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108
F. Cei et al.
pattern, indicating independent events in the genesis of multiple prostate cancers [36]. A more
recent study by Lindberg et al. assessed intraprostatic tumor heterogeneity through wholegenome proling, discovering a high level of
intraprostatic heterogeneity in individuals. Three
out of four individuals harbored tumors without a
common somatic denominator [37].
Given this conicting evidence, caution is
warranted, as no theory excludes the other, and
the truth may lie in between. One hypothesis is
that polyclonality may coexist with intraprostatic
metastasis. However, it is evident that the monoclonal hypothesis, coupled with the index theory,
has signicantly inuenced FT development, as
theoretically, patients with unifocal, biologically
unifocal, or at least unilateral tumors could be
treated with FT while maintaining a high standard of oncological safety. Despite this topic
remaining contentious in the eld of prostate
cancer’s biological nature, a growing body of
evidence supports the feasibility of achieving satisfactory cancer control through FT, particularly
during mid-term follow-up [38].
Conclusions
Prostate cancer predominantly presents as a multifocal disease. Nonetheless, the escalating trend
in early diagnosis has elevated the percentage of
patients exhibiting unilateral and unifocal diseases, rendering them potential candidates for
organ-sparing techniques such as FT.
Clinical signicance is attributed to lesions,
often identied as the index lesion, which substantially inuences the disease’s natural progression. Whenever feasible, addressing these
lesions is imperative. Although multiparametric
magnetic resonance imaging (mpMRI) has revolutionized the characterization of index lesions, it
still fails to detect clinically signicant prostate
cancer in approximately 30% of cases. Therefore,
transperineal mpMRI-guided biopsies remain
essential for accurately mapping the prostate.
The nature of prostate cancer remains a pivotal unresolved question. Despite lacking a denitive answer, both the index-lesion hypothesis
and the monoclonal origin of metastatic prostate
cancer advocate for considering FT in individuals
with biologically unifocal prostate cancer.
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Utility ofBiopsy-Based Genomic
Assays toRisk Stratify Patients
forActive Treatment
WeiPhinTan, SameerThakker, andJuddW.Moul
11
The eld of prostate cancer (PCa) diagnosis and
treatment has been signicantly transformed by
the advent of tissue-based biomarkers. These biomarkers represent a pivotal development, primarily due to their ability to provide a more detailed
understanding of the disease beyond the conventional parameters like prostate-specic antigen
(PSA) levels, histologic grade, and clinical stage.
The reliance on clinical and pathological variables alone often led to limitations in accurately
predicting the disease’s progression and responsiveness to treatments.
The introduction of biomarkers into the realm
of PCa management has been revolutionary,
especially in the context of personalized medicine. These biomarkers offer insights into the
biological behavior of the tumor, facilitating
more informed decision-making regarding treatment strategies. This is particularly relevant in
cases where the traditional methods of assessment may not fully capture the complexity and
W. P. Tan (*) · S. Thakker
Department of Urology, NYU Langone Health,
New York, NY, USA
e-mail: weiphin.tan@nyulangone.org;
Sameer.thakker@nyulangone.org
J. W. Moul
Department of Urology, NYU Langone Health, New
York, NY, USA
Department of Urology and Duke Cancer Institute,
University Medical Center, Durham, NC, USA
e-mail: judd.moul@duke.edu
heterogeneity of the disease. The role of biomarkers in PCa thus extends from early detection
and diagnosis to prognosis and monitoring of the
response to therapy.
In this context, this chapter will delve into
various tissue-based biomarkers such as
Decipher, Oncotype DX, Prolaris, and Conrm
MDx, exploring their scientic background, clinical applications, and the potential future directions in their usage. Each biomarker presents
unique attributes and challenges, which will be
discussed in detail to understand their place in the
current landscape of PCa management
(Table 11.1). These molecular biomarker tests
have been developed with extensive industry support, guidance, and involvement, and have been
marketed under the less rigorous U.S.Food and
Drug Administration (FDA) regulatory pathway
for biomarkers [1]. Although full assessment of
their clinical utility requires prospective randomized clinical trials, which are unlikely to be done,
patients with low or favorable intermediate disease and life expectancy greater than or equal to
10 years may consider the use of Decipher,
Oncotype DX Prostate, or Prolaris during initial
risk stratication [1].
