Like PSA measures, CA125, CEA, and the like, they try to
reduce everything to a single number. We argue here that such an approach is
problematic at best. Furthermore they fail totally to demonstrate any internal
pathway influence. There is no predictive basis for their approach predicated upon
the actual dynamics of the cell. It is purely correlative and there may be
substantial confounders involved. This approach is an example of what we fell
to be the poorer aspects of genomics applied to cancer prognostics.
In a recent study the authors develop a score called the GPS
score which is based upon know malignant PCs cells and then argue that then
score has significant prognostic value. The authors state:
The Oncotype DX Prostate Cancer Assay has been clinically
validated, demonstrating that the GPS, assessed in diagnostic biopsy tissue,
can predict the likelihood of the presence of adverse pathology (high-grade
and/or high-stage disease), and that it complements existing pre-treatment risk
assessment tools such as PSA levels, Gleason Score, and clinical stage. The
assay is intended to help guide treatment decisions in early-stage prostate
cancer, including the decision between immediate therapy and active
surveillance. As evidence that the analytical assay was designed well for its
intended use to test RNA from small biopsies, in a clinical validation study,
valid GPS results were generated for more than 95% of samples requiring 1 mm
and 30 microns of tumor tissue…
They continue:
Optimization of the Oncotype DX platform has enabled the
development and analytical validation of the Oncotype DX Prostate Cancer Assay
for use with prostate biopsy specimens. This RT-PCR assay has been clinically
validated to predict the risk of high grade and/or non-organ confined disease
at radical prostatectomy using biopsy samples containing as little as 1 mm of
tumor tissue. The Oncotype DX Prostate Cancer Assay complements traditional
clinical and pathologic diagnostic features and will assist clinicians to
discriminate patients with indolent prostate cancer from aggressive prostate
cancer to help make the most appropriate treatment decisions.
The approach is as follows as shown in the Figure below.
Basically take the malignant cells and measure the expression of certain genes
via their RNA using a baseline reference gene expression level.
Now the genes they have selected are categorized as follows.
They have four categories related to PCa and one category for the purpose of
setting a reference level.
Stromal
Gene
|
Cellular
Organization Group
|
Androgen
Group
|
Proliferation
Group
|
Reference
Genes
|
BGN
|
FLNC
|
FAM13C
|
TPX2
|
ARF1
|
COL1A1
|
GSN
|
KLK2
|
ATP5E
|
|
SFRP4
|
TPM2
|
AZGP1
|
CLTC
|
|
GSTM2
|
SRD5A2
|
GPSI
|
||
PGK1
|
Now based upon the levels of expression of these genes
against the gene reference level they have proposed a metric which they term
the GPS metric which is a measure of prognostic value related to the
aggressiveness of the cancer. The GPS metric is given by:
Finally the specific value calculations by class are given
by:
We summarize this below:
Group
|
Genes
|
Weight
|
Stromal Gene
|
||
BGN
|
0.527
|
|
COL1A1
|
0.457
|
|
SFRP4
|
0.156
|
|
Cellular Organization Group
|
||
FLNC
|
0.163
|
|
GSN
|
0.504
|
|
TPM2
|
0.421
|
|
GSTM2
|
0.394
|
|
Androgen Group
|
||
FAM13C
|
0.634
|
|
KLK2
|
1.079
|
|
AZGP1
|
0.642
|
|
SRD5A2
|
0.997
|
|
Proliferation Group
|
||
TPX2
|
1.00
|
|
Reference Genes
|
||
ARF1
|
||
ATP5E
|
||
CLTC
|
||
GPSI
|
||
PGK1
|
We present graphically below thevalues as shown above, namely the weights:
From an earlier Press Release there was reported the results
of a study stating[2]:
Results showed that the test, developed in collaboration
with UCSF and Cleveland Clinic, strongly predicted disease aggressiveness
(p=0.002) offering information beyond currently available clinical factors,
such as PSA and biopsy Gleason Score, to help physicians and their prostate
cancer patients confidently choose the most appropriate treatment based on an individualized
risk assessment.
Furthermore, this first-of-its-kind, multi-gene test has
been validated to guide treatment decisions using the prostate needle biopsy
sample taken before the prostate is removed -- thereby providing the
opportunity for low risk patients to avoid invasive treatments such as radical
prostatectomy or radiation.
"The results of our study showed that the individual
biological information from the Oncotype DX prostate cancer test tripled the number
of patients who can more confidently consider active surveillance and avoid
unnecessary treatment and its potential side effects. The test also identified
a smaller number of patients who, despite seemingly low-risk clinical factors,
had more aggressive disease and, would suggest that they consider immediate
treatment," said Peter Carroll, M.D., MPH, professor and chair, Department
of Urology, UCSF and principal investigator of this validation study.
