use of tumor markers in testicular, prostate, colorectal, breast, and ...

54 Use of Tumor Markers in Testicular, Prostate, Colorectal, Breast, and Ovarian Cancers
recommendations based on the information below and other
established guidelines.
CA125
In 1981, Bast et al identified the CA125 antigen with the
development of the OC 125 murine monoclonal antibody
against cell line OVCA 433, which was derived from a patient
with ovarian serous carcinoma (409). The CA125 molecule
has since been cloned using a partial cDNA sequence originating
from the peptide core of the molecule identified (410).
This new mucin molecule has been designated CA125/
MUC16 (gene MUC16) and consists of a 156-amino-acid
tandem repeat region in the N-terminus and a possible transmembrane
region and tyrosine phosphorylation site in the
C-terminus.
The first immunoassay for CA125, commercialized in
1983, used the OC 125 antibody for both capture and detection
(411, 412). A second-generation assay (CA125 II) was
subsequently developed, incorporating M11 and OC 125 antibodies,
which have distinct nonoverlapping epitopes. Assays
for CA125 have since been adapted to automated platforms
and although the majority of manufacturers quote a similar
reference interval, concentrations of CA125 may vary among
manufacturers due to differences in calibration, assay design,
and reagent specificities. The lack of an international standard
for CA125 hampers progress in improving betweenmethod
comparability and the clinical and laboratory communities
should work toward producing and adopting such a
standard. For the present, values from different methods are
not interchangeable and patients who are serially monitored
should be re-baselined If there is a change in methodology
(413). Manufacturers should specify the standard preparation
against which their method is calibrated and laboratories
should indicate the CA125 method used on their clinical
reports.
The cut-off of 35 kU/L for the CA125 and CA125II assays
was determined from the distribution of values in healthy individuals
to include 99% of normals (414). Values tend to decline
with menopause and aging (415). It has recently been reported
that CA125II concentrations vary 20% to 50% by race in postmenopausal
women, with concentrations in African and Asian
women lower than in white women (415). Menstrual cycle variations
can also be found (412). Elevated values may be found
in 1% to 2% of normal healthy individuals, 5% of those with
benign diseases, and 28% of those with non-gynecologic cancers
(15, 411, 412).
It is recommended that analysis be performed shortly after
prompt centrifugation of the specimen and separation of serum
from the clot, and that specimens be stored at either 4°C (1 to
5 days) or –20°C (2 weeks to 3 months) in the short-term or
–70°C in the long-term to ensure stability (15). Plasma is an
acceptable specimen type for some assays, where indicated by
the manufacturer. As in other immunoassays, assay interferences
may be observed if heterophilic antibodies are present
in the serum, particularly after therapeutic or diagnostic use of
monoclonal antibodies.
NACB Ovarian Cancer Panel Recommendation 1:
Handling of Specimens for CA125 Determination
Analysis should be performed shortly after prompt centrifugation
of the specimen and separation of serum from
the clot, and specimens stored at either 4°C (1 to 5 days)
or –20°C (2 weeks to 3 months) in the short-term or
–70°C in the long-term [LOE, not appliable; SOR, A].
The recommendations of the current NACB panel and
other groups with respect to the potential clinical utility for
CA125 are summarized in Table 16 and are described below.
Screening/Early Detection
For women with epithelial ovarian cancer, 80% have CA125
levels 35 kU/L, with elevations of 50% to 60% in clinically
detected stage I disease, 90% in stage II, and 90% in stages
III and IV (412, 416). Concentrations correlate with tumor burden
and stage. Due to the lack of sensitivity and specificity for
a single determination of the marker, CA125 is not recommended
for use in screening asymptomatic women by the
NACB panel as well as other authoritative organizations (15,
403, 405-408). An NIH Consensus Development Panel has
concluded that evidence is not yet available that either CA125
or transvaginal ultrasonography effectively reduce mortality
from ovarian cancer (408). However, the same panel did recommend
annual CA125 determinations, in addition to pelvic
and ultrasound examinations, for women with a history of
hereditary ovarian cancer who have an estimated lifetime risk
of 40%, as early intervention may be beneficial.
A number of approaches have been proposed to improve
the specificity of CA125 for early detection as very high specificity
(99.7%) is needed to achieve an acceptable positive predictive
value of 10% with a prevalence of disease of 40 per
100,000 in women older than 50 years (417). Strategies have
included sequential or two-stage strategies combining CA125
with ultrasound, longitudinal measurements of CA125, and
measurement of CA125 in combination with other markers,
such as OVX1, M-CSF, or other new biomarkers discovered
using proteomic profiling approaches (411, 417-419). In order
to evaluate the potential role for CA125 in screening for ovarian
cancer in asymptomatic populations, two major prospective
randomized trials are currently in progress in the United
States (420) and the United Kingdom (421). In total 200,000
women will be randomly assigned to either screening with
ultrasound, screening with CA125 plus ultrasound, or no
screening. The studies are adequately powered to detect a significant
improvement in survival among women screened with
serial CA125 measurements and transvaginal sonography.
NACB Ovarian Cancer Panel Recommendation 2:
CA125 in Screening
CA125 is not recommended for screening asymptomatic
women [LOE, III; SOR, B].