Free-PSA Ratio after Biochemical Recurrence

[pjoshea13]

New study below [1].

Some might recall the use of the free-PSA ratio to cut down on unnecessary biopsies. "The risk of cancer increases if the free to total ratio is less than 25%" [2].

Does the ratio have prognostic value after biochemical recurrence? Apparently it may.

"Posttreatment FPSAR>=0.10 is associated with more aggressive disease"

-Patrick

[1] pubmed.ncbi.nlm.nih.gov/329...

BJU Int

. 2020 Sep 14. doi: 10.1111/bju.15236. Online ahead of print.

Can postreatment free psa ratio be used to predict adverse outcomes in recurrent prostate cancer?

H Goldberg 1 2 , R Glicksman 3 , D Woon 1 , A Hoffman 1 , H Shaikh 1 , T Chandrasekar 4 , Z Klaassen 5 6 , C J D Wallis 1 , A E Ahmad 1 , N Salgado 3 , M Qu 3 , F Y Moraes 3 , E P Diamandis 7 , A Berlin 3 8 , N E Fleshner 1

Affiliations collapse

Affiliations

1 Division of Urology, Department of Surgical Oncology, Princess Margaret Cancer Centre, University Health Network and the University of Toronto, Toronto, Ontario, Canada.

2 Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA.

3 Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network and Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.

4 Department of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.

5 Division of Urology, Department of Surgery, Medical College of Georgia, Augusta University, Augusta, GA, USA.

6 Georgia Cancer Center, Augusta, GA, USA.

7 Department of Pathology and Laboratory Medicine, Sinai Health System, University of Toronto, Toronto, Ontario, Canada.

8 Techna Institute, University Health Network, Toronto, Ontario, Canada.

PMID: 32926761 DOI: 10.1111/bju.15236

Abstract

Objectives: To assess whether free PSA ratio (FPSAR) at biochemical recurrence (BCR) can predict metastasis, castrate-resistant PCa (CRPC), and cancer-specific survival (CSS), following therapy for localized disease.

Methods: A single-center retrospective cohort study (NCT03927287) including a discovery cohort composed of patients with an FPSAR after radical prostatectomy (RP) or radiotherapy (RT) between 2000-2017. For validation, an independent biobank cohort of patients with biochemical recurrence (BCR) after RP was tested. Using a defined FPSAR cutoff, the metastasis-free-survival (MFS), CRPC-free survival, and CSS were compared. Multivariable Cox models determined the association between posttreatment FPSAR, metastases, and CRPC.

Results: Overall, 822 patients (305 RP- and 363 RT-treated patients and 154 biobank patients) were analyzed. In the RP cohort, a total of 272/305 (89.1%) and 33/305 (10.9%) had an FPSAR test incidentally and reflexively, respectively. In the RT cohort, 155/363 (42.7%) and 208/263 (57.3%) had an FPSAR test incidentally and reflexively, respectively. However, in the prospective biobank RP cohort, FPSAR testing was done on all samples of patients diagnosed with BCR. An FPSAR cutoff of 0.10 was determined using receiver-operating characteristic-analyses in both RP and RT cohorts. FPSAR<0.10 resulted in longer median MFS (14.8 vs. 9.3 years, and 14.8 vs. 13 years, respectively), and longer median CRPC-free survival (median not reached vs. 9.9 years, and 20.7 vs. 13.8 years, respectively). Multivariable analyses showed that FPSAR>=0.10 was associated with increased metastasis in the RP cohort (HR 1.915 [95% CI 1.241-2.955], and RT cohort (HR 1.754 [95% CI 1.112-2.769]), and increased CRPC in the RP cohort (HR 2.470 [95% CI 1.493-4.088]). Findings were validated in the biobank cohort.

Conclusions: Posttreatment FPSAR>=0.10 is associated with more aggressive disease, suggesting a potentially novel role for this biomarker.

Keywords: Cancer-Specific Mortality; Castrate-resistant Prostate Cancer; Free PSA Ratio; Metastases; Prostate Cancer.

This article is protected by copyright. All rights reserved.

***

[2] en.wikipedia.org/wiki/Prost...

[Hidden]

Very interesting!

