TY - JOUR
T1 - Transcriptomic heterogeneity of androgen receptor activity defines a de novo low AR-active subclass in treatment Naïve primary prostate cancer
AU - Spratt, Daniel E.
AU - Alshalalfa, Mohammed
AU - Fishbane, Nick
AU - Weiner, Adam B.
AU - Mehra, Rohit
AU - Mahal, Brandon A.
AU - Lehrer, Jonathan
AU - Liu, Yang
AU - Zhao, Shuang G.
AU - Speers, Corey
AU - Morgan, Todd M.
AU - Dicker, Adam P.
AU - Freedland, Stephen J.
AU - Jeffery Karnes, R.
AU - Weinmann, Sheila
AU - Davicioni, Elai
AU - Ross, Ashley E.
AU - Den, Robert B.
AU - Nguyen, Paul L.
AU - Feng, Felix Y.
AU - Lotan, Tamara L.
AU - Chinnaiyan, Arul M.
AU - Schaeffer, Edward M.
N1 - Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/11/15
Y1 - 2019/11/15
N2 - Purpose: The heterogeneity of androgen receptor (AR)activity (AR-A) is well-characterized in heavily treated metastatic castration-resistant prostate cancer (mCRPC). However, the diversity and clinical implications of AR-A in treatment-naïve primary prostate cancer is largely unknown. We sought to characterize AR-A in localized prostate cancer and understand its molecular and clinical implications. Experimental Design: Genome-wide expression profiles from prostatectomy or biopsy samples from 19,470 patients were used, all with independent pathology review. This was comprised of prospective discovery (n ¼ 5,239) and validation (n ¼ 12,728) cohorts, six retrospective institutional cohorts with long-term clinical outcomes data (n ¼ 1,170), and The Cancer Genome Atlas (n ¼ 333). Results: A low AR-active subclass was identified, which comprised 9%-11% of each cohort, and was characterized by increased immune signaling, neuroendocrine expression, and decreased DNA repair. These tumors were predominantly ERG and basal subtype. Low AR-active tumors had significantly more rapid development of recurrence or metastatic disease across cohorts, which was maintained on multivariable analysis [HR, 2.61; 95% confidence interval (CI), 1.22-5.60; P ¼ 0.014]. Low AR-active tumors were predicted to be more sensitive to PARP inhibition, platinum chemotherapy, and radiotherapy, and less sensitive to docetaxel and androgen-deprivation therapy. This was validated clinically, in that low AR-active tumors were less sensitive to androgen-deprivation therapy (OR, 0.41; 95% CI, 0.21-0.80; P ¼ 0.008). Conclusions: Leveraging large-scale transcriptomic data allowed the identification of an aggressive subtype of treatment-naïve primary prostate cancer that harbors molecular features more analogous to mCRPC. This suggests that a preexisting subgroup of patients may have tumors that are predisposed to fail multiple current standard-of-care therapies and warrant dedicated therapeutic investigation.
AB - Purpose: The heterogeneity of androgen receptor (AR)activity (AR-A) is well-characterized in heavily treated metastatic castration-resistant prostate cancer (mCRPC). However, the diversity and clinical implications of AR-A in treatment-naïve primary prostate cancer is largely unknown. We sought to characterize AR-A in localized prostate cancer and understand its molecular and clinical implications. Experimental Design: Genome-wide expression profiles from prostatectomy or biopsy samples from 19,470 patients were used, all with independent pathology review. This was comprised of prospective discovery (n ¼ 5,239) and validation (n ¼ 12,728) cohorts, six retrospective institutional cohorts with long-term clinical outcomes data (n ¼ 1,170), and The Cancer Genome Atlas (n ¼ 333). Results: A low AR-active subclass was identified, which comprised 9%-11% of each cohort, and was characterized by increased immune signaling, neuroendocrine expression, and decreased DNA repair. These tumors were predominantly ERG and basal subtype. Low AR-active tumors had significantly more rapid development of recurrence or metastatic disease across cohorts, which was maintained on multivariable analysis [HR, 2.61; 95% confidence interval (CI), 1.22-5.60; P ¼ 0.014]. Low AR-active tumors were predicted to be more sensitive to PARP inhibition, platinum chemotherapy, and radiotherapy, and less sensitive to docetaxel and androgen-deprivation therapy. This was validated clinically, in that low AR-active tumors were less sensitive to androgen-deprivation therapy (OR, 0.41; 95% CI, 0.21-0.80; P ¼ 0.008). Conclusions: Leveraging large-scale transcriptomic data allowed the identification of an aggressive subtype of treatment-naïve primary prostate cancer that harbors molecular features more analogous to mCRPC. This suggests that a preexisting subgroup of patients may have tumors that are predisposed to fail multiple current standard-of-care therapies and warrant dedicated therapeutic investigation.
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U2 - 10.1158/1078-0432.CCR-19-1587
DO - 10.1158/1078-0432.CCR-19-1587
M3 - Article
C2 - 31515456
AN - SCOPUS:85074339563
SN - 1078-0432
VL - 25
SP - 6721
EP - 6730
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 22
ER -