IJC

International Journal of Cancer

Tumor markers in colorectal cancer, gastric cancer and

gastrointestinal stromal cancers: European group on tumor
markers 2014 guidelines update
M.J. Duffy1, R. Lamerz2, C. Haglund3, A. Nicolini4, M. Kalousova
5, L. Holubec6 and C. Sturgeon7
1
Clinical Research Center, St Vincent’s University Hospital, Dublin 4 and UCD School of Medicine and Medical Science, Conway Institute, University College
Dublin, Dublin, Ireland
2
Medical Department II, Klinikum Grosshadern, Med. Klinik II, Munich, Germany
3

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Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland
4
Department of Oncology, University of Pisa, Pisa, Italy
5
Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University in Prague and General University Hospital in
Prague, Prague, Czech Republic
6
Department of Oncology and Radiotherapy, University Hospital of Pilsen, Pilsen, Czech Republic
7
Department of Clinical Biochemistry, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom

Biomarkers currently play an important role in the detection and management of patients with several different types of gas-
trointestinal cancer, especially colorectal, gastric, gastro-oesophageal junction (GOJ) adenocarcinomas and gastrointestinal
stromal tumors (GISTs). The aim of this article is to provide updated and evidence-based guidelines for the use of biomarkers
in the different gastrointestinal malignancies. Recommended biomarkers for colorectal cancer include an immunochemical-
based fecal occult blood test in screening asymptomatic subjects 50 years of age for neoplasia, serial CEA levels in postop-
erative surveillance of stage II and III patients who may be candidates for surgical resection or systemic therapy in the event
of distant metastasis occurring, K-RAS mutation status for identifying patients with advanced disease likely to benefit from
anti-EGFR therapeutic antibodies and microsatellite instability testing as a first-line screen for subjects with Lynch syndrome.
In advanced gastric or GOJ cancers, measurement of HER2 is recommended in selecting patients for treatment with trastuzu-
mab. For patients with suspected GIST, determination of KIT protein should be used as a diagnostic aid, while KIT mutational
analysis may be used for treatment planning in patients with diagnosed GISTs.

In recent years, biomarkers have begun to play an increas- The main targets of these guidelines include surgeons,
ingly important role in the detection and management of physicians and nurses involved in the management of
patients with gastrointestinal malignancies. This applies espe- patients with gastrointestinal malignancies as well as labora-
cially for colorectal cancer (CRC), gastrointestinal stromal tory professionals involved in the measurement of tumor bio-
tumors (GISTs), gastric and gastro-oesophageal junction markers. The guidelines however, may also be useful for
(GOJ) cancers. In 2003 and 2007, the European Group on payers for healthcare, relevant policy makers, researchers and
Tumor Markers (EGTM) published guidelines on the use of companies involved in the manufacture of tumor marker
biomarkers in CRC.1,2 The aim of this article is to update assays.
those guidelines as well as to provide new guidelines on the To prepare these guidelines, the literature relevant to the
use of biomarkers in gastric and GOJ cancers and GISTs. use of tumor markers in gastrointestinal cancers was
The primary focus is on screening, prognostic, therapy pre- reviewed. Particular attention was paid to systematic reviews,
dictive and monitoring biomarkers. Genetic susceptibility pooled or meta-analyses and to relevant guidelines issued by
markers are not discussed in this article. Expert Panels. For each guideline, we indicate the level of
evidence (LOE)3,4 and strength of recommendation (SOR)5
for its clinical use (Table 1). In addition to reviewing clinical
Key words: gastrointestinal cancer, colorectal cancer, tumor
utility, we discuss cost-effectiveness of the recommended bio-
markers, biomarker, EGTM, guidelines
markers and make suggestions for further research.
DOI: 10.1002/ijc.28384
History: Received 15 Mar 2013; Accepted 25 June 2013; Online 13 Colorectal Cancer
Jul 2013 Use of fecal occult blood testing in screening for early
Correspondence to: M.J. Duffy, Clinical Research Center, St colorectal cancer
Vincent’s University Hospital, Elm Park, Dublin 4, Ireland. Tel.: Two types of FOBT are available, i.e., the older guaiac test
353-1-7165814, Fax: 353-1-2696018, E-mail: [email protected] (gFOBT) which detects the pseudo peroxidase activity of

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 2514 Tumor markers in different cancers