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
T. J. Polascik et al. (eds.), Imaging and Focal Therapy of Early Prostate Cancer,
https://doi.org/10.1007/978-3-031-66754-1_11
111
112
Table 11.1 Tissue-based biomarkers
Biomarker type Platform Populations studied
Decipher Whole- transcriptome 1.4M RNA
expression (46,050 genes and
noncoding RNA) oligonucleotide
microarray optimized for FFPE
tissue
Oncotype DX
Prostate
Prolaris Quantitative RT-PCR for 31 cell
Conrm MDx Detect an epigenetic eld effect or
FFPE formalin-xed parafn-embedded, RP radical prostatectomy, PSA prostate-specic antigen, EBRT external beam
radiation therapy, CRPC castrate-resistant prostate cancer, RT-PCR reverse transcription-polymerase chain reaction, AA
African American
Quantitative RT-PCR for 12
prostate cancer- related genes and
ve housekeeping controls
cycle-related genes and 15
housekeeping controls
“halo” associated with the
cancerization process at the DNA
level
Post-RP, adverse pathology/high-risk features
Post-RP, biochemical recurrence/PSA persistence
Post-RP, adjuvant, or post-recurrence radiation
Biopsy, localized prostate cancer post-RP or EBRT
M0 CRPC
Biopsy, very-low- to high-risk, treated with RP
Biopsy, conservatively managed (active surveillance)
Biopsy, localized prostate cancer
Biopsy, intermediate-risk treated with EBRT
RP, node-negative localized prostate cancer
Biopsy, Gleason grade 3+3 or 3+4
Risk of PCa on repeat biopsy after negative index biopsy
(AA men)
DOCUMENT—Risk of any PCa on repeat biopsy within
13months after negative index biopsy (all comers)
MATLOC—Risk of high grade (GGG>7) PCa on repeat
biopsy (all comers)
W. P. Tan et al.
Decipher
The Decipher test (Decipher Biosciences, San
Diego, CA, USA) utilizes a microarray platform
to measure the expression levels of 22 genes that
participate in the biological pathways of PCa.
This test requires the extraction of RNA tissue
from formalin-xed parafn-embedded tissue
and a tumor specimen of at least 0.5 mm. The
Decipher test can be performed on a biopsy specimen or a radical prostatectomy specimen. The
score reports a number ranging from 0 to 1. A
score of 0 to 0.45 is dened as low risk, 0.46 to
0.6 is average risk, and above 0.61 is high risk.
The Decipher biopsy report provides an assessment of adverse pathology at the time of radical
prostatectomy, risk of metastasis with radical
prostatectomy or radiation therapy at 5 and
10years, and risk of PCa-associated mortality at
15 years. Most of the data to support Decipher
Biopsy come from studies done on RP specimens
[2, 3]. Therefore, it may be particularly useful in
post-prostatectomy settings where it aids in making decisions about additional treatments like
adjuvant radiation therapy.
Multiple studies have evaluated the utility of
the Decipher test in clinical decision-making.
Many of these studies showed that Decipher testing resulted in changing the urologist’s adjuvant
treatment recommended post-prostatectomy [4].
According to the National Comprehensive
Cancer Network guidelines, patients with unfavorable intermediate- and high-risk disease and a
life expectancy of greater than or equal to
10 years may consider using Decipher [1]. The
goal of the test in this context is to aid in the
selection of candidates for active surveillance.
There are no data analyzing the utility of Decipher
testing to stratify patients for FT.
Oncotype DX
Oncotype DX (Genomic Health, Redwood City,
CA, USA) is a test that uses reverse transcriptasePCR to quantify the expression levels of 12 cancer genes and ve housekeeping genes. The
twelve cancer genes are integral parts of four primary cellular pathways: proliferation (TPX2),
androgen receptor pathway (AZGP1, KLK2,
11 Utility ofBiopsy-Based Genomic Assays toRisk Stratify Patients forActive Treatment
113
SRD5A2, FAM13C), cellular organization
(FLNC, GSN, TPM2, GSTM2), and stromal
response (BGN, COL1A1, SFRP4). The combination of these genes is used to determine the
Genomic Prostate Score (GPS), which ranges
from 0 to 100. The GPS delineates the 10-year
metastasis-free survival and 10-year PCaassociated mortality and adverse pathology [3].
