PIK3/Akt/mTOR pathway alterations in metastatic castration-sensitive prostate cancer

被引：3

作者：

Sutera, Philip ^{[1
]}

Kim, Jongmyung ^{[2
]}

Kumar, Ritesh ^{[2
]}

Deek, Rebecca A. ^{[3
]}

Stephenson, Ryan ^{[4
]}

Mayer, Tina ^{[4
]}

Saraiya, Biren ^{[4
]}

Ghodoussipour, Saum ^{[5
]}

Jang, Thomas ^{[5
]}

Golombos, David ^{[5
]}

Packiam, Vignesh ^{[5
]}

Ennis, Ronald ^{[1
]}

Hathout, Lara ^{[1
]}

Jabbour, Salma K. ^{[1
]}

Guler, Ozan ^{[6
]}

Onal, Cem ^{[6
]}

Tran, Phuoc T. ^{[7
]}

Deek, Matthew P. ^{[1
]}

机构：

[1] Johns Hopkins Univ, Dept Radiat Oncol & Mol Radiat Sci, Baltimore, MD USA

[2] Rutgers State Univ, Rutgers Canc Inst New Jersey, Rutgers Robert Wood Johnson Med Sch, Dept Radiat Oncol, New Brunswick, NJ USA

[3] Univ Pittsburgh, Dept Biostat, Pittsburgh, PA USA

[4] Rutgers State Univ, Rutgers Canc Inst New Jersey, Rutgers Robert Wood Johnson Med Sch, Div Med Oncol, New Brunswick, NJ USA

[5] Rutgers State Univ, Rutgers Canc Inst New Jersey, Rutgers Robert Wood Johnson Med Sch, Dept Urol, New Brunswick, NJ USA

[6] Baskent Univ, Dept Radiat Oncol, Ankara, Turkiye

[7] Univ Maryland, Dept Radiat Oncol, Sch Med, Baltimore, MD USA

来源：

PROSTATE | 2024年 / 84卷 / 14期

关键词：

genomics; PIK3; personalized medicine; prostate cancer; PTEN LOSS; MUTATIONS; OUTCOMES; THERAPY; TISSUE; BIOPSY; TRIAL;

D O I：

10.1002/pros.24765

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background: Alterations in the PIK3/Akt/mTOR pathway are commonly seen in metastatic castration-sensitive prostate cancer (mCSPC), however their role in outcomes is unknown. We aim to evaluate the prognostic significance as well as the genetic landscape of PIK3/Akt/mTOR pathway alteration in mCSPC. Methods: Fourhundred and seventy-two patients with mCSPC were included who underwent next generation sequencing. PIK3/Akt/mTor pathway alterations were defined as mutations in Akt1, mTOR, PIK3CA, PIK3CB, PIK3R1, PTEN, TSC1, and TSC2. Endpoints of interests were radiographic progression-free survival (rPFS), time to development of castration resistant prostate cancer (tdCRPC), and overall survival (OS). Kaplan-Meier analysis was performed and Cox regression hazard ratios (HR) were calculated. Results: One hundred and fifty-two (31.9%) patients harbored a PIK3/Akt/mTOR pathway alteration. Median rPFS and tdCRPC were 23.7 and 21.0 months in PIK3/Akt/mTOR altered compared to 32.8 (p = 0.08) and 32.1 months (p = 0.002) in wildtype tumors. On multivariable analysis PIK3/Akt/mTOR pathway alterations were associated with tdCRPC (HR 1.43, 95% CI, 1.05-1.94, p = 0.02), but not rPFS [Hazard ratio (HR) 1.20, 95% confidence interval (CI), 0.90-1.60, p = 0.21]. PIK3/Akt/mTOR pathway alterations were more likely to be associated with concurrent mutations in TP53 (40% vs. 28%, p = 0.01) and TMPRSS2-ERG (37% vs. 26%, p = 0.02) than tumors without PIK3/Akt/mTOR pathway alterations. Concurrent mutations were typically associated with shorter median times to rPFS and tdCRPC. DAVID analysis showed p53 signaling and angiogenesis pathways were enriched in PIK3/Akt/mTOR pathway altered tumors while beta-catenin binding and altered BRCA pathway were enriched in PIK3/Akt/mTOR pathway wildtype tumors. Conclusions: PIK3/Akt/mTOR pathway alterations were common in mCSPC and associated with poorer prognosis. The genetic landscape of PIK3/Akt/mTOR pathway altered tumors differed from wildtype tumors. Additional studies are needed to better understand and target the PIK3/Akt/mTOR pathway in mCSPC.

引用

页码：1301 / 1308

页数：8

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