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. 2017 Nov 21;117(11):1656-1664.
doi: 10.1038/bjc.2017.346. Epub 2017 Oct 3.

Ex vivo metabolic fingerprinting identifies biomarkers predictive of prostate cancer recurrence following radical prostatectomy

Peder R Braadland  1   2 , Guro Giskeødegård  3 , Elise Sandsmark  3 , Helena Bertilsson  4   5 , Leslie R Euceda  3 , Ailin F Hansen  3 , Ingrid J Guldvik  1 , Kirsten M Selnæs  3 , Helene H Grytli  1 , Betina Katz  6 , Aud Svindland  2   6 , Tone F Bathen  3 , Lars M Eri  2   7 , Ståle Nygård  8 , Viktor Berge  7 , Kristin A Taskén  1   2 , May-Britt Tessem  3
Affiliations

Ex vivo metabolic fingerprinting identifies biomarkers predictive of prostate cancer recurrence following radical prostatectomy

Peder R Braadland et al. Br J Cancer. .

Erratum in

Abstract

Background: Robust biomarkers that identify prostate cancer patients with high risk of recurrence will improve personalised cancer care. In this study, we investigated whether tissue metabolites detectable by high-resolution magic angle spinning magnetic resonance spectroscopy (HR-MAS MRS) were associated with recurrence following radical prostatectomy.

Methods: We performed a retrospective ex vivo study using HR-MAS MRS on tissue samples from 110 radical prostatectomy specimens obtained from three different Norwegian cohorts collected between 2002 and 2010. At the time of analysis, 50 patients had experienced prostate cancer recurrence. Associations between metabolites, clinicopathological variables, and recurrence-free survival were evaluated using Cox proportional hazards regression modelling, Kaplan-Meier survival analyses and concordance index (C-index).

Results: High intratumoural spermine and citrate concentrations were associated with longer recurrence-free survival, whereas high (total-choline+creatine)/spermine (tChoCre/Spm) and higher (total-choline+creatine)/citrate (tChoCre/Cit) ratios were associated with shorter time to recurrence. Spermine concentration and tChoCre/Spm were independently associated with recurrence in multivariate Cox proportional hazards modelling after adjusting for clinically relevant risk factors (C-index: 0.769; HR: 0.72; P=0.016 and C-index: 0.765; HR: 1.43; P=0.014, respectively).

Conclusions: Spermine concentration and tChoCre/Spm ratio in prostatectomy specimens were independent prognostic markers of recurrence. These metabolites can be noninvasively measured in vivo and may thus offer predictive value to establish preoperative risk assessment nomograms.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Metabolite levels in non-recurrent and recurrent prostate cancers at the 5-year mark. (A) Average HR-MAS MRS spectra from tumours from non-recurrent (black) and recurrent (red) prostate cancer groups in the NTNU1 cohort. Magnifications of the polyamine (containing spermine and putrescine) and citrate regions are shown. (B) Quantified peak integrals of spermine, citrate, choline and creatine (nmol mg−1), and tChoCre/Spm and tChoCre/Cit ratios in the groups from all samples in all included cases from the three cohorts are shown as beeswarm plots (n=158). The thin horizontal lines make out the 25% and 75% quartiles, and the median value is shown as thick black horizontal lines. Statistical significance was calculated by LMM to account for multiple samples per patient (*P<0.05, **Q<0.05). Ala, alanine; Cho, choline; Cit, citrate; Cre, creatine; Gln, glutamine; Glu, glutamate; Gly, glycine; Lac, lactate; Myo-ino, myo-inositol; NS, nonsignificant; PA, polyamines; PCho/GPC, phosphocholine and glycerophosphocholine peaks; Sc-ino, scyllo-inositol; Spm, spermine; Succ, succinate; Tau, taurine; tCho, total choline.
Figure 2
Figure 2
Kaplan-Meier curves for patients with high and low levels of metabolites and ratios. Recurrence-free proportions plotted against time to first report of recurrence for spermine (A), citrate (B), tChoCre/Spm (C), and tChoCre/Cit (D) dichotomised to above and below median concentrations. Mantel–Haenszel log-rank test was used to test for the null hypothesis of equal survival distributions. tChoCre/Cit, (total-choline+creatine)/citrate; tChoCre/Spm, (total-choline+creatine)/spermine.
Figure 3
Figure 3
Correlation heatmap. Correlations between metabolites and clinicopathological factors. The Spearman’s correlation coefficients are shown inside the boxes (large font), with corresponding P-values below. The colour scale indicates the sign of the correlation coefficients and the degree of correlation, where blue indicates negative correlation, white no correlation, and red positive correlation. EPE, extraprostatic extension; PSM, positive surgical margins; SVI, seminal vesicle invasion; tChoCre/Cit, (total-choline+creatine)/citrate; tChoCre/Spm, (total-choline+creatine)/spermine.
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