Athanasios C. Tsiatis

A Biopsy-based 17-gene Genomic Prostate Score Predicts Recurrence After Radical Prostatectomy and Adverse Surgical Pathology in a Racially Diverse Population of Men with Clinically Low- and Intermediate-risk Prostate Cancer

BACKGROUND Biomarkers that are validated in independent cohorts are needed to improve risk assessment for prostate cancer (PCa). OBJECTIVE A racially diverse cohort of men (20% African American [AA]) was used to evaluate the association of the clinically validated 17-gene Genomic Prostate Score (GPS) with recurrence after radical prostatectomy and adverse pathology (AP) at surgery. DESIGN, SETTING, AND PARTICIPANTS Biopsies from 431 men treated for National Comprehensive Cancer Network (NCCN) very low-, low-, or intermediate-risk PCa between 1990 and 2011 at two US military medical centers were tested to validate the association between GPS and biochemical recurrence (BCR) and to confirm the association with AP. Metastatic recurrence (MR) was also evaluated. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Cox proportional hazards models were used for BCR and MR, and logistic regression was used for AP. Central pathology review was performed by one uropathologist. AP was defined as primary Gleason pattern 4 or any pattern 5 and/or pT3 disease. RESULTS AND LIMITATIONS GPS results (scale: 0-100) were obtained in 402 cases (93%); 62 men (15%) experienced BCR, 5 developed metastases, and 163 had AP. Median follow-up was 5.2 yr. GPS predicted time to BCR in univariable analysis (hazard ratio per 20 GPS units [HR/20 units]: 2.9; p<0.001) and after adjusting for NCCN risk group (HR/20 units: 2.7; p<0.001). GPS also predicted time to metastases (HR/20 units: 3.8; p=0.032), although the event rate was low (n=5). GPS was strongly associated with AP (odds ratio per 20 GPS units: 3.3; p<0.001), adjusted for NCCN risk group. In AA and Caucasian men, the median GPS was 30.3 for both, the distributions of GPS results were similar, and GPS was similarly predictive of outcome. CONCLUSIONS The association of GPS with near- and long-term clinical end points establishes the assay as a strong independent measure of PCa aggressiveness. Tumor aggressiveness, as measured by GPS, and outcomes were similar in AA and Caucasian men in this equal-access health care system. PATIENT SUMMARY Predicting outcomes in men with newly diagnosed prostate cancer is challenging. This study demonstrates that a new molecular test, the Genomic Prostate Score, which can be performed on a patients original prostate needle biopsy, can predict the aggressiveness of the cancer and help men make decisions regarding the need for immediate treatment of their cancer.

A Biopsy-based 17-gene Genomic Prostate Score as a Predictor of Metastases and Prostate Cancer Death in Surgically Treated Men with Clinically Localized Disease

