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192
F.E. Marti and M.P. Saunders
It was initially described by Gold and Freedman [ 8 ] . It was named as such after being
found both in epithelial cancers (mostly gastrointestinal) and fetal tissue. Since then,
CEA has been the most widely used and best characterized biomarker in CRC.
CEA comprise a group of complex glycoproteins that are related to molecules of
the immunoglobulin gene superfamily. Among other functions, members of this fam-
ily play a role in the intercellular adhesion, antigen presentation, and as antigen recep-
tors. The genes coding for CEA are clustered in chromosome 19. As other members
of the Ig family, CEA has been linked to intercellular adhesion. Also, some experi-
mental models suggest that it might contribute to the development of metastasis by
binding to distant CEA receptors. These preclinical models have been able to link the
production of CEA to a higher rate of metastasis and also shown that migration and
metastasis can be induced by the artifi cial injection of CEA in the circulation [
9 ] .
The initial isolation and characterization of CEA was done in tissue. CEA pro-
duction was found in epithelial tumors of the colon, rectum, breast, and lung but
predominantly in those of the lower GI tract. Around 90% of CRCs will produce
CEA. Furthermore, the distribution of CEA within the cells has been linked to his-
tological grade (CEA is found apically in well-differentiated cells and within cyto-
plasm and intercellular surface in poorly differentiated cells).
The most widely used measurement, however, is that of serum CEA. This mea-
surement has overcome the diffi culties associated with an immunological assay (dif-
ference in specifi cities and epitopes for each antibody used) in order to become the
clinically reliable test that it is now. Although the process now has been standardized,
CEA readings are still subject to interlaboratory variability. As a result of this and in
order to minimize errors, longitudinal measurements of CEA should be performed by
the same laboratory through time if they are to infl uence clinical decision making.
The amount of CEA seen in plasma and that observed in the tumor are not neces-
sarily correlated. Well-differentiated and left-sided tumors have been associated
with higher levels of circulating preoperative CEA. As the clearance of CEA is done
through the liver, a high quantity of CEA will be eliminated by fi rst pass through the
portal system. This is why relatively higher levels of preoperative CEA are seen in
rectal tumors. Also, as CEA is found apically in well-differentiated cells, this posi-
tion makes them relatively more prone to shed some of this CEA due to trauma to
the cell into the circulation.
CEA is, however, not exclusively found in cancer patients in the adult popula-
tion, and there is a series of pathologies and conditions that will lead to increase
circulating levels of CEA. These include infl ammatory conditions of the bowel such
as infl ammatory bowel disease, liver pathology like cirrhosis and cholelithiasis,
renal failure, bowel obstruction, and smoking. What is common to all these noncan-
cerous conditions that can give raised levels of CEA is that, very rarely, this level
will be above 10 ng/mL and that it fails to display the typical upward trend found in
malignant conditions [ 10 ] .
In clinical practice and due to its relatively low sensitivity and specifi city, CEA
has no current role in the screening and diagnosis of CRC. With a cutoff level of
2.5 ng/mL, the sensitivity of the assay ranges from 30% to 80%. In the perioperative
setting, however, CEA provides prognostic information. Several studies have
193
14 Chemotherapy and Biomarkers
confi rmed high preoperative levels of CEA as an independent prognostic factor for
poor outcome and reduced 5-year survival in patients undergoing potentially cura-
tive resections. Wanebo et al. showed that at 30 months and for patients with Dukes’
B, the proportion of patients free of disease was 45% if they had a preoperative CEA
of >5 ng/mL and 78% if the value was <5 ng/mL. For patients with Dukes’ C can-
cers, they also found that at 30 months, the proportion of patients free of disease was
15% if CEA was >5 ng/mL and 41% if <5 ng/mL [
11 ] . CEA level has also been
correlated with disease stage in several studies. In these, levels of CEA above 5 ng/
mL were found in 3% of patients with Dukes’ A disease, in 25% of Dukes’ B
patients, in 45% of Dukes’ C patients, and in 65% of Dukes’ D tumors [ 11– 13 ] . The
information provided by CEA must be utilized in conjunction with other prognostic
and staging tools and never in isolation in order to make decisions with regard to
surgical resections.
