The Mutational Landscape of Metastatic Castration-sensitive Prostate Cancer: The Spectrum Theory Revisited

Abstract

Background: Emerging data suggest that metastasis is a spectrum of disease burden rather than a binary state, and local therapies, such as radiation, might improve outcomes in oligometastasis. However, current definitions of oligometastasis are solely numerical.

Objective: To characterize the somatic mutational landscape across the disease spectrum of metastatic castration-sensitive prostate cancer (mCSPC) to elucidate a biological definition of oligometastatic CSPC.

Design, setting, and participants: This was a retrospective study of men with mCSPC who underwent clinical-grade sequencing of their tumors (269 primary tumor, 25 metastatic sites). Patients were classified as having biochemically recurrent (ie, micrometastatic), metachronous oligometastatic (≤5 lesions), metachronous polymetastatic (>5 lesions), or de novo metastatic (metastasis at diagnosis) disease.

Outcome measurements and statistical analysis: We measured the frequency of driver mutations across metastatic classifications and the genomic associations with radiographic progression-free survival (rPFS) and time to castrate-resistant prostate cancer (CRPC).

Results and limitations: The frequency of driver mutations in TP53 (p = 0.01), WNT (p = 0.08), and cell cycle (p = 0.04) genes increased across the mCSPC spectrum. TP53 mutation was associated with shorter rPFS (26.7 vs 48.6 mo; p = 0.002), and time to CRPC (95.6 vs 155.8 mo; p = 0.02) in men with oligometastasis, and identified men with polymetastasis with better rPFS (TP53 wild-type, 42.7 mo; TP53 mutated, 18.5 mo; p = 0.01). Mutations in TP53 (incidence rate ratio [IRR] 1.45; p = 0.004) and DNA double-strand break repair (IRR 1.61; p < 0.001) were associated with a higher number of metastases. Mutations in TP53 were also independently associated with shorter rPFS (hazard ratio [HR] 1.59; p = 0.03) and the development of CRPC (HR 1.71; p = 0.01) on multivariable analysis. This study was limited by its retrospective nature, sample size, and the use of commercially available sequencing platforms, resulting in a limited predefined set of genes examined.

Conclusions: Somatic mutational profiles reveal a spectrum of metastatic biology that helps in redefining oligometastasis beyond a simple binary state of lesion enumeration.

Patient summary: Oligometastatic prostate cancer is typically defined as less than three to five metastatic lesions and evidence suggests that using radiation or surgery to treat these sites improves clinical outcomes. As of now, treatment decisions for oligometastasis are solely defined according to the number of lesions. However, this study suggests that tumor mutational profiles can provide a biological definition of oligometastasis and complement currently used numerical definitions.

Keywords: Next Generation Sequencing; Oligometastatic prostate cancer.

Fig. 1

– Metastatic categories are associated with time to castrate-resistance and overall survival. Metastatic categories of biochemically recurrent (BCR, i.e., micrometastatic), metachronous oligometastatic (≤ 5 lesions), metachronous polymetastatic (> 5 lesions), and de novo (metastasis at diagnosis). (A) Radiographic progression-free survival (rPFS) stratified by metastatic category (p = 0.16). (B) Time to CRPC (per Prostate Cancer Working Group 3) by metastatic category (p < 0.0001). (C) Overall survival (OS) from original diagnosis by metastatic category (p < 0.0001).

Fig. 2

– Cancer-relevant gene mutations correlate directly across the spectrum of metastatic castration-sensitive prostate cancer. An oncoprint of metastatic categories shows that the mutation frequency increases with increasing metastatic tendency and burden, including TP53 (p = 0.01), WNT (p = 0.04), and cell cycle (p = 0.004) genes. The metachronous oligometastatic (Oligomet) category had a frequency of driver mutations intermediate between those of BCR (micrometastatic) and metachronous polymetastatic (Polymet). The frequency of mutations in the Polymet category tended to mirror or were higher than those of the de novo metastatic category (no significant differences according to p values).

Fig. 3

– TP53 mutational status is prognostic for metachronous castration-sensitive prostate cancer. TP53 mutations are associated with outcomes for the metachronous oligometastatic (Met Oligo) category for: (A) rPFS (26.7 vs 48.6 mo; p = 0.002); (B) time to CRPC (95.6 vs 155.8 mo; p = 0.02); and (C) 8-yr OS (82.8% vs 96.1%; p = 0.2). TP53 mutation also stratifies the metachronous polymetastatic (Met Poly) category. (D) rPFS for men in the Met Poly category with TP53 WT (42.7 mo) or TP53 mutated tumors (18.5 mo; p = 0.01) (E) Time to CRPC for the Met Poly category with TP53 WT (86.3 mo) or TP53 mutated tumors (73.7 mo; p = 0.01); (F) 8-yr OS for the Met Poly category with TP53 WT (83.7%) or TP53 mutated tumors (50.0%; p = 0.02). rPFS = radiographic progression-free survival; CRPC = castrate-resistant prostate cancer; OS = overall survival; WT = wild type.