Review Editorial
014
Testosterone serum levels and prostate cancer prognosis: the double face of Janus “...the molecular alterations favoring a more indolent
disease course in the presence of higher serum testosterone levels in both in hormone-naive and castrate-resistant patients needs to be elucidated and is an exciting field for future research.”
oso
3
5
N.14.1
uture
& e
ure UK
Francesca Valcamonico1, Laura Ferrari1, Francesca Consoli1, Vito Amoroso1 & Alfredo Berruti*,1 Prostate cancer (PCa) is an androgendependent disease. Androgen action is mediated by the androgen receptor (AR), a hormone-activated transcription factor that plays a central role in the biology and progression of PCa [1] . AR amplification and mutations are the most important molecular alterations leading to the onset of castration-resistant PCa (CRPC). Testosterone is the natural growth factor for PCa. Administration of testosterone increases prostate growth in animal models and castration of patients results in regression of advanced PCa. However, from the literature data a direct relationship between circulating testosterone levels and PCa aggressiveness and prognosis is not evident in all circumstances and patient settings. It is actually clear that the long-held belief that high serum androgen concentrations increase the PCa risk can no longer be supported [2] . In untreated PCa patients multiple studies have reported that lower serum testosterone concentrations are associated with worrisome features such as high grade and higher stage
at presentation, positive surgical margins after prostatectomy and worse overall survival [3] . These studies suggest that PCas are stimulated to dedifferentiate in a testosterone-deficient environment, leading to more aggressive tumors. However, three studies demonstrated that serum testosterone levels measured in PCa patients after 6 months of luteinizing hormone releasing hormone analogue (LHRH-A) therapy were inversely correlated with the patient outcome [4–6] . Serum testosterone in these studies was measured with automatic techniques that are imprecise in assessing testosterone levels at low concentration ranges [4] . These concerns notwithstanding, all these studies concurrently demonstrated that considering only patients with serum testosterone within the castrate range, the attainment of serum testosterone levels as low as possible (i.e., below 20 ng/dl) was associated with a trend of better outcome. A recently published paper by Ryan et al. [7] provided further insights into the intriguing relationship between serum testosterone and PCa growth. These authors
Keywords
• castrate-resistant disease • prognosis • prostate cancer • testosterone serum levels
“...a direct relationship between circulating testosterone levels and prostate cancer aggressiveness and prognosis is not evident in all circumstances and patient settings.”
1 Department of Medical & Surgical Specialties, Radiological Sciences & Public Health, Medical Oncology, University of Brescia, Spedali Civili Hospital, Piazzale Spedali Civili 1, 25123 Brescia, Italy *Author for correspondence: Tel.: +39 030 399 5410;
[email protected]
10.2217/FON.14.1 © 2014 Future Medicine Ltd
Future Oncol. (2014) 10(7), 1113–1115
part of
ISSN 1479-6694
1113
Editorial Valcamonico, Ferrari, Consoli, Amoroso & Berruti
“...serum testosterone
during conventional androgen deprivation therapy has an opposite prognostic significance according to whether the measurement is performed when the patients are still responding to treatment or when they become castrate resistant.”
1114
showed that serum testosterone levels measured with mass spectrometry (an ultrasensitive technique that is the reference method for measuring serum testosterone at the castrate range) were prognostic in patients with CRPC recruited in the COU-AA-301 trial and these patients were subsequently randomized to receive abiraterone plus prednisone or prednisone alone. Longer survival was observed for patients with serum testosterone above median compared with below median. These results are consistent with previous data showing that higher androstenedione levels in patients with CRPC predicted better survival compared with patients with lower levels [8] . This scenario is therefore very similar to that observed in hormone-naive PCa; it seems that lower testosterone levels are poorly prognostic both in hormone-naive and CRPC. The only difference is that in the CRPC patients tumor growth occurs in a very low testosterone milieu and an ultrasensitive method of testosterone measurement is required to detect this phenomenon. These data suggest that the biological adaptation of PCa to castrate testosterone levels is very complex and testosterone may maintain a differentiating role also when the tumor progresses on androgen deprivation therapy. The mechanisms by which more elevated serum testosterone seems to select less-aggressive tumor clones in the castration-resistant state, however, are not clear. Upregulation of c-MET [9] and stimulation of the neuroendocrine differentiation [10] induced by greater testosterone inhibition may both be