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. 2024 Nov 30;13(11):6235-6245.
doi: 10.21037/tcr-24-123. Epub 2024 Oct 14.

Landscape and prognostic significance of oncogene drivers in metastatic castration sensitive prostate cancer

Theodore Wang  1 , Jongmyung Kim  1 , Ritesh Kumar  1 , Rebecca A Deek  2 , Ryan Stephenson  3 , Tina Mayer  3 , Biren Saraiya  3 , Saum Ghodoussipour  4 , Thomas Jang  4 , David Golombos  4 , Vignesh Packiam  4 , Ronald Ennis  1 , Lara Hathout  1 , Salma K Jabbour  1 , Ozan Guler  5 , Cem Onal  5 , Matthew P Deek  1
Affiliations

Landscape and prognostic significance of oncogene drivers in metastatic castration sensitive prostate cancer

Theodore Wang et al. Transl Cancer Res. .

Abstract

Background: Tumor suppressors are well known drivers of cancer invasion and metastasis in metastatic castration sensitive prostate cancer (mCSPC). However, oncogenes are also known to be altered in this state, however the frequency and prognosis of these alterations are unclear. Thus, we aimed to study the spectrum of oncogene mutations in mCSPC and study the significance of these alteration on outcomes.

Methods: Four hundred and seventy-seven patients with mCSPC were included who underwent next generation sequencing. Oncogene alterations were defined as mutations in ALK, AKT1-3, BRAF, CCND1-3, CTNNB1, EGFR, ERBB2, FGFR1, FGFR2, HRAS, KRAS, MDM2, MET, MITF, MYC, NOTCH1-3, NRAS, PIK3CA, PI3KCB, PIK3R1, RET. Endpoints of interests were radiographic progression-free survival (rPFS), time to development of CRPC (tdCRPC), and overall survival (OS). Kaplan Meier analysis was performed and Cox regression hazard ratios (HR) calculated.

Results: A total of 477 patients were included with baseline characteristics with 117 patients (24.5%) harbored a mutation within an oncogene. A total of 172 oncogene mutations were found within the population with the most common being MYC (n=29; 16.9%), PIK3CA (n=24; 14%), CTNNB1 (n=22, 12.8%), BRAF (n=10, 5.8%), and CCND1 (n=10, 5.8%). Oncogene mutations were associated with inferior rPFS (19.2 vs. 32.2 months, P=0.03), tdCRPC (15.7 vs. 32.4 months, P<0.001), and OS (5-year OS 75.3% vs. 55.4%, P=0.01). On multivariable analysis oncogene mutations were strongly associated with tdCRPC (HR 1.42, P=0.03).

Conclusions: Oncogenes are frequency mutated in mCSPC and associated with aggressive features and inferior outcomes. Future work will need to validate these results to better assess its significance in allowing for personalization of care.

Keywords: Prostate cancer; metastatic castration sensitive; oncogene.

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Conflict of interest statement

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-123/coif). The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
rPFS (A), tdCRPC (B), and OS (C) stratified by oncogene. mutational status. Oncogene alterations were associated with inferior rPFS (19.2 vs. 32.2 months, P=0.03), tdCRPC (15.7 vs. 32.4 months, P<0.001), and OS (5-year OS 75.3% vs. 55.4%, P=0.01). WT, wild type; rPFS, radiographic progression-free survival; tdCRPC, time to development of castration resistant prostate cancer; OS, overall survival.
Figure 2
Figure 2
rPFS (A), tdCRPC (B), and OS (C) stratified by MYC mutational status. MYC alterations were associated with poorer rPFS (median 19.8 vs. 28.8 months, P=0.27), tdCRPC (median 15.7 vs. 32.4 months, P<0.001), and OS (median 42.9 vs. 101.5 months, P=0.01). WT, wild type; rPFS, radiographic progression-free survival; tdCRPC, time to development of castration resistant prostate cancer; OS, overall survival.
Figure 3
Figure 3
rPFS (A), tdCRPC (B), and OS (C) stratified by CTNNB1 mutational status. CTNNB1 mutations were associated with inferior tdCRPC (median 14.7 vs. 29.8 months, P=0.01), but not rPFS (median 28.8 vs. 27.6 months, P=0.86) nor OS (median NR vs. 96.1 months, P=0.12). WT, wild type; rPFS, radiographic progression free survival; tdCRPC, time to development of castration resistant prostate cancer; OS, overall survival; NR, not reached.
Figure 4
Figure 4
Oncoprint of other mutations of interests split by oncogene mutation status. TP53 (38% vs. 30%, P=0.09) and PTEN (33% vs. 24%, P=0.05) mutations were more common in oncogene mutated tumors. WT, wild type.
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