Development and validation of a gene expression signature based on RB1, PTEN,and TP53 in patients with metastatic hormone-sensitive prostate cancer (mHSPC).
Authors: Reig Torras Oscar , Jiménez Natalia , Garcia de Herreros Marta , Aversa Caterina , Marin Mercedes , Ferrer Laura , Rodriguez-Carunchio Leonardo , Trias Isabel , Fernandez-Mañas Laia , García-Esteve Samuel , Font Pous Albert , Rodriguez-Vida Alejo , Domenech-Santasusana Montserrat , Figols Mariona , Climent Miguel Ángel , Cros Costa Sara , Chirivella Isabel , Herrero Rivera Daniel , Suárez Cristina , Mellado-Gonzalez Begoña 
Published: March 2023

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Background: Alterations on the tumor suppressor genes (TSG) RB1, PTEN and TP53 are associated with treatment resistance and aggressive clinical evolution of prostate cancer patients (pts). We developed and assessed the role of a TSG gene expression signature in mHSPC pts. Methods: This is a multicenter retrospective biomarker study in mHSPC pts receiving different therapies. RB1, PTEN and TP53 mutations were assessed by targeted sequencing and its gene expression was determined by the nCounter platform in FFPE tumor samples. Normalized and transformed (z-score) expression data of a training cohort was used to establish the cut-off for RB1, PTEN and TP53 expression, those cut-offs were then applied to the other cohorts. TSGlow was considered when ≥2 out of 3 TSG presented low expression, and TSGwt in the remaining cases. TSG signature was correlated with castration resistance-free survival (CRPC-FS) (primary endpoint) and overall survival (OS) by Kaplan Meier and multivariate Cox analysis. Results: Overall, 297 pts (baseline characteristics are shown) were included: 125 treated with ADT+Docetaxel (ADT+D) (54 and 71 in training and validation cohorts, respectively), 93 with ADT, and 79 with ADT+Abiraterone or Enzalutamide (ADT+A/E). Training cohort pts were tested for both, gene expression and targeted sequencing of TSG. Pts with low expression of PTEN showed higher frequency of PTEN mutations (p<0.05). TSGlow (14 (25.9%) out of 54 pts) had a worse CRPC-FS (14.3 vs. 21.7 months (m); HR 2.2 (95% CI, 1.1 - 4.4), p=0.022). In the validation cohort, 7 (9.9%) pts were TSGlow and had a worse CPRC-FS (11.7 vs. 20 m, HR 2.5 (95% CI, 1.1 - 5.5), p=0.027) and OS (27.6 vs 58.1 m, HR 3.5 (95% CI, 1.3 - 9.5) p=0.012). TSGlow signature was independently associated with CPRC-FS (HR 2.66 (95% CI, 1.17 - 6.06), p=0.02) and OS (HR 3.67 (95% CI, 1.33 - 10.10), p=0.012). In the ADT and ADT+A/E cohorts, 20 (21.5%) and 14 (17.7%) pts were TSGlow, respectively. TSGlow was not predictive of either CRPC-FS (p=0.23 and p=0.242, respectively) or OS (p=0.091 and p=0.66, respectively). We analyzed together high-volume pts from both ADT+D and ADT cohorts. TSGlow pts (16, 10.74%) treated with ADT+D had a CRPC-FS (13.6 m) similar to pts treated with ADT (TSGlow = 14.5 m and TSGwt = 12.8 m). Moreover, TSGwt pts treated with ADT+D had a better CRPC-FS (19.3m) (p=0.022) and OS (ADT/TSGlow = 31.7 m, ADT/TSGwt = 38.6 m, ADT+D/TSGlow = 31.5 m, ADT+D/TSGwt = 52.2 m, p=0.07). Conclusions: A TSG gene expression signature is predictive of taxanes benefit in mHSPC pts and may be useful to personalize the treatment in this setting. [Table: see text]