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interpret the relevance of hypoxia in IDC/CA tumors, and
larger data sets will be needed to evaluate these questions.
An interesting clinical question often raised regarding
the clinical implications of IDC/CA is the recommended
definitive treatment. There is no consensus on the preferred
treatment for patients with IDC. In addition, if tumor
hypoxia is truly higher in IDC/CA tumors, then it is plausible
that radiotherapy may be less effective given that the
primary method of DNA damage is via the generation of free
radicals, and it has been shown that hypoxia results in
radioresistance. However, Chua et al demonstrated that the
impact of IDC/CA on biochemical failure was similar
between radiotherapy and surgically treated cohorts.
Furthermore, the presence of IDC/CA actually had a greater
negative impact for surgically treated patients (hazard ratio
3.1) than for radiotherapy patients (hazard ratio 2.2) on
univariable analysis. Importantly, almost no patients who
received radiotherapy had hormone therapy, a treatment
that reduces tumor hypoxia, which would be expected to
further mitigate the impact of IDC/CA
[9]. Therefore, the
recommended treatment for this aggressive subpathology
remains unknown, but given the poor prognosis, probably
requires multimodal therapy and needs further study.
As part of the last step of the authors’ effort to identify a
molecular fingerprint for the IDC/CA phenotype, what
appeared most fruitful were the mRNA abundance analyses.
Using 156 tumors and assessing
>
25 000 genes, somewhat
surprisingly there was only one gene identified that had
more than threefold higher expression in IDC/CA
+
compared
to IDC/CA tumors:
SChLAP1
, a long noncoding RNA that
was independently associated with unfavorable oncologic
outcomes in a previous study
[10]. Furthermore, in an
additional 393 samples,
SChLAP1
expression had 82.4%
overall accuracy in identifying IDC/CA
+
tumors. Unlike PGA
or hypoxia,
SChLAP1
appeared to be the primary intrinsic
biomarker of the negative outcomes associated with the
IDC/CA phenotype. In fact, at 5 yr after treatment,
SChLAP1
+
IDC/CA tumors had identical rates of biochemical
failure to
SChLAP1
IDC/CA
+
tumors.
Future work that will be of immense value is characteri-
zation of the chronology of the molecular events (genomic
instability and
SChLAP1
expression) in the evolution of IDC/
CA+ tumors. This is especially important to understand,
since the authors had previously shown that the variant
subpathology and the adjacent adenocarcinoma share a
clonal ancestry. In addition, despite the impressive sample
size in the present study, larger independent validation
studies are warranted to confirm, for example, that
SChLAP1
IDC/CA
+
tumors truly have a relatively favorable
prognosis and that
SChLAP1
could be used as a potential
confirmatory marker for pathologists in characterizing IDC/
CA. Ultimately, we must find a way to
weather the storm
of
IDC, and clinical trials are needed to optimize treatment
paradigms for this unique biologic subgroup.
Conflicts of interest:
The author has nothing to disclose.
Acknowledgments:
The author is supported by a Prostate Cancer
Foundation Young Investigator Award.
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