Table 1. Biomarkers recommended by EGTM for use in gastrointestinal malignancies

Marker Cancer Use LOE SOR
FIT-based FOBT CRC Screening I A
CEA CRC Prognosis, especially in stage II patients III A
CEA CRC Postoperative surveillance I A
CEA CRC Monitoring therapy in advanced disease III A
1
K-RAS CRC Predicting response/resistance to anti-EGFR antibodies I A
MSI/dMMR CRC Prescreen for Lynch syndrome I A
MSI/dMMR CRC Prognosis, especially in stage II disease I A
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HER22 Gastric/GOJ Predicting response to trastuzumab I A/B

c-KIT GIST Diagnostic aid III A
c-KIT3 GIST Therapy decision making with imatinib III A/B
1
Mutational status, i.e., patients with specific mutations in K-RAS are unlikely to benefit from the anti-EGFR antibodies, cetuximab or panitumumab.
2
Gene amplification or overexpression, i.e., benefit from trastuzumab depends on HER2 gene amplification or overexpression.
3
Mutational status, i.e., mutational status of c-KIT may be used to determine optimum dose of imatinib for patients with advanced GIST. Abbrevia-
tions: LOE, level of evidence3,4; SOR, strength of recommendation; 4FIT, fecal immunochemical test; FOBT, fecal occult blood testing; dMMR, defec-
tive mismatch repair; FU, fluorouracil; GOJ, gastro-oesophageal junction; GIST, gastrointestinal stromal tumor.

Table 2. Advantages of FITs compared to gFOBTs CRC screening and diagnosis also recommend use of FIT
rather than gFOBT.15 All FOBTs however, lack specificity for
 FITs have better analytical sensitivity and specificity than
gFOBTs1 colorectal neoplasia. Positive tests must therefore be
 FITs have greater sensitivity for advanced adenomas than gFOBTs
followed-up with colonoscopy.10
An important consideration in introducing any new diag-
 Use of FITs leads to higher participation rates than use of gFOBTs
nostic procedure, especially disease screening, is cost-
 In contrast to gFOBTs, FITs can be automated effectiveness. Indeed, the World Health Organization has
 Use of FITs require fewer stool samples than gFOBTs stated that screening should only be implemented when a
 FITs are quantitative or at least semi-quantitative “good balance” exists between costs and benefits.16 In the
 FITs provide an adjustable cut-off point context of CRC, several studies have concluded that when
 With FITs, no dietary or medication restriction is necessary
compared to no screening, all the widely investigated screen-
ing tests including FOBT offers additional years of life at a
 FITs are more cost-effective than gFOBTs
cost that is considered acceptable by most advanced countries
Summarized from refs. 10–15. and indeed may be cost-saving.17–25 Thus, in five cost-
1
gFOBTs detect the presence of any blood, FITs are specific for human effectiveness analyses, the estimated mean cost per life-year
blood.
gained from annual screening of subjects 50 years or older
with a specific gFOBT ranged from $5,691 to $17,805.18
hemoglobin and the newer fecal immunochemical test (FIT)
These costs are substantially less than the cost-effectiveness
which detects the globin component of hemoglobin.6,7
thresholds commonly used to evaluate medical interventions
Although extensively validated for reducing mortality form
(e.g., e30,000 to e40,000 per quality life-year (QALY)
CRC,8,9 the gFOBT has many limitations as a screening test
gained in the EU, and $50,000–$100,000 in the USA).
for CRC.10–15 These limitations include lack of specificity for
The EGTM panel recommends that screening for CRC
human hemoglobin, (certain foodstuffs and medications may
and advanced colorectal adenomas be performed with a
interfere with test) and relatively low clinical sensitivity and
FOBT.2,10 For new centers undertaking screening, the panel
specificity for colorectal neoplasia. Furthermore, it is difficult
recommend use of a quantitative FIT that posses an adjusta-
to automate, rendering it unsuitable for large population-
ble cut-off point. Results using FITs should be expressed as
based screening.10
micrograms of hemoglobin per gram of feces.26 Work to
Because of these limitations, the use of gFOBT, as a
improve the standardization of FIT assays would be highly
screening test for CRC, is gradually being replaced by
desirable,11 as would further research into DNA-based tests,27
FITs.10–15 As summarized in Table 2, FITs possess many
including automation and cost reduction.10
advantages over gFOBTs.10,12–15 Because of their superior
performance, the EGTM panel have recommended that a FIT
should be used in new centers embarking on FOBT screen- CEA in determining prognosis and staging
ing. Specifically, the panel recommends use of a quantitative A multiplicity of studies carried out over the last 30 years
FIT, with an adjustable cut-off concentration.10 Recently pub- have addressed the prognostic impact of CEA levels at initial
lished European Union guidelines for quality assurance in presentation in patients with CRC (reviewed in Refs. 28,29).

