Neoadjuvant Docetaxel before Radical Prostatectomy in Patients with High-Risk Localized Prostate Cancer

Abstract

Purpose: To determine the clinical, pathologic, and molecular effects of neoadjuvant docetaxel chemotherapy in high-risk localized prostate cancer. Experimental Design: Patients with biopsy Gleason scores of 8 to 10, serum prostate-specific antigen levels >20 ng/mL, and/or clinical stageT 3 disease received weekly docetaxel (36 mg/m 2 ) for 6 months, followed by radical prostatectomy, and were monitored with weekly visits, serum prostate-specific antigen measurements, and endorectal magnetic resonance imaging (MRI). Frozen tumor specimens were collected for microarray analysis. Results:The19 patients enrolled received 82% of the planned chemotherapy.Toxicity was mild to moderate; fatigue and taste disturbance were common. Prostate-specific antigen declines of >50% were seen in 11 of 19 patients (58%; 95% confidence interval, 33-80%) and endorectal MRI showed maximum tumor volume reduction of at least 25% in 13 of 19 patients (68%; 95% confidence interval, 47-85%) and at least 50% in 4 patients (21%; 95% confidence interval, 6-46 %). Sixteen patients completed chemotherapy and had radical prostatectomy; none achieved pathologic complete response. Microarray analysis identified coordinate up-regulation of genes involved in androgen metabolism associated with docetaxel therapy. Specifically, RNA expression for genes that decrease cellular levels of bioactive androgens was coordinately increased in response to chemotherapy. Conclusions: Neoadjuvant docetaxel administered for 6 months before radical prostatectomy is feasible, well tolerated, and often results in prostate-specific antigen declines of >50% and decreased tumor volume on endorectal MRI. No pathologic complete responses were observed. Altered androgen metabolism may partially account for the noted declines in prostate-specific antigen and be a mechanism for chemotherapy resistance.

Androgen receptor mediates the expression of UDP‐glucuronosyltransferase 2 B15 and B17 genes

“…The lack of androgen regulated PSA expression in LNCaP-abl cells is also suggestive of an altered co-regulator status or altered chromatin structures, given that both the AR and upstream AR binding sites are present in this cell line. In sum, our finding of AR being a necessary component for UGT2B15 and B17 gene expression explains the altered expression of UGT2B15 and B17 genes observed in conjunction with changes of AR or AR related function as reported [10,11,[19][20][21][22]29,30]. The increased expression of UGT2B15 and B17, presumably facilitating androgen catabolism, in CRPC is apparently paradoxical to the relatively high levels of testosterone observed in androgen-independent prostate biopsy samples [6,31,32].…”

Epithelial-to-Mesenchymal Transition Mediates Docetaxel Resistance and High Risk of Relapse in Prostate Cancer

“…Other studies have used a similar approach in patients treated with neoadjuvant chemotherapy alone (32,33). One group performed microarray analysis of tumor specimens from 31 patients treated with docetaxel plus mitoxantrone (33).…”

The relationship of body mass index and serum testosterone with disease outcomes in men with castration-resistant metastatic prostate cancer

“…[13][14][15][16] Docetaxel clearance may be increased in obese men, and may vary according to testosterone levels, thus potentially leading to heterogeneity in dose intensity and undertreatment. 17,18 There is evidence that prostate cancer may remain androgen-receptor-dependent even in the castration-resistant state, [19][20][21][22] but it remains unclear if obesity and/or testosterone levels in men with CRPC have prognostic significance. We therefore sought to investigate the prognostic significance of baseline BMI and serum testosterone levels in predicting outcomes for men with CRCP recruited to the international multicenter TAX327 study.…”