BACKGROUND A 17-gene biopsy-based reverse transcription polymerase chain reaction assay, which provides a Genomic Prostate Score (GPS-scale 0-100), has been validated as an independent predictor of adverse pathology and biochemical recurrence after radical prostatectomy (RP) in men with low- and intermediate-risk prostate cancer (PCa). OBJECTIVE To evaluate GPS as a predictor of PCa metastasis and PCa-specific death (PCD) in a large cohort of men with localized PCa and long-term follow-up. DESIGN, SETTING, AND PARTICIPANTS A retrospective study using a stratified cohort sampling design was performed in a cohort of men treated with RP within Kaiser Permanente Northern California. RNA from archival diagnostic biopsies was assayed to generate GPS results. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS We assessed the association between GPS and time to metastasis and PCD in prespecified uni- and multivariable statistical analyses, based on Cox proportional hazard models accounting for sampling weights. RESULTS AND LIMITATIONS The final study population consisted of 279 men with low-, intermediate-, and high-risk PCa between 1995 and 2010 (median follow-up 9.8 yr), and included 64 PCD and 79 metastases. Valid GPS results were obtained for 259 (93%). In univariable analysis, GPS was strongly associated with time to PCD, hazard ratio (HR)/20 GPS units=3.23 (95% confidence interval [CI] 1.84-5.65; p<0.001), and time to metastasis, HR/20 units=2.75 (95% CI 1.63-4.63; p<0.001). The association between GPS and both end points remained significant after adjusting for National Comprehensive Cancer Network, American Urological Association, and Cancer of the Prostate Risk Assessment (CAPRA) risks (p<0.001). No patient with low- or intermediate-risk disease and a GPS of<20 developed metastases or PCD (n=31). In receiver operating characteristic analysis of PCD at 10 yr, GPS improved the c-statistic from 0.78 (CAPRA alone) to 0.84 (GPS+CAPRA; p<0.001). A limitation of the study was that patients were treated during an era when definitive treatment was standard of care with little adoption of active surveillance. CONCLUSIONS GPS is a strong independent predictor of long-term outcomes in clinically localized PCa in men treated with RP and may improve risk stratification for men with newly diagnosed disease. PATIENT SUMMARY Many prostate cancers are slow growing and unlikely to spread or threaten a mans life, while others are more aggressive and require treatment. Increasingly, doctors are using new molecular tests, such as the17-gene Genomic Prostate Score (GPS), which can be performed at the time of initial diagnosis to help determine how aggressive a given patients cancer may be. In this study, performed in a large community-based healthcare network, GPS was shown to be a strong predictor as to whether a mans prostate cancer will spread and threaten his life after surgery, providing information that may help patients and their doctors decide on the best course of management of their disease.

MP20-05 A DIAGNOSTIC BIOPSY-BASED GENOMIC PROSTATE SCORE AS AN INDEPENDENT PREDICTOR OF PROSTATE CANCER DEATH AND METASTASIS IN MEN WITH LOCALIZED PROSTATE CANCER

prostatectomy (RP), brachytherapy (BT), external beam radiation (EBRT) or no local treatment (NLT). METHODS: Using the Surveillance Epidemiology and End results (SEER)-database, we identified 242 531 patients diagnosed with nonmetastatic PCa between 2004 and 2009. Patients were grouped according to local treatment type (RP, BT, EBRT) or NLT. Biopsy and/or pathological Gleason score was categorized either in 6, 7 and 8-10 or according to the newgrading system intoGGG I ( 6), II (3+4), III (4+3), IV (8) and V (9-10). Primary endpoint was prostate cancer specific mortality (PCSM). Univariable Kaplan-Meier plots graphically depict PCSM-free survival (PCSM-FS) according to the different GGG. Multivariable Cox regression analyses adjusted for age, clinical/pathological tumor stage and lymph node status were used to compare the different GGG in each treatment cohort. The discriminant ability was assessed using the area under the Receiver Operating Characteristics (ROC) curve. RESULTS: Median follow-up was 76 months (IQR: 59 94). For all local treatment types and NLT, PCSM-FS rates differed significantly between the five strata of the 2014 ISUP GGG. All five GGG strata independently predicted PCSM. Relative to GGG II, GGG III exhibited a 1.5to 2-fold higher PCSM rate. Similarly, across all local treatment types and NLT, GGG V patients exhibited a 2-fold higher PCSM rate than GGG IV patients. The multivariable discriminant ability of the 2014 ISUP GGG was between 0.4% to 1.1% better than the old Gleason stratification. CONCLUSIONS: This large population-based cohort validates the ability of the new GGG to predict PCSM. The new GGG offers a modesty more accurate ability to predict PCSM-FS across all different local treatment types and NLT.

Association of PSA and number of cores positive with likelihood of adverse pathology at radical prostatectomy based on a 17-gene expression assay.

e16570Background: The overtreatment of prostate cancer and underutilization of active surveillance in men with Gleason 6 (GS6) cancer stems from uncertainty with current risk instruments such as vo...