2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

adhesion molecule and further characterized by cytokeratin
expression and lack of the leukocyte marker CD45. 14 The
CTC count is a prognostic biomarker in CRPC and in other
solid tumors. Before the start of chemotherapy for CRPC,
the detection of five or more CTCs is associated with an
inferior OS compared to patients with less than five. Furthermore,
a drop in CTCs to below five during treatment is
associated with an improvement in survival. 15 Whether
CTCs have a greater association with survival than PSA or
radiographic changes over time is an important and unresolved
question. 16
Flares in the CTC count have not been reported, and
changes in the CTC count often precede changes in PSA. 17
Therefore, the CTC trend may be valuable for therapeutic
decision making in cases where other clinical assessments of
response are equivocal, though its use in this setting is
purely speculative. Prospective evaluation of whether the
CTC count may act as a surrogate for OS is ongoing, but the
initial study assessing its use as a surrogate in CRPC was
promising. 18
The potential use of CTCs as a biomarker is not restricted
to the current CTC detection method and definition. One
limitation of the CellSearch epithelial-based method is the
lack of detection of CTCs in many men with progressive,
metastatic CRPC. 17 Recent findings suggest that there is
CTC phenotypic heterogeneity, with some CTCs expressing
not only epithelial proteins, but also mesenchymal and
stemness proteins. 19 Therefore, epithelial-mesenchymal
transitions may explain the relative underdetection of CTCs
in patients with advanced malignancy using the standard
epithelial antigen-based technology. A number of technologies
that employ nonepithelial targets for CTC capture and
characterization are under development, though the prognostic
and predictive implications of these CTC phenotypes
must be independently and prospectively validated.
Because CTCs may be a direct measurement of the underlying
tumor biology, enhanced capture of CTCs may aid in
the development of CTCs as a predictive biomarker. For
example, the identification of phosphatase and tensin homolog
(PTEN) loss and androgen receptor amplification in
CTCs suggests that personalization of therapy using biomarker
guidance is achievable. 21,22 As additional CTC phenotypes
are discovered, potential therapeutic targets may
emerge. Thus, CTCs may provide prognostic information
through enumeration, but more importantly, they may provide
a noninvasive window into tumor biology and provide
predictive information for therapeutic decision making.
Lactate Dehydrogenase
The enzyme lactate dehydrogenase (LDH) converts pyruvate
to lactate and vice versa as part of the normal glycolysis
and gluconeogenesis pathways of the cell, and those pathways
are preferentially upregulated in cancer cells as a
result of oncogenic signaling. 22 LDH is an independent
prognostic biomarker in CRPC and other tumor types, and
elevations are thought to reflect the underlying tumor burden.
23 Assessments of LDH in conjunction with other biomarkers
such as PSA or CTCs may improve on the current
clinical utility of LDH for risk stratification and prognostication.
18 Also, although baseline LDH is strongly prognostic
in multivariate models in CRPC, increases in LDH following
therapy carry an unfavorable prognosis and may be useful in
interpreting treatment response. 24 Given the strong associ-
294
ation of LDH with OS in CRPC over time, however, serial
measurement and reporting of this factor during treatment
and in the context of clinical trials are useful and recommended.
Markers of Bone Turnover
Prostate cancer commonly metastasizes to the bone, and
this may be mediated by adhesion molecules that target the
bone microenvironment and promote osteomimicry. 25 As
such, agents that impede this tumor-bone stromal interaction
such as zoledronic acid and denosumab delay the
development of skeletal-related events in CRPC. 26,27 Bony
metastatic effects can be indirectly measured using bone
turnover markers such as N-telopeptide, tartrate-resistant
acid phosphatase 5b, C-telopeptide, and osteopontin, and
these are being evaluated for use as prognostic and predictive
biomarkers. 28 Bone-derived alkaline phosphatase,
which is a measure of osteoblastic activity, is an established
prognostic biomarker in CRPC. 29 The reduction in total
alkaline phosphatase with docetaxel is independently prognostic
in CRPC and may provide evidence of a survival
benefit even in the absence of decline in PSA or improvement
in imaging. 30 Overall, the measurement of total or
bone-derived alkaline phosphatase at baseline and over time
provides prognostic information but does not predict response
to bone-targeted therapy.
Urinary N-telopeptide, which is a breakdown product of
type 1 collagen, is elevated in men with CRPC and bony
metastases, and high N-telopeptide levels are associated
with an increased risk of skeletal-related events, disease
progression, and death. 31 Treatment with the receptor activator
of nuclear factor kappa B (RANK)-ligand antagonist
denosumab reduces the levels of N-telopeptide in the urine
beyond the reduction seen with zoledronic acid, though
whether this reduction correlates with denosumab’s superiority
in preventing skeletal-related events is unclear. 27 The
utility of N-telopeptide and other bone turnover markers as
predictive biomarkers for the use of bone-targeted agents is
an area of active investigation.
Hemoglobin
BITTING AND ARMSTRONG
Anemia in the setting of CRPC is often multifactorial,
related to androgen deprivation therapy, renal disease,
chemotherapy toxicity, bone marrow infiltration or failure,
or other comorbid conditions. Anemia has long been recognized
as a prognostic factor in CRPC and, in multivariate
analysis, is among the strongest predictors for docetaxelrelated
PSA declines, tumor response, and OS for men with
CRPC. 32 Thus, the measurement of hemoglobin over time
has both practical management and prognostic implications
in the treatment of men with CRPC.
Post-treatment Prognostic and Potential Surrogate
Endpoints in CRPC
Although imaging measurements are performed routinely
to assess disease status in oncology, the absolute size of a
metastatic lesion does not always correlate with clinical
outcome. The use of the Response Evaluation Criteria in
Solid Tumors (RECIST) in CRPC is especially problematic,
as RECIST does not account for skeletal lesions, the most
common site of metastasis and source of morbidity in
CRPC. 33 Bone scintigraphy is used to assess skeletal lesions;