Following surgery, the levels of CEA should normalize within 4–6 weeks [ 14 ] .
The reported half-life (T1/2) for CEA is of 4–5 days [ 15, 16 ] . Because of this, a rela-
tively quick drop in CEA levels is expected postoperatively. Persistently high levels
of CEA in this setting indicate the presence of metastatic disease or incomplete
resection [ 17 ] .
Another area where CEA testing has a current role is that of surveillance follow-
ing a curative resection [ 18 ] . Both the European Group on Tumor Markers (EGTM)
[ 19 ] and the American Society for Clinical Oncology (ASCO) [ 20 ] recommend the
regular analysis (2–3 monthly) of CEA values in the follow-up setting of patients
with stage II and III disease for at least 2–3 years following diagnosis. Serial CEA
testing has a sensitivity of around 80% and a specifi city of 70% in the detection of
recurrences from CRC. Although initially the surveillance was proposed only for
those patients for whom curative liver resection was an option [ 21 ] , the indications
have been recently extended as, for the less fi t patients, the detection of a recurrence
will mean a more prompt initiation of palliative treatment with chemotherapy. Both
expert bodies, however, stress the importance of concomitant imaging investiga-
tions and clinical assessment as part of the decision making.
CEA has also been used as a biomarker of response for those patients with
advanced disease undergoing a course of treatment as around 70% of patients with
stage IV disease will have measurable levels of CEA. Even in this setting, clinical
decisions will be made with accompanying imaging and clinical information (see
previously cited guidelines).
14.5 Pharmacological Biomarkers
Variation in an individual’s germ-line DNA affects their response to chemothera-
peutic agents. These variations can alter drug metabolism and moderate the side-
effect risk of the patient. 5-Fluorouracil (5-FU), an antimetabolite, is the mainstay
of all current standard CRC chemotherapy regimens. Its side effects include
myelosuppression, mucositis, diarrhea, hand and foot syndrome, and cardiac
194
F.E. Marti and M.P. Saunders
toxicity. Up to 30% of patients will experience serious side effects (grade 3 or 4),
with 0.5% of these being fatal. Dihydropyrimidine dehydrogenase (DPD) is a
hepatic enzyme involved in the catabolism of uracil and thymine and is the initial
rate limiting enzyme of 5-FU hepatic metabolism. Defi ciency in DPD enzyme
has been associated with increased 5-FU toxicity. The reduced metabolism
results in 5-FU accumulation and hence more serious and life-threatening side
effects. DYPD is the gene which encodes DPD. More than 17 functional muta-
tions have been identifi ed which are associated with increased 5-FU toxicity.
Mutations in the DYPD gene only account for some of the severe 5-FU adverse
reactions and there is not a clear genotype-phenotype association. Currently
there are no assays for assessing DPD or DYPD status, with suffi cient predictive
accuracy prior to commencing 5-FU therapy. It is hoped that following further
assay development and prospective trials, DPD phenotyping and/or DYPD geno-
typing will have a clinical utility in predicting those patients who are likely to
suffer serious life-threatening 5-FU toxicity.
With the exception of the EGFR-inhibitors, current chemotherapeutic treatment
for CRC is not tailored to individual tumor characteristics. This results in many
patients undergoing treatment with ‘toxic’ chemotherapy drugs from which they are
unlikely to benefi t. In recent years, potential predictive biomarkers for response/
resistance to chemotherapeutic agents have been reported. The overexpression of
thymidylate synthetase (TS), a key enzyme in the metabolism of 5-FU, has been
associated in vitro with resistance to this drug [
22, 23 ] and poor prognosis [ 24, 25 ] .
Irinotecan is a topoisomerase I (Topo I) inhibitor currently used in advance CRC.
