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

Tumor Markers in Colorectal Malignancy 33
(258, 259). Indeed, the median survival for patients with metastatic
CRC has almost doubled in the past 10 years as a result of
these new treatments (258-260). However, because these treatments
are potentially toxic as well as expensive, it is important
to establish as quickly as possible that they are effective in halting
tumor progression.
According to the 2006 ASCO guidelines, CEA is the
marker of choice for monitoring metastatic CRC during systemic
therapy (244). CEA should be measured at the start of
treatment for metastatic disease and every 1 to 3 months during
active treatment. Persistently increasing concentrations
suggest progressive disease even in the absence of corroborating
radiographs (242, 243). In 2003, the EGTM panel recommended
that serial CEA concentrations should be measured
every 2 to 3 months while patients are receiving systemic
therapy (246). Both the ASCO and EGTM guidelines stated
that caution should be used when interpreting increasing CEA
concentrations during the early phase of systemic treatment
(16, 18). This is because certain treatments (eg, 5-fluorouracil
and levamisole; oxaliplatin) can cause transient elevations in
CEA levels in the absence of disease progression (246).
For monitoring patients with advanced CRC undergoing systemic
therapy, the NACB panel recommends that regular CEA
determinations should be carried out. In agreement with the
ASCO panel (242, 243), a confirmed CEA increase (eg, 30%)
may be regarded as evidence of progressive disease. Of course,
it should be established that the increases are not false-positive
elevations due to either chemotherapy-mediated release of marker
or the development of a benign disease that produces CEA.
NACB Colorectal Cancer Panel Recommendation 4:
Serum CEA in Monitoring Patients With Advanced
Disease
In patients with advanced CRC undergoing systemic therapy,
regular CEA determinations should be carried out.
A confirmed CEA increase (eg, 30%) suggests progressive
disease provided the possibility of false-positive
elevations can be excluded [LOE, III; SOR, B].
OTHER SERUM MARKERS
CA 19-9
The CA 19-9 assay detects a mucin containing the sialated
Lewis-a pentasacharide epitope, fucopentaose II (for review, see
(261). CA 19-9 is a less sensitive marker than CEA for CRC
(262, 263). Preliminary findings suggest that like CEA, preoperative
concentrations of CA 19-9 are also prognostic in patients
with CRC (264-268). Based on available data, routine measurement
of CA 19-9 cannot be recommended for patients with CRC.
CA 242
The CA 242 assay also detects a mucin-like molecule.
Although less sensitive than CEA for CRC, assay of CA 242
may complement CEA in the surveillance of patients with CRC
(263, 269). Furthermore, a number of preliminary reports suggest
that preoperative concentrations of CA 242 are prognostic
in CRC (270, 271). Routine determinations of CA 242
should not be used at present in patients with CRC.
Tissue Inhibitor of Metalloproteinases Type 1
Tissue inhibitor of metalloproteinases type 1 (TIMP-1) is a 25
kDa glycoprotein with multiple activities including inhibition
of matrix metalloproteinases, promotion of cell proliferation,
and inhibition of apoptosis. Using a research enzyme-linked
immunosorbent assay (ELISA), which detects total TIMP-1
(ie, the non-complex form as well as TIMP-1 complexed to
matrix metalloproteinases), plasma concentrations of the
inhibitor were found to be significantly higher in patients with
CRC than in healthy controls, subjects with inflammatory
bowel diseases, subjects with adenomas or patients with breast
cancer (272, 273). For patients with Dukes’A and B colon cancers,
TIMP-1 appeared to be more sensitive than CEA for the
detection of cancer (ie, 58% vs 40% at 95% specificity and
56% vs 30% at 98% specificity). For patients with early rectal
cancer, TIMP-1 and CEA had similar sensitivity (272).
Other studies have shown that preoperative plasma TIMP-1
concentration is an independent prognostic factor in patients
with CRC (ie, independent of Dukes’ stage and tumor location
(274, 275)). Of particular note was the finding that stage II
patients with low plasma TIMP-1 concentrations
(dichotomized at the 70% percentile) exhibited a survival pattern
similar to an age and sex-matched background population.
Although these preliminary findings with TIMP-1 are
promising, the marker cannot be recommended at present
either for detecting early CRC or for evaluating prognosis in
patients with this malignancy.
NACB Colorectal Cancer Panel Recommendation 5:
CA19.9, CA 242, and TIMP-1 in CRC
Routine measurement of CA19.9, CA 242, or TIMP-1 is
not recommended [LOE, III/IV; SOR, B/C].
TISSUE MARKERS
Several tumor tissue markers have been evaluated for potential
prognostic and predictive value in patients with CRC. These
include thymidylate synthase (TS) (276-280), microsatellite
instability (MSI) (281-285), deleted in colon cancer (DCC)
(286-288), urokinase plasminogen activator (uPA)/plasminogen
activator inhibitor 1 (PAI-1) (289-291), mutant ras (292), and
mutant/overexpression of p53 (293). Based on available evidence,
none of these markers can at present be recommended
for routinely determining prognosis or for therapy prediction.
However, emerging evidence suggests that the presence of wild
type k-ras is associated with benefit from the anti-epidermal
growth factor receptor (EGFR) antibodies, cetuximab, and
panitumumab (294-297).