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Molecular Characterization and Clinical Outcomes of Primary Gleason Pattern 5 Prostate Cancer After Radical Prostatectomy.

ABSTRACT: PURPOSE:Very high-risk prostate cancer (PC) is associated with poor response to local and systemic treatments; however, few cases have been molecularly profiled. We studied clinical outcomes and molecular profiles of patients with clinically localized primary Gleason pattern 5 PC. PATIENTS AND METHODS:Clinicopathologic features, targeted somatic and germline sequencing, and PTEN, TP53, and ERG status by immunohistochemistry were assessed in patients undergoing surgery from 2005 to 2015; 60 consecutive patients were identified with Gleason score 5 + 4 = 9 or 5 + 5 = 10 PC after radical prostatectomy with available tissue and clinical follow-up. Clinicopathologic and genomic parameters were correlated with biochemical relapse, metastasis-free survival, time to castration resistance, and overall survival using Cox proportional hazards models. RESULTS:Of patients with somatic sequencing data and clinical follow-up, 34% had DNA repair gene mutations, including 22% (11 of 49) with homologous recombination and 12% (six of 49) with mismatch repair gene alterations. Homologous recombination mutations were germline in 82% (nine of 11) of patients. In addition, 33% (16 of 49) had TP53 mutation, and 51% (29 of 57) had PTEN loss. Overall, 43% developed metastasis, with a time to castration resistance of 12 months. On multivariable analysis of clinicopathologic variables, only ductal/intraductal histology (hazard ratio, 4.43; 95% CI, 1.76 to 11.15; P = .002) and seminal vesicle invasion (hazard ratio, 5.14; 95% CI, 1.83 to 14.47; P = .002) were associated with metastasis. Among genomic alterations, only TP53 mutation and PTEN loss were associated with metastasis on univariable analysis, and neither remained significant in multivariable analyses. These data are retrospective and hypothesis generating. CONCLUSION:Potentially actionable homologous recombination and mismatch repair alterations are observed in a significant proportion of patients with very high-risk PC at the time of radical prostatectomy. These findings could inform the design of prospective trials in this patient population.

SUBMITTER: Velho PI

PROVIDER: S-EPMC6812513 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Molecular Characterization and Clinical Outcomes of Primary Gleason Pattern 5 Prostate Cancer After Radical Prostatectomy.

Velho Pedro Isaacsson PI Lim David D Wang Hao H Park Jong Chul JC Kaur Harsimar B HB Almutairi Fawaz F Carducci Michael A MA Denmeade Samuel R SR Markowski Mark C MC Isaacs William B WB Antonarakis Emmanuel S ES Pritchard Colin C CC Eisenberger Mario A MA Lotan Tamara L TL

JCO precision oncology 20190726

<h4>Purpose</h4>Very high-risk prostate cancer (PC) is associated with poor response to local and systemic treatments; however, few cases have been molecularly profiled. We studied clinical outcomes and molecular profiles of patients with clinically localized primary Gleason pattern 5 PC.<h4>Patients and methods</h4>Clinicopathologic features, targeted somatic and germline sequencing, and PTEN, TP53, and ERG status by immunohistochemistry were assessed in patients undergoing surgery from 2005 to ...[more]

