Patients were eligible for this matched, retrospective study if they were included in one of five published US studies (cohort, case-cohort, and case-control studies) of patients with prostate
adenocarcinoma who had radical
prostatectomy (with or without postoperative
radiotherapy) and had gene expression analysis of the tumour, with long-term follow-up and complete clinicopathological data. Additional treatment after surgery was at the treating physician's discretion. In each cohort, patients who had postoperative
radiotherapy were matched with patients who had not had
radiotherapy using Gleason score,
prostate-specific antigen concentration,
surgical margin status,
extracapsular extension, seminal vesicle invasion, lymph node invasion, and
androgen deprivation
therapy. We constructed a matched training cohort using patients from one study in which we developed a 24-gene Post-Operative
Radiation Therapy Outcomes Score (PORTOS). We generated a pooled matched validation cohort using patients from the remaining four studies. The primary endpoint was the development of distant
metastasis.
FINDINGS: In the training cohort (n=196), among patients with a high PORTOS (n=39), those who had
radiotherapy had a lower incidence of distant
metastasis than did patients who did not have
radiotherapy, with a 10-year
metastasis rate of 5% (95% CI 0-14) in patients who had
radiotherapy (n=20) and 63% (34-80) in patients who did not have
radiotherapy (n=19; hazard ratio [HR] 0·12 [95% CI 0·03-0·41], p<0·0001), whereas among patients with a low PORTOS (n=157), those who had postoperative
radiotherapy (n=78) had a greater incidence of distant
metastasis at 10 years than did their untreated counterparts (n=79; 57% [44-67] vs 31% [20-41]; HR 2·5 [1·6-4·1], p<0·0001), with a significant treatment interaction (pinteraction<0·0001). The finding that PORTOS could predict outcome due to
radiotherapy treatment was confirmed in the validation cohort (n=330), which showed that patients who had
radiotherapy had a lower incidence of distant
metastasis compared with those who did not have
radiotherapy, but only in the high PORTOS group (high PORTOS [n=82]: 4% [95% CI 0-10] in the
radiotherapy group [n=57] vs 35% [95% CI 7-54] in the no
radiotherapy group [n=25] had
metastasis at 10 years; HR 0·15 [95% CI 0·04-0·60], p=0·0020; low PORTOS [n=248]: 32% [95% CI 19-43] in the
radiotherapy group [n=108] vs 32% [95%
CI 22-40] in the no
radiotherapy group [n=140]; HR 0·92 [95% CI 0·56-1·51], p=0·76), with a significant interaction (pinteraction=0·016). The conventional prognostic tools Decipher, CAPRA-S, and microarray version of the cell cycle progression signature did not predict response to
radiotherapy (pinteraction>0·05 for all).
INTERPRETATION: Patients with a high PORTOS who had postoperative
radiotherapy were less likely to have
metastasis at 10 years than those who did not have
radiotherapy, suggesting that treatment with postoperative
radiotherapy should be considered in this subgroup. PORTOS should be investigated further in additional independent cohorts.
FUNDING: None.