Similar to the Decipher test, studies pertaining to
the role of Oncotype DX showed that it resulted
in a change of treatment recommendation.
Specically, utilizing Oncotype DX resulted in
an increase in active surveillance (41% to 51%)
and decreased prostatectomy from 21% to 19%
[5]. According to the NCCN guidelines, Oncotype
DX may be offered to men with very-low, low-,
or favorable intermediate-risk PCa on biopsy and
a life expectancy of at least 10years [1]. There
are no data analyzing the utility of Oncotype DX
testing to stratify patients for FT.
Prolaris
The Prolaris test (Myriad Genetics, Salt Lake
City, UT, USA) measures the expression of 31
cell cycle progression (CCP) genes related to
cancer proliferation and can be performed on
either a biopsy or RP specimen [6]. The biopsy
test delineates the 10-year PCa-specic mortality
and 10-year metastasis-free survival.
Combining the patient’s PSA, clinical stage,
percentage of positive cores, biopsy grade group,
and AUA risk group, the Prolaris biopsy test
offers a 10-year risk of PCa-specic mortality.
The PROCEDE-1000, a substantial prospective
registry involving nearly 1600 participants, indicated that the CCP score led to a treatment modication for 47.8% of patients [7].
Despite the utilization of the CCP score to
assist physicians and patients in making personalized treatment decisions, there are currently no
prospective data demonstrating the clinical superiority of the decisions informed by the test. There
are no data analyzing the utility of Prolaris testing
to stratify patients for FT.According to the NCCN
guidelines, the Prolaris biopsy test may be recommended to men with very-low, low-, and favor-
able intermediate-risk PCa on biopsy and a life
expectancy of at least 10years [1].
Conrm MDx
Conrm MDx (MDxHealth, Plano, TX, USA) is
a tissue-based gene assay that again helps stratify
patients who are considering a repeat biopsy.
Conrm MDx focuses on epigenetic changes in
the DNA of cells in the prostate. Specically, the
test focuses on the hypermethylation of genes
associated with prostate cancer, thus serving as a
robust biomarker for the disease. This test is particularly useful when considering the limitations
of traditional biopsies, which can miss cancer
due to sampling errors.
The Conrm MDx test looks for a “eld
effect” or epigenetic changes in the DNA of cells
adjacent to cancer foci. This effect can help to
identify men who may have had a false-negative
biopsy and determine whether they should
undergo another biopsy. The “halo” around a
prostate cancer tumor can be detected by this test
even when the tumor itself is not sampled, due to
the epigenetic changes that occur in both cancerous and surrounding cells.
In the era of prebiopsy MRI, there might be
limited role for the test. There are no data analyzing the utility of Conrm MDx testing to stratify
patients for FT, but perhaps this test could be
used in the post-FT setting to determine if the
ablated prostate tissue has been adequately
treated. This is clearly hypothesis-generating and
has never been utilized in this setting to date.
Critical Reections onFocal Therapy
andTissue-Based Genomic Tests
One of the inherent challenges of FT is the risk of
missing or undertreating high-risk tumor areas
within the prostate. This concern arises because
FT primarily targets the index lesion, potentially
leaving behind viable tumor cells within the
treated zone or elsewhere in the prostate. The
precision of FT is heavily reliant on the accuracy
of multiparametric MRI (mpMRI) and biopsy
results, which, despite advancements, are not
infallible. Follow-up biopsy studies have demon-
114
W. P. Tan et al.
strated instances of upgrading from intermediateto high-risk disease in patients post-FT,
underscoring the need for rigorous patient selection and monitoring. Advances in molecular
diagnostics and biomarkers offer promising avenues for enhancing the detection of residual disease in the FT context. Liquid biopsies, detecting
circulating tumor DNA or cells, could potentially
provide a non-invasive method to monitor for
residual or recurrent cancer. Additionally,
research into specic genetic or epigenetic
changes associated with prostate cancer progression may yield new biomarkers that can be leveraged to improve the accuracy of post-FT
surveillance.
