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Aggressive variant prostate cancer (AVPC) molecular signature in castration-sensitive, de novo metastatic prostate cancer (M1PCa)

Background: AVPC are a subset of prostate cancers (PC) that share clinical features with the small-cell prostate carcinomas, a rare morphological variant with atypical and virulent behavior. They are estimated to represent 30% of lethal PC and are characterized by a molecular signature of combined defects (≥2) in Tp53, RB1 and PTEN (AVPC_MS). The AVPC_MS is associated with androgen indifference in preclinical models and predicts for benefit from the addition of carboplatin to cabazitaxel in men with castration resistant prostate cancer (CRPC). The prevalence and significance of the AVPC_MS in castration sensitive M1PC is unknown. 

Methods: In a Phase II trial 119 men with M1PC treated with 6 months of standard systemic therapy (SST) were randomized to the addition of local therapy. PCa samples obtained at diagnosis and after 6 months of SST were stained for markers including Tp53, RB1 and PTEN, and subject to whole genome sequencing. Tp53 was considered defective if expressed in ≥ 10% of tumor cells, and RB1 and PTEN if in ≤ 10%. Progression free survival (PFS) was estimated from SST start. 

Results: To date specimens from 38 men have been evaluated. Immunohistochemistry (IHC) results are shown below. The median PFS of men with AVPC_MSPOSITIVE vs AVPC_MSNEGATIVEbaseline prostate tumors was 9.3 vs 15 months (HR 1.09, 95%CI 0.42-2.87, P=0.852). 

Conclusions: The rate at which the AVPC molecular signature is detected in castration sensitive M1PCa appears similar to that in CRPC. This may have therapeutic implications. Updated molecular and outcome data will be presented upon acceptance.

Ana Aparicio, Miao Zhang, Naveen Ramesh, Xuemei Wang, Paul Gettys Corn, Amado J. Zurita, John W. Davis, Curtis Alvin Pettaway, Mehrad Adibi, Sean Eric Mcguire, Shi-Ming Tu, Jennifer Wang, Sumit Kumar Subudhi, Mohamed A Elsheshtawi, Eleni Efstathiou, Christopher Logothetis, Nicholas Navin, Patricia Troncoso, Brian Francis Chapin
The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; University of Texas MD Anderson Cancer Center, Houston, TX; UT MD Anderson Cancer Center, Houston, TX; The University of Texas, MD Anderson Cancer Center, Houston, TX; Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX

DOI: 10.1200/JCO.2019.37.15_suppl.5052 Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019) 5052-5052. Published online May 26, 2019.