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Duffy et al. 2515

Table 3. Recent studies reporting a prognostic impact of preopera- CEA in postoperative surveillance
tive CEA in patients with CRC cancer At least eight published randomized controlled trials, includ-
No. of Tumor ing almost 3,000 patients in total, have addressed the impact
patients stages Key findings Ref. of intensive postoperative surveillance on outcome in patients
9083 I-IV1 CEA an independent prognostic (30) who have undergone curative surgery for colorectal cancer
marker, prognosis was worse in
(for review, see Ref. 43). These randomized trials varied with
high CEA patients with a lower
stage compared to low CEA respect to intensity of follow-up and diagnostic modalities
patients with a higher stage. High used, and most were statistically underpowered to detect a
CEA as strong as nodal positivity significant effect of surveillance on survival. Furthermore,
for predicting poor outcome.
many were carried out prior to the use of adjuvant chemo-
474 I-III CEA an independent prognostic (31) therapy for CRC and availability of modern and more effec-

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marker, CEA prognostic in stage II
patients. tive systemic treatment for recurrent CRC.
Nevertheless, meta-analyses of these trials44–49 showed
1637 I-III CEA an independent prognostic (32)
marker in total population, as well that intensive follow-up resulted in a reduction of 20–30% in
as in patients with either stages II the hazard rate for all cause mortality.43 However, due to the
or III disease different follow-up strategies used in both the intensive and
1263 I-III CEA an independent prognostic (33) nonintensive follow-up arms, it was not possible to draw
marker in total population, as well conclusions about the best combination of tests or the fre-
as in patients with either stages II
quency of their performance. Despite this, regular measure-
or III disease
ment of CEA, as part of an intensive follow-up regime,
82 IIA CEA prognostic in stage IIA (34)
patients
appears to be necessary to achieve significant improvement
in survival.44,48,49
2230 I-IV CEA an independent prognostic (35)
marker
Compared to other available diagnostic modalities, serial
CEA determinations appear to be the most sensitive for the
572 II CEA prognostic in stage II patients (36)
detection of early recurrent disease (i.e., provide the first
1
Investigated colon cancer patients only. indication), especially liver metastasis.50–53 Thus, in a recent
large randomized prospective trial comparing laparoscopic-
assisted colectomy with open colectomy in patients with cur-
Although these different studies varied with respect to the able colon cancer, serial CEA measurements outperformed
specific CEA assay used, cut-off point for CEA, number of other diagnostic modalities for patients with both early stage
patients included, follow-up period and whether or not adju- (stage I and IIa) and late stage disease (stage IIb and III).53
vant chemotherapy was used, almost all concluded that ele- For the 537 patients with early stage CRC, CEA detected
vated preoperative CEA levels were associated with adverse 29.1% of the first recurrences compared with 23.6% by CT
outcome. Indeed, several of these studies showed that CEA scan, 12.7% for colonoscopy and 7.3% for chest X-ray. For
was an independent prognostic factor and, importantly, pre- the 254 patients with late stage disease, CEA detected 37.4%
dicted outcome in patients with stage II disease.30–36 Key of the first recurrences, CT scan 26.4%, chest X-ray 12.1%
findings from the more recent and larger studies on the prog- and colonoscopy 8.8%.53
nostic value of CEA in CRC are summarized in Table 3. Similar to the situation with CRC screening, intensive
In agreement with other organizations,37–42 the EGTM follow-up after curative surgery for CRC has been shown to
recommends measuring preoperative CEA levels in newly be cost-effective.54,55 Based on data from five randomized tri-
diagnosed CRC patients.1,2 Preoperative levels provide prog- als, Renehan et al.55 calculated that the number of years
nostic information as well as a baseline value for interpreting gained through intensive surveillance over 5 years was
subsequent levels. No study however, has shown that CEA between 0.73 and 0.82. The adjusted net cost for each patient
can be used to select those patients with stage II CRC who was £2479 and for each life year gained was £3402. Although
would benefit from adjuvant chemotherapy. the most cost-effective strategy is unknown, measurement of
For future research, the EGTM recommends that preoper- CEA appears to be one of the least expensive tests performed
ative levels of CEA be included for risk stratification in clini- as part of an intensive follow-up strategy.56 Thus, in an early
cal trials evaluating new adjuvant systemic treatments for study carried out in the US, the cost per recurrence detected
patients with CRC. We also suggest that the prognostic was $5,696 using CEA, $10,078 with chest X-ray and $45,180
impact of CEA be compared with other emerging prognostic using colonoscopy.56 Although the absolute costs of these
markers for CRC such as microsatellite instability (MSI) and tests are likely to have increased since publication of this
gene expression profiling (see below). In the context of bio- report, the relative costs are likely to be the similar.
logical/molecular prognostic biomarkers for CRC, measure- Because of its ease of measurement, relatively low costs
ment of CEA is likely to be considerably simpler and less and sensitivity for early metastasis, most expert panels rec-
expensive than determination of tissue-based biomarkers. ommend regular CEA measurements during the follow-up of