contributory. Putting together the pieces of the puzzle, it seems that serum testosterone during conventional androgen deprivation therapy has an opposite prognostic significance according to whether the measurement is performed when the patients are still responding to treatment or when they become castrate resistant. If this hypothesis is true, then CRPC patients with baseline testosterone levels above the median may be patients in whom previous endocrine therapy was less efficacious than in CRPC patients with testosterone levels below the median. We believe that this issue deserves to be explored and the patients enrolled in the abirat erone Phase III study are the best candidates for such analyses. Noteworthy, in the Ryan et al. study [7] serum testosterone in CRPC was not only prognostic but also predictive of abiraterone efficacy. A
Future Oncol. (2014) 10(7)
more pronounced treatment effect of abiraterone over prednisone, in fact, was observed in patients with lower androgens as opposed to their counterpart. As the authors pointed out, AR amplification may explain why, in the subset with low androgen levels, the survival of patients treated with abiraterone was better than those receiving prednisone. However, it is not clear why higher testosterone levels, although associated with a greater overall survival, seemed to be predictive of lower abiraterone efficacy over prednisone. The relationship of decline in androgen levels with PSA decline, which is an ongoing analysis, will provide further important elements to better understand this discrepancy. In addition, in our small personal experience [Berruti A et al., Unpublished Data] we have shown that testosterone measured with an ultrasensitive technique after abiraterone therapy is undectectable in many cases, but not in all cases, so it will be interesting to know whether detectable testosterone levels during abiraterone has a prognostic significance or not and whether there is a correlation with pretreatment testosterone levels. Notewothy, glucocorticoid receptors have been recently demonstrated to confer resistance to antiandrogen therapies [11] . Since the patients enrolled in the COU-AA-301 trial had previously received prednisone in association with docetaxel and continued receiving prednisone either in association with abiraterone or in the control arm, this may represent a confounder in the interpretation of the prognostic and predictive role of serum testosterone in this series. In conclusion, the role of serum testosterone in the modulation of PCa growth is complex and the molecular alterations favoring a more indolent disease course in the presence of higher serum testosterone levels in both in hormonenaive and castrate-resistant patients needs to be elucidated and is an exciting field for future research. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
future science group
Testosterone serum levels & prostate cancer prognosis: the double face of Janus References 1
2
Shafi AA, Yen AE, Weigel NL. Androgen receptors in hormone-dependent and castration-resistant prostate cancer. Pharmacol. Ther. 140, 223–238 (2013). Khera M, Crawford D, Morales A, Salonia A, Morgentaler A. A new era of testosterone and prostate cancer: from physiology to clinical implications. Eur. Urol. 65(1), 115–123 (2013).
3
Morgentaler A. Testosterone and prostate cancer: an historical perspective on a modern myth. Eur. Urol. 50, 935–939 (2006).
4
Bertaglia V, Tucci M, Fiori C et al. Effects of serum testosterone levels after 6 months of androgen deprivation therapy on the outcome of patients with prostate cancer. Clin. Genitourin. Cancer 20, 1–6 (2013).
future science group
5
6
7
8
Perachino M, Cavalli V, Bravi F. Testosterone levels in patients with metastatic prostate cancer treated with luteinizing hormonereleasing hormone therapy: prognostic significance? BJU Int. 105, 648–651 (2010). Morote J, Orsola A, Planas J et al. Redefining clinically significant castration levels in patients with prostate cancer receiving continuous androgen deprivation therapy. J. Urol. 178, 1290–1295 (2007). Ryan CJ, Molina A, Li J, Kheoh T et al. Serum androgens as prognostic biomarkers in castration-resistant prostate cancer: results from an analysis of a randomized Phase III trial. J. Clin. Oncol. 31, 2791–2798 (2013) Ryan CJ, Halabi S, Ou SS, Vogelzang NJ, Kantoff P, Small EJ. Adrenal androgen levels as predictors of outcome in prostate cancer patients treated with ketoconazole plus
Editorial
antiandrogen withdrawal: results from a cancer and leukemia group B study. Clin. Cancer Res. 13, 2030–2037 (2007). 9
Liu T, Mendes DE, Berkman CE. From AR to c-Met: androgen deprivation leads to a signaling pathway switch in prostate cancer cells. Int. J. Oncol. 43, 1125–1130 (2013).
10 Berruti A, Bollito E, Cracco CM et al. The
prognostic role of immunohistochemical chromogranin a expression in prostate cancer patients is significantly modified by androgen-deprivation therapy. Prostate 70, 718–726 (2010). 11 Arora VK, Schenkein E, Murali R et al.
Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell 155, 1309–1322 (2013).
www.futuremedicine.com
1115
