Serum Sex Steroids Depict a Nonlinear U-Shaped Association with High-Risk Prostate Cancer at Radical Prostatectomy

Salonia, Andrea; Abdollah, Firas; Capitanio, Umberto; Suardi, Nazareno; Briganti, Alberto; Gallina, Andrea; Colombo, Renzo; Ferrari, Matteo; Castagna, Giulia; Rigatti, Patrìzio; Montorsi, Francesco

doi:10.1158/1078-0432.ccr-11-2799

Cited by 61 publications

(37 citation statements)

References 51 publications

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“…Moreover, our study prospects the potential for further clinical research for investigating critical events in the natural history of PCa where preoperative serum TT has to be considered because of the hormone dependence of the disease. Our investigation showed that higher mean serum levels of TT were closely associated with high-risk PCa (pGS ≥ 8.0, table 2), thus confirming recent findings demonstrating that high-risk PCa is associated with both the highest and lowest circulating levels of TT [32]. …”

Section: Discussionsupporting

confidence: 90%

Serum Total Testosterone Is a Significant Preoperative Variable Independently Contributing to Separating the Prostate Cancer Population into Prostatectomy Gleason Score Groups

Porcaro

Petrozziello²,

Ghimenton³

et al. 2013

Urol Int

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Aim: To investigate the potential of preoperative serum total testosterone (TT) in contributing to the definition of separate prostatectomy Gleason score (pGS) groups of the prostate cancer (PCa) population. Materials and Methods: The data of 220 patients operated on for PCa were retrospectively reviewed. No patient had previously received 5α-reductase inhibitor, luteinizing hormone-releasing analogs or testosterone replacement treatment. The patient population was grouped according to the pGS as 6 = 3+3, 7 = 3+4, 7 = 4+3 and 8-10. Eight variables were simultaneously investigated in each group: prostate-specific antigen (PSA), TT, free testosterone, age, percentage of positive prostate biopsy cores (P+), biopsy Gleason score (bGS), overall cancer volume estimated as percentage of prostate volume (V+) and prostate weight (Wi). Univariate analysis of variance (ANOVA), multivariate analysis of variance (MANOVA) and multivariate discriminant analysis (MDA) were the statistical methods used for evaluating the data. Results: There were 89 patients in pGS 6 = 3+3, 84 in pGS 7 = 3+4, 24 in pGS 7 = 4+3 and 23 in pGS 8-10. ANOVA showed that bGS (p < 0.0001), P+ (p < 0.0001), V+ (p < 0.0001), PSA (p = 0.0001), Wi (p = 0.0002) and TT (p = 0.01) were significantly different in the four pGS groups. MANOVA tests showed that only bGS (p < 0.0001), V+ (p = 0.0003), TT (p = 0.001) and, to a lesser extent, PSA (p = 0.06) were the significant variables that individually and independently contributed a significant amount to separation of the four pGS groups of the PCa population. MDA showed that the independent variables ranked as bGS (p < 0.0001), TT (p = 0.001), V+ (p = 0.001) and PSA (p = 0.06). Conclusions: Serum TT is a significant preoperative variable that independently contributes to separating the PCa population into pGS score groups. Pretreatment baseline serum TT levels should be measured and their inclusion in neural networks predicting PCa natural history be considered in the patient population diagnosed with PCa.

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Section: Discussionsupporting

confidence: 90%

Serum Total Testosterone Is a Significant Preoperative Variable Independently Contributing to Separating the Prostate Cancer Population into Prostatectomy Gleason Score Groups

Porcaro

Petrozziello²,

Ghimenton³

et al. 2013

Urol Int

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“…Focal PSMs also associated with higher median levels of TT as well as with higher rates of high-grade cancer (34%) when compared to controls (19%). The model of our study supports the U-shaped curve theory of the risk between TT and aggressive PCA [30] as well as basic science and controlled trial findings of TT biology in PCA microenvironment [31,34]. In this prospective, our study has important implications for clinical and basic science research of PCA biology.…”

Section: Discussionsupporting

confidence: 83%

“…Preoperative TT levels are closely related to aggressive cancers, which show features including high-grade diseases, extraprostatic extension, and PSMs [3,4,[17][18][19][20][21][22][23][24][25][26][27]. Preoperative TT has shown to be an independent predictor of high-risk PCA; moreover, there is evidence that both the lowest and the highest TT levels are involved because they show a U-shaped association with aggressive PCA [30]. The positive association between TT and aggressive tumor biology has also been proven by a randomized trial, which showed that neoadjuvant androgen blockade significantly reduced the risk of PSMs by inducing apoptosis in cancer cells with consequent tumor shrinkage [31].…”

Section: Discussionmentioning

confidence: 99%

Positive Association between Preoperative Total Testosterone Levels and Risk of Positive Surgical Margins by Prostate Cancer: Results in 476 Consecutive Patients Treated Only by Radical Prostatectomy

et al. 2018

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Objective: To evaluate preoperative total testosterone (TT) as a predictor of positive surgical margins (PSM) in prostate cancer (PCA). Patients and methods: During the period from November 2014 to July 2017, preoperative TT was measured in 476 PCA patients undergoing only radical prostatectomy (RP) and including all risk classes. Surgical margins were stated negative, focal positive (single and less than 1 mL), and multifocal positive (more than 1). The risk of TT and clinical factors associated with the risk of PSM (focal or multifocal versus negative) was evaluated by the multinomial logistic regression model. Results: Overall, PSM were detected in 149 cases (31.3%), which included 99 patients with focal cancer invasion (20.8%) and 50 subjects with multifocal cancer invasion (10.5%). In univariate analysis, PSM associated with higher median levels of TT and prostate-specific antigen than controls. Multifocal PSM associated with higher rates of high-risk PCA (42%) than focal (22.2%) or control cases (18.3%). In multivariate analysis, TT was the only independent factor positively associated with the risk of focal PSM when compared to controls (OR 1.002; p = 0.035). TT (OR 1.003; p = 0.002) and high-risk PCA (OR 1.002; p = 0.047) were independent factors, which positively associated with the risk of multifocal PSM when compared to controls. Risk models were computed. Conclusions: In a large and contemporary cohort of patients elected to primary RP, TT was an independent positive factor associated with the risk of focal and multifocal PSM. TT associated with aggressive PCA biology.