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patients following curative surgery for CRC.1,2,37–40 Accord- of-function mutations in the mismatch repair (MMR) genes,
ing to the EGTM panel, CEA should be measured at baseline MLH1, MSH2, PMS2 and MSH6. Loss of these genes results
and then every 2–3 months for at least 3 years after diagnosis in defective MMR (dMMR), which in turn results in microsa-
in patients with Stage II or III CRC who may be candidates tellite instability (MSI).
for further intervention (e.g., liver resection or systemic treat- As MSI or dMMR is present in >90% of cases, their
ment) in the event of recurrent disease. After 3 years, CEA detection is used as an initial test in the detection of LS in
may be measured approximately every 6 months for 5 years.2 patients with CRC. If MSI/dMMR is present, further investi-
Any increase in levels must be confirmed with a second sam- gations including mutational analysis of the MSH2 and
ple prior to undertaking further investigations. As different MLH1 genes should be performed. The absence of MSI or
CEA assays may give different results, ideally, the same assay dMMR makes the presence of LS unlikely. Although MSI
should be used throughout. Broadly similar recommendations and MRR protein status are relative sensitive tests for LS,
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have been published by other expert panels including the they are not specific, as 12–17% of all CRCs exhibit these
American Society for Clinical Oncology (ASCO),37 the defects, the majority of which are sporadic. In sporadic CRC
National Comprehensive Cancer Network (NCCN),38 the however, MSI generally results from loss of MLH1 and PMS2
National Academy for Clinical Biochemistry (USA) proteins.68 Loss of MLH1 expression in sporadic CRCs is due
(NACB)39 and the European Society for Medical Oncology to epigenetic silencing by hypermethylation of CpG nucleo-
(ESMO).40 Caution however, should be exercised in interpret- tides in its gene promoter region.
ing increases in CEA levels as certain benign diseases may Establishing a diagnosis of LS in patients with CRC is
also increase its concentration.57–59 important, as these subjects are at increased risk of develop-
ing other cancers. In addition, since some family members
Monitoring systemic therapy in advanced disease will have inherited LS, they are also at high risk of develop-
Radiology has been and remains the “gold standard” for eval- ing CRC and possible other malignancies. Although random-
uating response to systemic therapy in patients with ized trials have not been reported, several observational
advanced CRC.60 For most patients however, good agreement studies suggest that close surveillance of Lynch syndrome
has been found between radiological and CEA-defined subjects decreases both cancer rates and mortality.69–74
responses.61–63 Thus, in a recent study using a well defined While traditionally, MSI/MMR protein measurement in
population of patients with isolated liver metastasis from CRC was limited to subjects fulfilling specific clinical charac-
CRC, de Hass et al.61 reported agreement between CT scan teristics such as the Amsterdam and Bethesda criteria,75–77
and CEA response in >90% of cases. For patients with radio- more recently several expert panels and some individual
logical response or stable disease, agreement with CEA investigators have recommended that all patients with CRC
response was found in 94% of cases, while in patients with should undergo such testing.78–82 Advantages of a universal
radiological evidence of disease progression, agreement was testing approach include cost-effectiveness80,82 and increased
present in 95% of cases. Based on these findings, the authors sensitivity for detecting mutation carriers.78,79 Limited resour-
concluded that use of CEA is as accurate as CT imaging for ces may however, restrict universal testing in some countries.
assessing response of colorectal cancer liver metastasis to In agreement with other organizations,37–39 the EGTM
chemotherapy. recommends measurement of MSI or MMR proteins as pre-
Most expert panels, including the EGTM, currently rec- screens for LS in patients with CRC.2 If MSI is present or
ommend measurement of CEA in monitoring patients with MMR enzyme loss is detected, subjects should be offered
advanced CRC receiving chemotherapy.1,2,37–40 As previously genetic counseling and undergo germline gene testing for LS.
pointed out however,1,37 caution is necessary when interpret- Subjects with MSI-positive tumors that are negative for
ing serial CEA levels shortly after initiation of specific cyto- MLH1 protein may be considered for BRAF mutation and/or
toxic therapies, as spurious or transient rises may occur.64,65 MLH promoter methylation testing, prior to further genetic
These transient increases occur in 10–15% of patients with testing. Future research should focus on the optimum and
advanced CRC receiving chemotherapy,64,65 and appear to be most cost-effective approach for LS prescreening.
associated with a favorable outcome.64,65 They have been
attributed to apoptosis and/or necrosis of tumor cells caused Prognosis and therapy prediction. In addition to being used
by the cytotoxic agents. as a prescreen for LS, MSI/MMR status may also have use as
a prognostic marker in CRC, as several studies have shown
DNA mismatch repair and microsatellite instability that the presence of MSI or defective MMR activity is a
As a prescreen for lynch syndrome in patients with colorectal marker of favorable outcome. Two separate pooled analy-
cancer. Lynch syndrome (LS) is an autosomal dominant sis,83,84 as well as several large randomized trials have shown
disorder, associated with a predisposition to multiple types of that the presence of MSI/dMMR was associated with a favor-
malignancy including cancers of the colon, rectum, endome- able outcome, especially in patients with Stages II and III
trium, stomach and small bowel.66,67 Approximately 3% of all colon cancer.85–90 All these studies when taken together pro-
CRC are LS-related. This syndrome is due to germline loss- vide strong evidence that MSI/MMR status is a prognostic