The degradation of the active form of irinotecan (SN-38) is dependent on the
UGT1A1 enzyme. The different polymorphisms of this enzyme determine the effec-
tiveness of irinotecan degradation and, as a result, potential toxicity. Homozygosity
for the UGT1A1*28 allele has been linked to severe hematological and nonhemato-
logical toxicity with irinotecan treatment [ 26, 27 ] . The FDA recommends routine
testing for UGT1A1 polymorphism in the US prior to treatment with irinotecan.
Other markers, such as Topo I expression within the tumor, have been linked to
response to irinotecan and other agents as well as combination regimens [ 28 ] , but
these results are yet to be independently validated.
14.6 Predictive BM
14.6.1 KRAS
KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) is a protein coded
by the KRAS gene that plays a key role in many signal transduction pathways within
the cell. When an activation mutation in the KRAS gene occurs, KRAS promotes
cell proliferation. In their model for the development of CRC, Fearon and Volgestein
linked mutations in KRAS to the conversion of intermediate adenomas to colon
carcinomas [ 29 ] . We now know that around 40% of the CRC harbor a mutation in
195
14 Chemotherapy and Biomarkers
KRAS. Furthermore, a mutated KRAS confers worse prognosis than a wild-type
copy of the gene [ 30 ] for which KRAS can be used as a prognostic biomarker.
Two drugs (panitumumab and cetuximab) have been recently introduced to the
treatment of CRC. These two drugs are monoclonal antibodies targeting the epider-
mal growth factor receptor (EGFR). The activation of EGFR by the epidermal
growth factor (EGF) induces downstream signals that ultimately infl uence cell pro-
liferation, differentiation, and survival. The rationale for the use of these anti-EGFR
drugs is that by blocking the binding to the receptor, the proproliferation signal
found in the cancer cells might cease. Mutations of downstream KRAS (see Fig .
14.1 ) in this process mean that regardless of the blockade of EGFR, there is an inde-
pendent stimulus for the cell which results in sustained proliferation. The two large
randomized controlled trials that established the use of cetuximab in the treatment
of advanced CRC (BOND and CRYSTAL trials) illustrate clearly the importance of
choosing the right biomarker when introducing a new therapeutic agent. In the
BOND trial, patients were randomized to irinotecan plus cetuximab versus cetux-
imab monotherapy [ 32 ] . In this trial, the expression of EGFR by IHC in the tumor
was part of the inclusion criteria. The results of the study, however, made it clear
that the degree of EGFR expression within the tumor did not correlate with the
degree of response. The subsequent CRYSTAL study focused on the mutational
status of KRAS as a predictor of effi cacy for cetuximab. In this study, patients were
randomized to irinotecan-based chemotherapy plus or minus cetuximab. KRAS
analysis in the patients receiving cetuximab therapy revealed that the benefi t of the
drug was limited to those patients with tumors harboring no mutations within
the KRAS gene [ 33 ] . As a result of this one and similar other studies, the KRAS
Fig. 14.1 Adapted from Landayi et al . [ 31 ] shows the link between EGFR and KRAS. An activa-
tion mutation on KRAS will act as an independent stimulus for proliferation despite the blockade
at the receptor level by an anti-EGFR drug
Intracellular domain of EGFR
Extracellular domain of EGFR
Grb-2
SOS RAS
RAF
MEK
MAPK
196
F.E. Marti and M.P. Saunders
“wild-type” (WT) genotype has become a predictive biomarker for the treatment
with anti-EGFR drugs. Conversely, KRAS “mutant” genotype is a biomarker of
resistance to these drugs.
14.6.2 BRAF
BRAF is a member of the RAF kinase family of serine/threonine-specifi c protein
kinases which is encoded by the BRAF gene. As seen in Fig. 14.1 , RAF is a com-
ponent of the MAPK pathway, being downstream from RAS and its signaling affects
cell division and proliferation.
Mutations in the BRAF gene are found in around 10% of the CRC and are gener-
ally seen in the V600E allele. BRAF and KRAS mutations have been reported as
being mutually exclusive [ 34, 35 ] . In the context of therapy with EGFR-inhibitors,
resistance has been reported in patients with WT KRAS but with downstream muta-
tions in BRAF, making BRAF mutations a predictive maker of resistance. Also,
patients harboring mutations in this gene appear to have a worse prognosis regard-
less of the treatment given [ 35 ] .