Thanks for posting.

PS. Some numerical evaluation:

Free PSA test has a sensitivity comparable to total PSA.

For example, this assay gets minimal calibration at about 4pg/mL = 0.004ng/mL.

abcam.com/ps/products/188/a...

Whether such low counts are reportable or not, I don't know, but I will assume they are for the sake of the following analysis. Cutoff value is 0.1 (10%) consequently, theoretically meaningful ratios (PSAR) start at 0.004/0.09=0.044 (0.05) total PSA for the good prognosis group and can go down to 0.004/0.11= 0.036 (0.04) for the poor prognosis one. Introducing a practical common 20% lab error, we get some more sound numbers:

(1+20%)/(1-20%)=1.5x0.044=0.066 (or 0.07 as a 2 digits conservative rounded value) for the former and (1-20%)/(1+20%)=0.66x0.036=0.024 (or 0.03 as above) for the latter.

Conclusion: Bellow 0.03 tPSA a PSAR ratio is not a good marker for either prognosis. Over 0.07 tPSA a less than 10% PSAR, according to the mentioned article, promises some good prognosis. The in between values of 0.04, 0.05 and 0.06 compose the gray area between the two.

This is not medicine, it is pure mathematics.

[timotur]

Interesting, but odd that this study indicates the opposite of a pre-biopsy fPSA where a lower ratio is bad, i.e. a cutoff of <0.25 is indicative of disease. fPSA measure unbound PSA-- a tumor binds the fPSA dropping the level below the cutoffs. Mine was only 2.7% pre-biopsy. Why then after a recurrence would a higher fPSA, i.e. more unbound PSA, indicate a more aggressive tumor? Assuming most of these patients had the prostate removed or irradiated, it is saying recurrent PCa does not bind PSA, and a higher fPSA ratio is bad.

[pjoshea13 in reply to timotur]

A 2012 Italian paper: "A pilot study evaluating serum pro-prostate-specific antigen in patients with rising PSA following radical prostatectomy" [1] had this to say about the free-PSA ratio [%fPSA]:

"A noteworthy finding of our study was that fPSA and %fPSA were significantly higher in metastatic vs. non-metastatic patients. fPSA is a circulating catalytically inactive form of PSA (18). In patients with increased PSA due to benign prostate disease, a high %fPSA is associated with a significant reduction in false positive results and allows a reduction in unnecessary bioptic procedures (19). Conversely, a low %fPSA predicts a positive finding at prostate biopsy across a wide range of increasing PSA values (20-23). Although fPSA and %fPSA have been extensively studied in the setting of prostate cancer screening, their value in the metastatic setting has rarely been considered. A single study, published in 1998, failed to reveal a clear %fPSA pattern in 52 males who had undergone radical prostatectomy and who subsequently developed biochemical recurrence (24). In contrast to that study, our series included 31 patients with diagnostic imaging-proven metastatic prostate cancer. We believe that the biological significance of our findings in prostatectomized patients developing a high burden of metastatic disease should be further investigated."

***

I had the same reaction as you to the new Canadian paper & wondered if I had been thinking incorrectly about free-PSA being protective. Before diagnosis, a %fPSA >=25% is considered to be good. But that's because it largely defines BPH. So, with decreasing %fPSA we have a decreasing BPH component. The 'noise' of BPH confuses our understanding of the role of free-PSA.

-Patrick

[1] ncbi.nlm.nih.gov/pmc/articl...

[Hidden in reply to pjoshea13]

As plausible as the above BHP vs Cancerous (Ca) fPSA explanation may sound, this can't be mathematically supported under constant fPSA ratio BHP and Ca coefficients. Noted reversal can only be objerved if the fPSA ratio coefficients are variable following the "maturity" of the producing cells. Let me hypothesize that young Ca cells produce minimal, say 0-5% fPSA and as time passes and they climb the agresiveness ladder, this percentage climbs along, say to 15% and beyond. For BHP, the same mechanism may apply, as usually at the time of diagnosis and lab testing BHP has already matured. Under such an assumption a reversal can be possible.

[pjoshea13 in reply to Hidden]

Sounds good. Thanks! -Patrick

[tango65]

Thanks for posting.