Personalized Utilization Of P2PSA And PHI In Clinical Practice

Background:Prostate cancer(PCa)has become one of the most common malignancies in men worldwide,especially in developed regions such as Oceania,Europe,and North America.The incidence of PCa in China is lower than the world average;however,it has been increasing rapidly in recent years,especially in the economically developed east-coastal areas where aging population,high caloric eating habits,environment changes and the application of tumor screening technologies have changed the risk and detection rate of the disease.Among them,the traditional tumor marker prostate-specific antigen(PSA)has played a vital role.Prostate biopsy is performed on patients with abnormally elevated PSA levels.Through this approach,a large number of PCa patients who are difficult to find or even asymptomatic can be diagnosed at early stage.However,the specificity of PSA in diagnosing PCa is very low,leading to the occurrence of "unnecessary biopsy" in clinical practice.Unnecessary biopsies will not only increase a physical and psychological burden to patients,but also cause a waste of national medical resources.A new tumor marker for PCa,as known as pro-peptide 2 PSA(p2PSA)and its derivative index prostate health index(PHI),has been introduced and shown to be a better predictor than PSA for both PCa and clinically significant PCa.Using PHI as a supplementary tool on PSA may also reduce the number of unnecessary biopsies.However,due to the heterogeneity of each individual,genetic variants may also affect the level of p2 PSA and PHI which may change their diagnostic efficiency.The use of p2 PSA or PHI alone still has limitations in clinical decision-making.In addition,as potential screening markers for this high-incidence tumor,the application of p2 PSA and PHI in the Chinese population also requires health-economics evaluation to provide a multi-dimensional basis for the rational allocation of national medical resources.This topic will explore the following three aspects:(1)Explore whether prostate volume(PV)can improve the predictive ability of p2 PSA and PHI for prostate biopsy;(2)Explore the influence of known PSA-related genetic variants(single nucleotide polymorphisms in related genes)on the predictive performance of p2 PSA and PHI;(3)To evaluate the health economic evaluation(cost-effectiveness analysis)of PHI in the Chinese population.By combining clinical variables,genetic information and health economics indicators,we hope to improve the clinical application of p2 PSA and PHI.Methods and Results:We conducted a prospective,observational study in an established multi-center prostate biopsy cohort.All the patients underwent transrectal ultrasound-guided prostate biopsies.Blood samples were collected for genotyping and the measurement of t PSA,f PSA,and p2 PSA prior to biopsies on the same day in a central certified lab per the study protocol.All biopsy specimens were examined in the Department of Pathology at each hospital.Tumor grade was classified by the Gleason score.In the Part I,two independent biopsy cohorts were enrolled.Cohort 1 included 595 patients from three medical centers from 2012 to 2013,and Cohort 2 included 1025 patients from four medical centers from 2013 to 2014.Area under the receiver operating characteristic curves(AUC)and logistic regression models were used to evaluate the predictive performance of PV-based derivatives and models.Linear regression analysis showed that p2 PSA was significantly correlated with PV in the merged cohort,while no significant association was observed between PHI and PV.When combining PHI with PV,PHI density(PHID)did not outperform PHI for predicting PCa or high-grade PCa in either Cohort 1 or Cohort 2.Logistic regression analysis also showed that PHI and PV were independent predictors for both PCa and high-grade PCa(all P < 0.05);however,PV did not provide additional predictive value to PHI when combining these derivatives in logistic regression models(all models vs PHI were not statistically significant,all P >0.05).In the Part II,we conducted an observational prospective study with 2,268 consecutive patients in three tertiary medical centers from August 2013 to March 2019.Genotyping data of the 46 candidate genes with a ±100-kb window was tested for association with p2 PSA and PHI levels using linear regression.Multivariable logistic regression models were performed and internally validated using repeated 10-fold cross validation.We further calculated adjusted PHI cutoff values based on the significant genotypes.Discriminative performance was assessed using decision curve analysis and net reclassification improvement(NRI)index.We detected 11 significant variants at 19q13.33 which were p2PSA-associated independent of PCa.The most significant SNP,rs198978 in KLK2(Pcombined = 5.73×10-9),was also associated with PHI values(Pcombined = 3.20×10-6).Compared to the two commonly used PHI cutoffs of 27 and 36,the adjusted PHI cutoffs had a significant NRI for PCa ranged from 5.23% to 9.70% among men carrying variant types(all P < 0.01).In the Part III,3,348 men with elevated t PSA underwent initial prostate biopsy from August 2013 to May 2019 were enrolled.We constructed a decision model to evaluate the incremental cost-effectiveness ratios of different PHI cutoffs.Total costs and reimbursement payments were based on the fee schedule of Shanghai Basic Medical Insurance and converted into United States dollars($).Two willingness-to-pay thresholds were estimated as one or three times the average gross domestic product per capita of China($7,760 or $23,279,respectively).The total costs of prostate biopsy and PSA tests were estimated at $315 and $19,respectively.The cost of PHI test varied between $72 to$130 in different medical centers.Under different PHI cutoffs(from 23 to 35),PHI test predicted reductions of 420(21.7%)to 972(50.2%)in unnecessary biopsies,with a total gain of 23.8–57.6 quality adjusted life-years compared to PSA tests.All the cutoffs would be cost-effective for patients with t PSA levels of 2–10 ng/ml.Applying 27 as the cutoff was cost-effective for each t PSA range,with missing positive cases ranging from 11(3.4%)to 33(11.5%).Conclusions:In conclusion,based on the multicenter prostate biopsy cohort,we found:(1)PV-based derivatives and models incorporating PV did not improve the predictive abilities of PHI for either PCa or clinically significant PCa;(2)rs198978,is independently associated with p2 PSA values,and can improve diagnostic ability of PHI for PCa using personalized cutoff values;(3)using PHI test was cost-effective in the decision-making process for initial prostate biopsy and the PHI cutoff of 27 was cost-effective regardless of t PSA ranges and should be recommended from a health-economic perspective.