14.7 Predictive Value of MSI in Chemotherapy
MSI has been widely studied in relation to 5-fl uorouracil (5-FU) which for decades
has been the cornerstone of the treatment for CRC. The main research effort in this
area was to ascertain the potential benefi t of 5-FU in tumors harboring a defi cient
MMR system. Initial reports seem to point toward an increased benefi t for 5-FU in
this population [ 36, 37 ] . These initial results, however, have not been corroborated by
later studies. This is thought to be because of the relative low number of patients in
the MMR stratifi cation and the fact that these studies were retrospective. The results
of a large retrospective study that included data from six randomized, controlled trials
looking at the benefi t of adjuvant 5-FU in patients with stage II and III CRC presented
in 2008 showed that patients with MSI and stage II do not benefi t from 5-FU chemo-
therapy and that indeed, this treatment might be harmful [ 38 ] . This data cannot be
extrapolated to patients with stage III disease for whom treatment with 5-FU-based
chemotherapy continues to be the standard of care. Further clinical trials are currently
ongoing which will hopefully clarify the role of adjuvant 5-FU for this population.
14.8 Prognostic Biomarkers
Stage at diagnosis is currently the major determinant of whether a surgical cure
will be achieved or not. This cure rate ranges from 90% to 50% in stages I–III
respectively, to <10% in stage IV disease. KRAS mutation, BRAF mutation, and
197
14 Chemotherapy and Biomarkers
mismatch repair defi ciency have all been found to be independent predictors of
prognosis [ 30 ] . Mutant KRAS is an independent predictor of poorer outcome
regardless of stage or intervention. Several large trials have also demonstrated that
BRAF mutation is also a predictor of poor outcome, notably independent of MSI.
MMR defi ciency [
35 ] .
Several studies have now demonstrated that MSI tumors carry a better prognosis
than those MSS stable. Gryfe et al. reported an initial series of 607 patients that
were less than 50 years of age. This series found high-frequency MSI in 17% of
these colorectal cancers and in multivariate analysis; MSI was associated with a
more favorable prognosis (HR 0.42) and less risk of local and distant spread [
39 ] .
These results were corroborated by subsequent series and a meta-analysis including
32 studies corroborated the previously reported survival benefi t [ 40 ] .
14.9 Other Biomarkers
14.9.1 Circulating Tumor Cells
Metastatic spread to distant organs occurs as part of the natural history of many
cancers. The fact that the cancer cells acquire the capacity to enter the circulation
has made the isolation of circulating tumor cells a major focus of research. Recent
advances in the techniques for the isolation and identifi cation of CTCs have
meant that they now can be incorporated to clinical trial design. Several methods
which have largely been based on fl ow cytometry techniques have been used
through the years. In recent years, the isolation of cells by immunomagnetic
techniques has also been used. Of all these, the immunomagnetic isolation of
CTCs by the CellSearch™ system has now been approved by the FDA for use in
clinical trials. This system relies in the identifi cation of EpCAM positive cells in
the circulation.
A systematic review by Peach et al. on the prognostic signifi cance of CTC fol-
lowing surgical resection concluded that the presence of circulating tumor cells at
³ 24 h is an independent prognostic marker of recurrence [ 41 ] . In the advance set-
ting, a prospective multicenter study that included 430 patients with metastatic
CRC embarking on chemotherapy treatment concluded that CTCs isolated by
CellSearch™ can confer both prognostic and predictive information. This particu-
lar study divided patients in a favorable (<3 CTCs/ 7.5 mL of blood) and an unfa-
vorable ( ³ 3 CTCs/ 7.5 mL of blood) category. Regardless of treatment, patients in
the unfavorable group were found to have worse prognosis than those with less
CTCs (PFS 4.5 vs 7.9 months; p = 0.0002 and OS 9.4 vs 18.5 months; p < 0.0001).