Concurrently, an ongoing challenge in FT is
the potential for the development of de novo
prostate cancer in the untreated portions of the
prostate. It is not clear what percentage of men
undergoing FT subsequently go on to develop
truly de novo disease as opposed to recurrence of
the index lesion at another site due to multi-focal
disease. Currently, no genomic test can denitively predict this risk, highlighting an area for
future research. The ability of a test to forecast
the likelihood of new cancer formation post-FT
would represent a signicant advancement in
personalized prostate cancer care.
With regard to current applications, the integration of tissue-based genomic tests, such as
Decipher, Oncotype DX, Prolaris, and Conrm
MDx, could signicantly augment the FT treatment algorithm. By providing a more detailed
molecular prole of PCa, these tests offer
insights into the aggressiveness and potential
behavior of the disease that goes beyond traditional clinical and pathological assessments. For
instance, a genomic test indicating a high risk of
aggressive disease could suggest the need for a
more extensive treatment approach, even in the
context of FT.
However, the cost implications of incorporating genomic tests into the FT algorithm warrant
consideration. While FT aims to be a costeffective treatment option by reducing morbidity
and preserving quality of life, the addition of
expensive genomic tests could increase the overall cost burden. However, if these tests can rene
patient selection, guide more precise targeting of
therapy, and potentially reduce the need for subsequent treatments by avoiding undertreatment,
they may offer value that justies their cost.
Limitations
The use of tissue biomarkers for PCa necessitates
consideration of their limitations. Firstly, many
of these biomarkers have been validated predominantly in cohorts of White Caucasian men, overlooking potential differences in PCa
aggressiveness among different races, particularly evident in African American men who face
higher incidence and mortality rates [8–10]. The
mortality disparities may be attributed to unequal
access to care rather than genetics, an area
actively under research, requiring further validation for the use of genetic risk classiers in
African American men [11].
Secondly, most tissue-based biomarkers face
inconsistent insurance coverage in the United
States, potentially limiting their accessibility for
certain patient populations due to nancial constraints. Thirdly, these tests are extremely costly,
and there is a lack of data on cost-effectiveness,
although studies indicate potential cost savings
with specic care models [12].
Fourthly, the heterogeneity and multifocality
of primary PCa present challenges, as gene
expression assays on low-grade biopsy tissue
may not capture the presence of coexisting
aggressive disease [13]. The genomic classier
scores can also vary depending on the biopsy
core or area of the prostatectomy specimen analyzed, highlighting the challenges in genomic
risk classication for tumors with clonal and
genomic heterogeneity.
Fifthly, many tissue biomarker studies were
conducted in the pre-MRI era, raising questions
about their clinical utility beyond MRI-guided
interventions. The absence of head-to-head comparative studies leaves uncertainty regarding the
superiority of one tissue biomarker over another,
making the choice dependent on individual clinician and patient preferences, as well as nancial
considerations. Sixth, there are no data pertaining
11 Utility ofBiopsy-Based Genomic Assays toRisk Stratify Patients forActive Treatment
115
to these tissue biomarker tests to determine if a
patient should receive whole gland treatment versus FT.
Finally, the lack of prospective studies underscores the need to assess the role of tissue biomarkers in guiding specic therapies and
impacting PCa-specic outcomes, necessitating
trials similar to the TAILORx trial in breast cancer for a comprehensive evaluation [14].
Aside from the tissue biomarkers, there is the
emerging concept of “Liquid Biopsy,” using
peripheral blood or urine to help inform clinical
decision-making. One example is the Exosome
Dx molecular urine assay (Bio-Techne
Corporation, 266 Second Avenue, Suite 200,
Waltham, MA 02451). This urine assay exploits
the measurement of three prostate-related genes
in exosomes which are released into the urine
from the prostate gland. The three genes are PCA3, SPEDF, and EGR, and this test is based on
RT-PCR expression analysis. While currently
FDA-cleared for use in men with a PSA between
2 and 10 to predict the presence of Gleason 7
(grade group 2 or greater) disease, it is not yet
cleared for use in men with known prostate cancer. An ongoing study in men with prostate cancer
on active surveillance is exploring the value of
this molecular biomarker to predict progression.