PMID: 31650100

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Project description:BACKGROUND:While the new Gleason grade grouping (GGG), which started in 2016, has been widely validated in prostate cancer, it does not incorporate the concept of tertiary Gleason pattern 5. Furthermore, no study has "quantified" the individual risk of each Gleason pattern, including tertiary Gleason pattern 5, after radical prostatectomy. METHODS:We reviewed 1022 men with adjuvant-treatment-naïve prostate cancer who underwent radical prostatectomy between 2005 and 2017. The primary endpoint was biochemical recurrence-free survival, defined as two consecutive prostate-specific antigen measurements ?0.2?ng/ml after surgery. The individual quantitative risk score (IQRS) of each amount (primary/secondary/tertiary) of each Gleason pattern (3/4/5) was calculated using the Cox regression model. On the basis of the IQRS, the modified Gleason grade grouping (mGGG) model was developed. As a robustness analysis of the mGGG model, salvage treatment-free survival was also assessed. RESULTS:During a median follow-up of 45?months, 229 of 1022 (22.4%) patients developed biochemical recurrence. The IQRS of each Gleason pattern was as follows: primary 5, 1.81 points (hazard ratio [HR] 6.13); secondary 5, 1.37 points (HR 3.92); tertiary 5, 0.87 points (HR 2.39); primary 4, 1.07 points (HR 2.91); secondary 4, 0.79 points (HR 2.21); and any Gleason pattern 3, 0 points (HR 1). Based on the IQRS, the mGGG model was developed, which classified patients into the following five groups: I (3?+?3 or less); II (3?+?4); III (4?+?3); IV (3?+?4?+?t5, 4?+?3?+?t5, 3?+?5, 5?+?3, and 4?+?4); V (4?+?4?+?t5, 4?+?5, 5?+?4, and 5?+?5). The c-index for biochemical recurrence-free survival was significantly improved from 0.655 of the original GGG model to 0.672 of the mGGG model (P?<?0.05). In the robustness analysis, the c-index for salvage treatment-free survival was also significantly improved from 0.619 of the original GGG model to 0.638 of the mGGG model (P?<?0.05). CONCLUSIONS:The quantitative risk of tertiary (<?5%) Gleason pattern 5 is slightly higher than that of secondary (5-50%) Gleason pattern 4. Our newly developed mGGG model more accurately predicts outcomes after radical prostatectomy than the original GGG model.

Project description:IntroductionThe optimal salvage treatment strategies for lymph node-positive (LNP) patients after radical surgery have not been clearly defined in prostate cancer with biochemical recurrence or persistence of elevated prostate-specific antigen (PSA). In this study, we compared the clinical outcomes of two different salvage treatments, androgen deprivation therapy (ADT) alone versus ADT with radiotherapy (RT). We also investigated prognostic factors that could support the use of ADT with RT in LNP prostate cancer.Materials and methodsWe retrospectively reviewed 94 LNP prostate cancer patients who underwent radical prostatectomy (RP) followed by salvage treatment between 2004 and 2018. Salvage treatments involved either ADT alone or ADT with RT according to the clinical judgment of the physician. We analyzed clinicopathological and treatment factors related to 2nd biochemical failure (2nd BCF), clinical progression (CP), and progression-free survival (PFS). The cumulative failure after salvage treatment was defined as including both 2nd BCF and CP.ResultsThe median duration of follow-up was 55 months (interquartile range, 35-97 months). Thirty-seven (39.4%) patients were treated with ADT alone, and 57 patients (60.6%) were treated with a combination of ADT with RT. During follow-up period, the incidence of failure after salvage treatment in the ADT alone group and the combined treatment group was 89.2% and 45.6%, respectively (HR, 22.4; 95% CI 5.43-92.1; P < 0.001). The combination of ADT with RT was associated with better 2nd BCF and PFS than ADT alone (P = 0.007 and P = 0.015, respectively). In multivariate analyses, number of positive LN ≥ 2 and PSA nadir ≥ 0.005 ng/ml after RP were associated with poor 2nd BCF, CP, and PFS after salvage treatment. Salvage by combined ADT plus RT showed better 2nd BCF and PFS than ADT alone. Specifically, patients with number of positive LN ≥ 2 or PSA nadir ≥ 0.005 ng/ml after RP showed better 2nd BCF (P = 0.004) or PFS (P = 0.011) when treated with ADT plus RT rather than ADT alone.ConclusionsIn patients with LNP prostate cancer, salvage ADT plus RT improved 2nd BCF and PFS compared to ADT alone. In particular, when the patients had more than two positive lymph nodes or PSA nadir ≥ 0.005 ng/ml after RP, ADT with RT seems to be a more beneficial salvage treatment resulting in better 2nd BCF and PFS.

Dataset Information

Molecular Characterization and Clinical Outcomes of Primary Gleason Pattern 5 Prostate Cancer After Radical Prostatectomy.

Publications

Molecular Characterization and Clinical Outcomes of Primary Gleason Pattern 5 Prostate Cancer After Radical Prostatectomy.

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