Also, change in numbers of CTCs during treatment with chemotherapy served as
a surrogate marker for response. Conversion from the unfavorable to favorable
group during treatment was associated with longer PFS and OS [
42 ] . Similar
results have been shown by Tol et al. for treatment with chemotherapy plus a tar-
geted agent [ 43 ] .
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F.E. Marti and M.P. Saunders
14.10 Future Work
As we move toward a more personalized medicine and as a consequence of a better
understanding of cancer molecular biology, the role of biomarkers and indeed the
research effort into their discovery will continue to expand. While established bio-
markers like CEA and MSI will continue to infl uence the decision making in CRC,
a set of new biomarkers are likely to join in to add clinically relevant information.
These biomarkers will rely more heavily in genetic and phenotypic characteristics
of individual tumors. “Virtual biopsies” might be possible with the study of CTCs
and circulating cell-free DNA, helping in diagnostic process.
Another potential role of all these biomarkers is to assist in drug development.
Currently, the majority of the candidate drugs fail in phase III trials which means
that they fail late and are costly. Robust biomarker programs in early drug develop-
ment might prevent patients being exposed to ineffective drugs and also might help
determine the population that will benefi t from the studied drug.
The discovery of validated biomarkers and their implantation will continue to be
a challenge as all these measurements need to clearly demonstrate robustness prior
to clinical use, aiming ultimately to a personalization of treatment.
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Key Points
Common biomarkers in CRC and their clinical value
Biomarker
Value
KRAS
Prognostic – worse outcome associated to mutant KRAS status
Predictive – KRAS wild type predicts response to anti-EGFR
agents
MSI Prognostic – better clinical outcome
Predictive – ongoing controversy with regard to 5-FU resistance
and MSI status
CEA Prognostic – high preoperative levels relate to poor outcome
Predictive – monitoring of treatment response in patients having
palliative treatment
CTCs Prognostic – high levels of CTCs associated to poor outcome
Predictive – falling numbers of CTCs during treatment associ-
ated to treatment response
199
14 Chemotherapy and Biomarkers
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DOI 10.1007/978-0-85729-889-8_15, © Springer-Verlag London Limited 2012
15.1 Overview
Colorectal cancer can metastasize to the liver by three potential routes; the most
common are via the portal venous drainage of the liver and the lymphatic drainage
of the large intestine with a third mechanism being direct invasion of the liver by a
tumor of the hepatic fl exure [ 1 ] .
Although patients can develop metastases in other organs bypassing the liver –
for example, pulmonary metastases – a well-recognized component of the cancer
biology of colorectal cancer is its tendency to give rise to liver metastatic disease
[ 1 ] . More than a third of patients with bowel cancer will either have liver metastases
at the time of index presentation (synchronous metastases) or will go on to develop
disease in the liver during follow-up (metachronous metastases) [ 2 ] .
Over the last half century, liver resection has developed based on the observation
that the disease may remain confi ned to the liver for a variable period of time and
that clearance of the liver can render patients free of disease [ 3 ] . Initial reports
described liver resection mainly for patients with solitary hepatic metastases, but
indications for liver resection have broadened with time. Although there is no
S. Jamdar , M.D., FRCS
Specialist Registrar in HPB Surgery, Hepatobiliary Surgery Unit,
Department of Surgery , Manchester Royal Infi rmary ,
Oxford Rd. , Manchester , M13 9WL , UK
A. J. Sheen , M.D., FRCS
Consultant Hepatobiliary Surgeon, Hepatobiliary Surgery Unit,
Department of Surgery , Manchester Royal Infi rmary ,
Oxford Rd. , Manchester , M13 9WL , UK
A. K. Siriwardena , M.D., FRCS (
*)
Professor of Hepatobiliary Surgery, Hepatobiliary Surgery Unit,
Department of Surgery , Manchester Royal Infi rmary ,
Oxford Rd. , Manchester , M13 9WL , UK
e-mail: ajith.siriwardena@cmft.nhs.uk
Chapter 15
Colorectal Liver Metastases
Saurabh Jamdar , Aali J. Sheen , and Ajith K. Siriwardena
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