N0M0, a radical prostatectomy was performed. The histological diagnosis is low-grade adenocarcinoma, a score on the Glisson scale of 7 (3 + 4).

Clinical example No. 2:

Patient C, 62 years old (Case History No. 23234). Received November 1, 2010. Blood for the study of markers was taken on November 2, 2010. Matrilizin concentrations were 5.0 ng / ml, sFas 2.6 ng / ml, which totaled 7.6 ng / ml. The prognosis is a moderate degree of malignancy. For prostate cancer T2N0M0, a radical prostatectomy was performed. The histological diagnosis is adenocarcinoma, a score on the Glisson scale of 5 (2 + 3).

Clinical example No. 3:

Patient S. 70 years old (medical history No. 1017). Received March 2, 2011. Blood was collected for the study of markers on March 3, 2011. Matrilizin concentrations were 3.5 ng / ml, sFas 1.6 ng / ml, which totaled 5.1 ng / ml. The prognosis is a non-cancerous process. Performed a radical prostatectomy. The histological diagnosis is benign prostatic hyperplasia.

The invention was based on the results of examination and treatment of 65 patients with prostate tumors. The average age of patients was 63.5 ± 0.4 years (51 to 74 years). 45 patients underwent surgical treatment (a radical post-pulmonary prostatectomy was performed) (Table 1).

The diagnosis of prostate cancer was made on the basis of a morphological study of prostate tissue obtained by transrectal biopsy under ultrasound guidance, as well as postoperative pathological examination of prostate tissue. The degree of malignancy of the neoplasm was determined according to the Glisson scale.

The conducted studies allowed a comprehensive assessment of risk factors taking into account the informative significance of each factor. The results of the study are presented in table 1.

Positive = 35 (77.8%); false positive = 4 (8.9%); false negative = 6 (13.3%).

The sensitivity of the method: True Positive / True Positive + False Negative = 77.8 / 91.1 = 85.4%.

Specificity: True negative / true negative + false positive = 22.2 / 22.2 + 8.9 = 71.4%.

Thus, this means: in 85.4% of patients with prostate cancer, the prognostic test is correct. Specificity is 71.4%, therefore, in 71.4% of patients with a clearly negative prognosis, the test results are negative. A positive difference of 14% between a reliably positive prognosis and a reliably negative prognosis is a factor in overdiagnosis and in this case works in favor of patients.

The proposed method has the following advantages:

- improves the accuracy of the prognosis of prostate cancer.

- allows to predict the degree of malignancy of a prostate tumor on the basis of determining the total concentration of sFas and matrilisin with a high probability of prediction of 85.4% (r = 0.7; P <0.00001).

- It has simplicity, accessibility and economic feasibility, as it is based on the assessment of only laboratory methods that have been introduced into widespread practice and does not require the use of expensive laboratory equipment.

- is an open predictive system, because allows you to easily enter additional laboratory parameters to increase sensitivity and reduce the number of false positive results, i.e. increase specificity.

METHOD FOR PREDICTING THE DEGREE OF CANCER OF PROSTATE CANCER

Table 1 Evaluation of the effectiveness of the proposed method in comparison with the data of morphological studies. Ordinal Score Concent Concent Amount Result number on a scale traction traction concent tat Glisson matrilysin, sFas, walkie-talkies forecast ng / ml ng / ml one four 5D 2.7 7.8 polo w 2 3 4.7 1.9 6.6 polo w 3 7 8.9 3.6 12.5 polo w four four 4.9 2.1 7.0 False floor 5 7 9.1 3.4 12.5 polo w 6 6 9.2 2,8 12.0 polo w 7 6 7.9 3,7 11.6 polo w 8 8 9.8 4.4 14.2 polo w 9 7 8.7 5.1 12.8 polo w 10 7 11.1 1,6 12.7 polo w eleven 6 8.1 2,3 10,4 polo w 12 6 7.8 3,5 11.3 polo w 13 7 9.2 3.3 12.5 polo w fourteen 5 5,0 2.6 7.6 polo w fifteen four 4.2 1.7 5.9 Falsely neg 16 5 8.1 3,7 11.8 polo w 17 7 10.6 3,5 14.1 polo w eighteen 8 10.3 2.7 13.0 polo w 19 5 5,4 2.1 7.5 polo w twenty 3 3.2 1,6 4.8 Falsely neg 21 6 9.2 1,5 10.7 polo w 22 6 7.6 3.2 10.8 polo w 23 8 15.8 3.6 19,4 polo w 24 four 3.2 2.7 5.9 Falsely neg

25 7 2.1 3.4 5.5 Falsely neg 26 7 10.3 3.4 13.7 polo w 27 6 7.8 2,4 10,2 polo w 28 6 5,6 3.9 9.5 polo w 29th 7 9.6 3,1 12.7 polo w thirty 5 11.6 2.0 13.6 False floor 31 6 7.6 3.2 10.8 polo w 32 7 8.4 3,7 12.1 polo w 33 four 9.3 3.4 12.7 False floor 34 6 7.1 1.4 8.5 polo w 35 8 8.6 3,7 12.3 polo w 36 7 9.1 3,1 12,2 polo w 37 7 7.7 3,7 11,4 Falsely neg 38 7 7.5 4.8 12.3 polo w 39 four 5,6 1.7 7.3 polo w 40 6 6.8 2,5 9.3 polo w 41 5 7.9 4.3 12,2 False floor 42 8 9.6 4.7 14.3 polo w 43 7 8.1 3,7 11.8 Falsely neg 44 7 9.5 4.7 14.2 polo w 45 four 5.3 2,8 8.1 polo w

Claims (1)

A method for predicting the degree of malignancy of prostate cancer by biochemical examination of blood serum, characterized in that the level of matrilysin and soluble Fas antigen (sFas) is determined in the blood serum and a non-cancerous process is judged by the sum of their concentrations up to 7.0 ng / ml, by the sum concentrations from 7.0 to 12.0 ng / ml are judged to be a moderate degree of malignancy and the sum of concentrations above 12.0 ng / ml is judged to be a high degree of malignancy.