In advanced disease, a growing number of
molecular assays are exploiting circulating tumor
cells from blood to help inform clinical decisions. The cellular yield in advanced disease
makes this an attractive option; however, for
early-stage disease (in particular, men who have
limited disease for possible FT), the technology
is still not capable of consistently detecting informative molecular results.
Conclusion
In recent years, numerous tissue-based genomic
tests have surfaced, providing prognostic information that goes beyond standard clinicopathologic variables [15]. These tests are accessible at
different stages in the PCa care pathway, offering
valuable insights into the risk of high-grade disease, metastasis rates, and cancer-specic sur-
vival. Despite the advancements, several
challenges remain. As of now, Decipher and
Prolaris have the most extensive supporting data;
however, neither has demonstrated superiority in
comparative studies. While some tests have
shown a signicant impact on management—
guiding decisions related to active surveillance,
denitive therapy, and adjuvant radiation postprostatectomy—there is a lack of prospective
studies supporting their inuence on diseasespecic outcomes. Further, none of these tests
have been evaluated in the FT setting [16].
Nevertheless, integration into daily clinical practice and insurance coverage remain areas that
require further attention for physicians and
patients to fully benet.
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Can Understanding andUtilizing
theTumor Microenvironment
Enhance theTherapeutic Ecacy
ofFocal Therapy?
PetrMacek, RafaelTourinho-Barbosa,
LucaLunelli, andRafaelSanchez-Salas
12
Focal therapy (FT) or partial gland ablation
(PGA) destroys only a selected part of the prostate with prostate cancer (PCa) and its surroundings to ensure correct treatment. The efcacy of
such treatment depends on multiple factors, such
as cancer location, its extent, and aggressiveness,
but also based on the selected energy, duration of
its exposure, and the experience of the treating
physician. However, a comparison of the efcacy
of different energies and treatment patterns is difcult due to inconsistency in the reporting and
the mostly retrospective nature of published data
[1]. In order to increase the efcacy of the treatment, it is not only necessary to correctly select
the energy, treatment pattern, and duration of a
treatment cycle, but we may potentially increase
its impact by understanding the tumor microenvironment (TME). TME seems to play an impor-
P. Macek (*)
Department of Urology, Institut Montsouris,
Paris, France
e-mail: petr.macek@imm.fr
R. Tourinho-Barbosa
Instituto D’Or de Pesquisa e Ensino and Hospital
Cardio Pulmonar, Salvador, Brazil
L. Lunelli
Department of Urology, Hôpital Louis Pasteur,
Chartres, France
R. Sanchez-Salas
Department of Surgery, Division of Urology, McGill
University, Montreal, QC, Canada
tant role in PC progression and metastasis [2, 3].
PCa cells may escape the immune system via this
complex microenvironment as it may have antitumor activity. It has been demonstrated that FT
has an immunomodulatory effect and may elicit
an immune response that can impact tumor evolution [4–6]. Therefore, TME itself could be an
additional target for pharmacological or nonpharmacological manipulation in order to achieve
better oncological control.
Background
TME is a complex tissue space composed of a
tumor cell population and its surrounding space
(stroma). TME may be, therefore, also called a
reactive stroma as tumor cells modulate its activity [3]. The surrounding space includes stromal
cells (mainly broblasts or their altered versions),
immune cells, extracellular matrix (ECM) with
multiple humoral factors (e.g., chemokines, cytokines, matrix-degrading enzymes), and blood
vessels [7, 8]. There is a continuing interaction
among individual cells and their clusters via cellto- cell signaling either directly or indirectly by
cytokines or extracellular vesicles [3, 9].
Tumor cells may inuence the extracellular
matrix, and broblasts promote angiogenesis
with resulting disease progression and/or
increased metastatic potential [7]. Tumor cells
alter as well functioning of immune cells, such as
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
T. J. Polascik et al. (eds.), Imaging and Focal Therapy of Early Prostate Cancer,
https://doi.org/10.1007/978-3-031-66754-1_12
117
118
P. Macek et al.
macrophages, neutrophils, natural-killers (NK
cells), and T and B cells [9, 10].
