516 656
threshold of 25% (AUC = 0.80 and net benefit = 0.052),
compared with either metastatic assay (AUC = 0.71 and
net benefit = 0.035) or CAPRA-S alone (AUC = 0.76 and net
benefit = 0.021) (Supplementary Table 17 and Supplemen-
tary Fig. 6). This suggests that for patients with a 25% risk of
developing metastatic recurrence, a greater net benefit is
achieved using the metastatic assay in conjunction with
CAPRA-S. In addition, the continuous combinedmodel had a
C-index of 0.82 (0.76–0.86) compared with a C-index of 0.71
(0.64–0.78) for metastatic assay and a C-index of 0.73
(0.66–0.79) for CAPRA-S alone (Supplementary Table 17).
4.
Discussion
The majority of early prostate cancer patients treated by
radical resection are cured. However, up to 25% of patients
develop metastatic disease within 15
[38_TD$DIFF]
years
[1,2]. In
surveillance for low/intermediate-risk disease, there is
concern about risks of clinical undergrading and disease
progression, with a proportion of patients needing treat-
ment within 5
[38_TD$DIFF]
years
[3]. This engenders clinical uncertainty
in modern practice in two key areas: firstly, in the
appropriate and safe selection of patients for active
surveillance, particularly in the Gleason 3 + 4 intermediate
group, and secondly, in patients undergoing radical local
treatment for intermediate- and higher-grade tumours,
where adjuvant locoregional and systemic treatment may
improve outcome. A test that helps select patients at a
higher risk of progression in these settings will have
significant clinical utility.
Several prognostic gene expression assays have been
developed by comparing gene expression data between
good and poor outcome patients
[16–18] .In contrast, we
identified a molecular subgroup of primary prostate cancer
samples that shared biology with metastatic disease. We
developed an assay for this molecular subgroup, which
identified patients at risk of biochemical and metastatic
recurrence in three publicly available and one prospectively
collected multicentre dataset.
Consistent with the molecular subgroup representing
metastatic biology, the assay was better at predicting
metastatic
[8_TD$DIFF]
recurrence rather than biochemical recurrence.
The latter does not necessarily predict metastatic develop-
ment; only one-third of patients with biochemical recur-
rence develop measurable metastatic disease 8
[38_TD$DIFF]
years after
resection
[27]. In addition, the HR of 3.20 for metastatic
recurrence compares favourably to the reported hazard
ratios for other prognostic assays to predict metastatic
disease, with HRs ranging between 1.40 and 3.30
[16–18] .A
significant feature of assay performance was independence
from CAPRA-S, allowing the development of a combined
risk model with superior performance to either CAPRA-S or
the metastatic assay individually.
An interesting feature of the metastatic subgroup was
methylation and loss of gene expression such as OLFM4
known to inhibit metastatic processes including WNT
signalling
[28]. It is therefore possible that novel therapies
aimed at reversing epigenetic silencing or targeting WNT
signalling may act against the metastatic biology in this
molecular subgroup
[29]. Regarding upregulated genes in
the metastatic-subgroup, a significant proportion was
regulated by FOXM1 known to promote prostate cancer
progression
[30]. Indeed, others have found increased
FOXM1
gene expression to be prognostic and have included
it in a 31-gene expression assay
[16]. Interestingly only 6/70
genes in the metastatic assay overlapped with three
prognostic signatures that are entering clinical practice
(AZGP1
[18], PTTG1, TK1 and KIF11
[16] ,and ANO7 and
MYBPC1
[17])—Oncotype Prostate (
p
= 0.16), Prolaris
(
p
= 0.06), and Decipher (
p
= 0.06)—after multiple test
correction using a Benjamini–Hochberg correction, likely
reflecting the distinct approach of molecular subtyping
versus trained
[50_TD$DIFF]
endpoint analysis (Supplementary Fig. 7).
A potential limitation of this study is the retrospective
validation of the assay in historic datasets. Diagnostic and
surgical approaches have improved with time, which may
reduce disease recurrence. We expect, however, that the
effect of these improvements would mostly be on local
recurrence, whereas this assay has been developed to
predict metastatic disease progression, likely largely
beyond surgical control at presentation.
5.
Conclusions
We have identified a molecular subgroup of primary prostate
cancer with metastatic capacity. We hypothesise that using
this molecular subtyping approach may improve patient
stratification considering active surveillance and may benefit
patients with higher-risk clinically localised disease by
focusing
[51_TD$DIFF]
loco-regional and systemic adjuvant therapy in
those at the highest risk of regional and systemic failure.
Author contributions:
Richard
[27_TD$DIFF]
D. Kennedy had full access to all the data
in the study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design:
Walker, Harkin, Kennedy.
Acquisition of data:
Walker, Knight, Logan, Blayney, McCavigan, Price,
Jellema, Steele.
Analysis and interpretation of data:
Walker, Knight, Kennedy.
Drafting of the manuscript:
Walker, Logan, Knight, Clarke, Kennedy.
Critical revision of the manuscript for important intellectual content:
Waugh, Mills, Neal, Clarke, Harkin.
Statistical analysis:
McCavigan, Knight
[52_TD$DIFF]
, Steele.
Obtaining funding:
Kennedy, Harkin.
Administrative, technical, or material support:
Sherif, Warren, Neal, Berge,
Svindland, Pandha, Mason, McDade, Watson, Davidson, Uprichard, Kay
[53_TD$DIFF]
,
Eden, Foster.
Supervision:
Kennedy, Harkin.
Other:
None.
Financial disclosures:
Richard
[27_TD$DIFF]
D. Kennedy certifies that all conflicts of
interest, including specific financial interests and relationships and
affiliations relevant to the subject matter or materials discussed in the
manuscript (eg, employment/affiliation, grants or funding, consultan-
cies, honoraria, stock ownership or options, expert testimony, royalties,
or patents filed, received, or pending), are the following: StevenWalker—
employment at Almac Diagnostics, patent or IP ‘‘Molecular Test for
Prostate Cancer’’. Laura Knight—employment at Almac Diagnostics,
patent or IP ‘‘Molecular Test for Prostate Cancer’’. Andrena McCavigan—
employment at Almac Diagnostics, patent or IP ‘‘Molecular Test for
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