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. 2019:3:PO.19.00081.
doi: 10.1200/PO.19.00081. Epub 2019 Jul 26.

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

Pedro Isaacsson Velho  1 , David Lim  1 , Hao Wang  1 , Jong Chul Park  1 , Harsimar B Kaur  1 , Fawaz Almutairi  1 , Michael A Carducci  1 , Samuel R Denmeade  1 , Mark C Markowski  1 , William B Isaacs  1 , Emmanuel S Antonarakis  1 , Colin C Pritchard  2 , Mario A Eisenberger #  1 , Tamara L Lotan #  1
Affiliations

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

Pedro Isaacsson Velho et al. JCO Precis Oncol. 2019.

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.

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Conflict of interest statement

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Pedro Isaacsson Velho Honoraria: Bayer HealthCare Pharmaceuticals Speakers’ Bureau: AstraZeneca, Pfizer, Bristol-Myers Squibb Research Funding: Bristol-Myers Squibb, Pfizer (Inst) Expert Testimony: Bayer HealthCare Pharmaceuticals Travel, Accommodations, Expenses: AstraZeneca, Astellas Pharma, Pfizer, Merck Serono, Merck Michael A. Carducci Consulting or Advisory Role: Astellas Pharma, AbbVie, Roche/Genentech, Pfizer, Foundation Medicine Research Funding: Bristol-Myers Squibb (Inst), Pfizer (Inst), AstraZeneca (Inst), Gilead Sciences (Inst), EMD Serono (Inst), eFFECTOR Therapeutics (Inst) Samuel R. Denmeade Stock and Other Ownership Interests: Sophiris Bio Consulting or Advisory Role: Sophiris Bio Travel, Accommodations, Expenses: Sophiris Bio Mark C. Markowski Honoraria: Clovis, Exelixis William B. Isaacs Honoraria: AstraZeneca Travel, Accommodations, Expenses: AstraZeneca Emmanuel S. Antonarakis Honoraria: Sanofi, Dendreon, Medivation, Janssen Biotech, ESSA, Astellas Pharma, Merck, AstraZeneca, Clovis Oncology Consulting or Advisory Role: Sanofi, Dendreon, Medivation, Janssen Biotech, ESSA, Astellas Pharma, Merck, AstraZeneca, Clovis Oncology Research Funding: Janssen Biotech (Inst), Johnson & Johnson (Inst), Sanofi (Inst), Dendreon (Inst), Aragon Pharmaceuticals (Inst), Exelixis (Inst), Millennium Pharmaceuticals (Inst), Genentech (Inst), Novartis (Inst), Astellas Pharma (Inst), Tokai Pharmaceuticals (Inst), Merck (Inst), AstraZeneca (Inst), Clovis Oncology (Inst), Constellation Pharmaceuticals (Inst) Patents, Royalties, Other Intellectual Property: Coinventor of biomarker technology licensed to Qiagen Travel, Accommodations, Expenses: Sanofi, Dendreon, Medivation Mario A. Eisenberger Leadership: Veru Stock and Other Ownership Interests: Veru Honoraria: Sanofi, Pfizer Consulting or Advisory Role: Astellas Pharma, Ipsen, Bayer HealthCare Pharmaceuticals, Sanofi, Pfizer Research Funding: Sanofi, Tokai Pharmaceuticals, Genentech Travel, Accommodations, Expenses: Bayer HealthCare Pharmaceuticals, Astellas Pharma, Sanofi, Pfizer, Veru Tamara L. Lotan Consulting or Advisory Role: Janssen Oncology Research Funding: Ventana Medical Systems No other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
Kaplan-Meier analysis of metastasis-free survival in primary Gleason pattern 5 cohort by (A) seminal vesicle invasion (SVI) status, (B) ductal or intraductal (DOI) histology status, (C) TP53 mutation status, and (D) PTEN protein status using immunohistochemistry. NR, not reached.
FIG A1.
FIG A1.
Pathology database query for consecutive radical prostatectomies (RPs) with primary Gleason score 5 (PG5) from 2005 to 2015, where 60 patient cases were identified with available tissue and clinical follow-up. JHH, Johns Hopkins Hospital.
FIG A2.
FIG A2.
Kaplan-Meier analysis of biochemical recurrence–free survival in primary Gleason pattern 5 cohort by (A) seminal vesicle invasion (SVI) status, (B) ductal or intraductal (DOI) histology status, (C) p53 mutation status, and (D) PTEN protein status.
See this image and copyright information in PMC

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