Fibroblasts alter ECM by secretion of collagen type I and III and are able to transform into
myobroblasts. Furthermore, smooth muscle
cells of normal stroma are substituted during
tumorigenesis by myobroblasts, which progress
to cancer-associated broblasts (CAF). These are
somewhat similar to those present in tissue healing and brosis as they result from an activation
process [8]. Transformation into CAF is affected
by the production of tumor growth factor-β
(TGFβ) [11]. CAF are responsible for crosstalk
with tumor cells and ECM remodeling with overexpression of certain matrix proteins such as collagen I, bronectin, and tenascin C (TNC) [8, 10,
12]. CAF are also responsible for prostate cancer
progression, metastatic potential, and castration
resistance [11].
Important production of proteins and cytokines such as PDGFRB (platelet-derived growth
factor receptor beta), broblastic-specic protein
1 (FSP-1), and α-SMA (smooth muscle actin),
broblast-activating protein (FAP), interleukin-1
(IL-1), IL-6, and IL-8, chemokine C-X-C receptor (CXCR4), chemokine C-X-C ligand
(CXCL12), growth differentiation factor 15
(GDF15), broblast growth factor (FGF), hepatocyte growth factor (HGF), hypoxia-inducible
factor 1 alpha (HIF-1α), and vascular endothelial
growth factor (VEGF) has been described in the
TME.Transforming growth factor-beta is upregulated, and TGFβ-receptors are downregulated
[8, 9]. There is an increase of macrophages and T
cells, with a decrease of mast cells and, as previously mentioned, of smooth muscle cells [8].
There are two main phenotypes of macrophages—M1 and M2. M1 types are cytotoxic and
M2 are associated with immunosuppressive TME
[3, 13, 14]. M2 macrophages are also responsible
for the transformation of broblasts to CAF [13].
There is a difference in macrophage inltration
in localized and metastatic tumors. Localized
prostate cancers have a great proportion of the
M1 population, whereas metastatic PCa has an
increased population of M2 macrophages [15].
Prostate cancer belongs among cold tumors
with rather low T-cell inltration, reduced den-
dritic cell activation, and the presence of myeloidderived suppressor cells (MDSC), which are a
heterogeneous population of rapidly proliferation
cells with immunosuppressive potential [16].
Tumor cells within a cold tumor also express
reduced major histocompatibility complex
(MHC) class I glycoproteins and tumor antigen
expression, which is related to poorer immune
recognition of these tumors [17].
TME may also be impacted by a relative
hypoxia which is possible due to increased tumor
oxygen demands and aberrant microvascular network due to aberrant vessel formation. The
hypoxia induces HIF1-α production and, with
subsequent VEGF expression, iNOS, and Arg-1
production [10]. Hypoxia is related to increased
mutational load and PTEN alterations [18].
Focal therapy / partial gland ablation is aimed
at destroying a tumor population. This is achieved
by several different energy sources available.
They are either thermal-based, such as cryoablation, high-intensity focal ultrasound, and lasers,
or non-thermal, such as irreversible electroporation. Different energy sources are described in
appropriate chapters of this book.
FT destroys the tissue by multiple actions,
above all, namely physical cell damage (rupture
of the cell membrane) with the extracellular
release of intracellular content, protein denaturation, disturbance of normal metabolic function
of mitochondria, initiation of cellular stress
responses, necrosis and apoptosis cascade activation, vascular damage, and possibly by activation
of immune response [19]. Tumor necrosis is
linked with a large availability of tumor antigens,
which may be taken by macrophages for immune
activation. On the other hand, energy-induced
vascular damage (vasostasis and destruction of
microvascularity) results in poor vascularization
of the treated area.
Mechanical cellular destruction leads to the
release of danger signals, such as damageassociated molecular patterns (DAMP), ATP, and
the activation of heat shock proteins (HSP) [16].
Such HSP activation may lead to the activation of
antigen-presenting cells (APC= dendritic cells,
NK cells, and macrophages) and increase inltration of cytotoxic T cells in the tissue. This is, in