"With these new study results, I believe we may be
able to significantly increase the use of active surveillance, which has been
limited to some extent by the absence of a validated genomic tool to more
accurately distinguish low and high risk disease at the time of biopsy." Active
surveillance is a treatment plan that employs careful and consistent monitoring
of the cancer in a man's prostate without removing it. Under active
surveillance, patients have regular check-ups and periodic PSA blood tests,
clinical exams and potential biopsies to closely monitor for signs of prostate
cancer progression.
The Oncotype DX prostate cancer test measures the level
of expression of 17 genes across four biological pathways to predict prostate
cancer aggressiveness. The test results are reported as a Genomic Prostate
Score (GPS) that ranges from 0 to 100 and is combined with other clinical
factors to further clarify a man's risk prior to treatment intervention.
Now there are many significant issues in this analysis.
1. The weights are arguably chosen to maximize the risk of
missing an aggressive PCa. However I have not yet seen adequate clinical
evidence to that effect.
2. Prior proposed genes and the ones included herein are
shown below, one from the study currently in discussion and the other from a
prior study of a Myriad genetic profile:
Target Genes
Oncotype DX
|
Housekeeping Genes
Oncotype DX
|
Target
Gene
Myriad
|
Housekeeping
Gene
Myriad
|
AZGP1
|
ARF1
|
ASF1B
|
CLTC
|
BGN
|
ATP5E
|
ASPM
|
MMADHC
|
COL1A1
|
CLTC
|
BIRC5
|
MRFAP1
|
FAM13C
|
GPSI
|
BUB1B
|
PPP2CA
|
FLNC
|
PGK1
|
C18orf24
|
PSMA1
|
GSN
|
CDC2
|
PSMC1
|
|
GSTM2
|
CDC20
|
RPL13A;LOC728658
|
|
KLK2
|
CDCA3
|
RPL37
|
|
SFRP4
|
CDCA8
|
RPL38
|
|
SRD5A2
|
CDKN3
|
RPL4
|
|
TPM2
|
CENPF
|
RPL8
|
|
TPX2
|
CENPM
|
RPS29
|
|
CEP55
|
SLC25A3
|
||
DLGAP5
|
TXNL1
|
||
DTL
|
UBA52
|
||
FOXM1
|
|||
KIAA0101
|
|||
KIF11
|
|||
KIF20A
|
|||
MCM10
|
|||
NUSAP1
|
|||
ORC6L
|
|||
PBK
|
|||
PLK1
|
|||
PRC1
|
|||
PTTG1
|
|||
RAD51
|
|||
RAD54L
|
|||
RRM2
|
|||
TK1
|
|||
TOP2A
|
It should be obvious that these two tests are dramatically
different. Yet they claim similar results. The question is; what genetic
expression has gone astray? Why, for example, do we see such a massive
disparity? Frankly, other than CLTC we see no other commonality. What causes
these disparate expressions? The answers are left hanging. At least with PSA we
have some clear cause and effect. Here, at best, we have some correlative
values.
With such disparate sets of genes one wonders why and how
can these tests be compared if at all. Or, are these results just suggestive
and are neither causative or resulting from the lesions.
3. In the current test under discussion the cells used for
extraction are arguably from the prostate biopsy. The Myriad appear to be more
wide spread.
4. Are these tests worth anything? Furthermore, groups are
offering tests to assess risks based upon genetic profiles. As stated[3]:
Myriad also rolled out new tests. In September, the
company launched its myRisk Hereditary Cancer™ test, a 25-gene panel covering
eight major cancers (breast, colorectal, endometrial, gastric, melanoma,
ovarian, pancreatic, and prostate) at an average selling price of $3,700. In
October the company introduced myPlan Lung Cancer, which carries a $3,400 list
price; followed in November by myPath Melanoma, which has an average selling
price of $1,500. By 2015, Myriad has said, it expects to discontinue several
current tests, including the BRACAnalysis test at the center of the Supreme
Court case.
Just because some genetic profile may have some correlative
relationship the genetic profile is not causative. Tests like these can be
costly and of yet to be fully justified clinical value. Take a melanoma, if one
has a suspect pigmented lesion then a simple excision and competent path study
should suffice. That is an order of magnitude less than the genetic profile. In
fact if one were to do a profile it should be of the melanocytes and not of the
cells in general.
References
Knezvic, D., et al, Analytical validation of the Oncotype DX
prostate cancer assay – a clinical RT-CR assay optimized for prostate needle
biopsies, BMC Genomics 2013, 14:690.
[1]
See http://www.telmarc.com/Documents/White%20Papers/98%20CCP.pdf Note that
this study was based upon a different vendor with different genes.
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