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“…The present investigation demonstrated that higher mean serum levels of TT were associated with and independently predicted high-grade pGS; moreover, it developed a predictive model which was the logic consequence of our preceding study showing that, along the pituitary-testis-prostate axis, the preoperative serum level of TT was a significant variable independently contributing to separating pGS groups of the patient population [33]. These results seem to contradict those studies showing that lower TT was associated with high-grade PCa [18,20,27]; however, a recent investigation demonstrated that high-risk PCa was significantly associated with both the lowest and the highest circulating serum levels of TT, depicting a nonlinear U-shaped risk relationship [34]. As a result, the present study showed that TT was an independent predictor of high-grade pGS because of high pretreatment levels of TT associated with high-risk PCa; moreover, it might explain why higher levels of FT, which depends on TT, were associated with an increased risk of aggressive PCa among older men [35] as well as high-grade PCa [36].…”

Section: Discussionmentioning

confidence: 97%

Associations of Pretreatment Serum Total Testosterone Measurements with Pathology-Detected Gleason Score Cancer

Porcaro

Petrozziello²,

Ghimenton³

et al. 2013

Urol Int

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Background and Objective: Prostate cancer is an endocrine-dependent tumor which is still under-investigated for physiopathology factors related to its natural history. The association of pretreatment total testosterone (TT) serum levels with prostate cancer is still a controversial topic. The objective of this study was to investigate potential associations and functional relationships of preoperative TT serum level and pathology-detected Gleason score (pGS). Materials and Methods: Pretreatment and pathological variables of 220 patients operated with radical prostatectomy were retrospectively reviewed. Age, prostate-specific antigen (PSA), percentage of positive biopsy cores (P+), biopsy Gleason score (bGS), pGS, TT and free testosterone were the continuous variables, while clinical stage (cT: cT1c, cT2/3), biopsy Gleason pattern (bGP: ≤3+3, 3+4, >3+4), pathology Gleason pattern (pGP: ≤3+3, 3+4, >3+4), pathology stage (pT: pT2, pT3a, pT3b), pathology nodal staging (pN: pN0, pN1, pNx) and surgical margin invasion by cancer (R-, R+) were the categorical variables. Statistical methods were computed for assessing associations of TT and pGS; moreover, simple and multiple linear regression analysis (SLRA and MLRA) were used for assessing functional relationships of TT and pGS. Results: High-grade tumors (pGS ≥8.0) were associated with bGS >6.0 (p < 0.0001), pGP ≥3+4 (p < 0.0001), P+ >0.31% (p = 0.006), cT2/3 (p = 0.01), TT >15.5 nmol/l (p = 0.0004) and, to a lesser extent, PSA >6.27 μg/l (p = 0.06). The odds ratio (OR) ranked as follows: 2.01 (PSA >6.27 μg/l), 2.88 (cT2/3), 3.23 (P+ >0.31%), 5.53 (TT >15.5 nmol/l) and 12.09 (pGP ≥3+4 and pGS ≥8.0). On SLRA, pGS variation was significantly predicted by bGS (p < 0.0001), P+ (p < 0.0001), PSA (p = 0.0005) and TT (p = 0.02); on MLRA, pGS variation was still significantly predicted by bGS (p < 0.0001), P+ (p = 0.04), PSA (p = 0.03) and TT (p = 0.002). When bGS, P+, PSA and TT were dichotomized to their median value, only bGS (p < 0.0001) and TT (p = 0.001) showed independence in predicting pGS variation. The best model for predicting pGS variations was by dichotomizing TT above its median (>15.5 nmol/l) because the predictive coefficient increased to 0.32, which means that patients with TT >15.5 have a significantly higher estimated risk for high-grade pGS than patients with TT ≤15.5 nmol/l (OR = 1.31). Conclusion: In a patient population undergoing radical prostatectomy, increased pretreatment serum measurements of TT are associated with and functionally related to high-grade pGS; moreover, baseline TT together with bGS and PSA are important factors for predicting pGS and assessing high-grade tumors. Baseline TT serum levels might have prognostic potential for assessing treatment response for continuous as well as intermittent androgen deprivation therapy.

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Serum Sex Steroids Depict a Nonlinear U-Shaped Association with High-Risk Prostate Cancer at Radical Prostatectomy

Cited by 61 publications

References 51 publications

Serum Total Testosterone Is a Significant Preoperative Variable Independently Contributing to Separating the Prostate Cancer Population into Prostatectomy Gleason Score Groups

Serum Total Testosterone Is a Significant Preoperative Variable Independently Contributing to Separating the Prostate Cancer Population into Prostatectomy Gleason Score Groups

Positive Association between Preoperative Total Testosterone Levels and Risk of Positive Surgical Margins by Prostate Cancer: Results in 476 Consecutive Patients Treated Only by Radical Prostatectomy

Associations of Pretreatment Serum Total Testosterone Measurements with Pathology-Detected Gleason Score Cancer

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