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Duffy et al. 2517

biomarker for Stages II and III colon cancer. Additionally, the G13D mutation appeared to benefit to approximately the
MSI status is now recommended in the WHO classification same extent as patients with K-RAS wild-type tumors from
of mucinous-type CRC, with high MSI indicating good prog- the addition of cetuximab to first-line chemotherapy.103
nosis and low or absent MSI suggesting poor outcome. Clearly, these findings require validation in a large prospec-
Several studies including two randomized trials,85,86 a ret- tive randomized trial.
rospective case study91 and a systematic review92 also suggest As with several of the biomarkers discussed above, an eco-
that MSI/MMR status may be a predictive biomarker for nomic benefit for K-RAS testing prior to prescribing anti-
adjuvant 5-FU-based therapy, i.e., the presence of MSI/ EGFR antibodies for patients with metastatic CRC has been
dMMR is associated with lack of benefit.85,86,91 demonstrated.104 Using modeling data, Vijayaraghavan
Although most studies have shown a relationship between et al.104 calculated that administration of anti-EGFR antibod-
MSI/dMMR and lack of benefit from adjuvant 5-FU, some ies only to patients with wild-type K-RAS would result in a

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have not confirmed these findings.87,93,94 Possible reasons for net saving of e3,900–e9,600 in Germany and $7,500–$12,400
the conflicting data include the different protocols used for in the US. For these calculations, it was assumed that all
determining MSI/MMR status, especially the number of patients had previously received at least one line of chemo-
microsatellites measured when assessing MSI status, the therapy treatment.
number of patients investigated in the various studies, inad- Because of its clinical and economic benefit, EGTM rec-
equate randomization and length of follow-up. ommends mutation testing of K-RAS prior to administering
Because of the multiplicity of studies linking MSI/dMMR cetuximab or panitumumab to patients with advanced CRC.
with good prognosis, the EGTM states that these parameters Patients with specific activating mutations especially at codon
may be measured in patients with Stage II colon cancer who 12 should not be treated with anti-EGFR antibodies. Patients
are under consideration for adjuvant 5-FU-based therapy. with the G13D mutation may however, benefit from com-
Patients with MSI/dMMR may not require such therapy as bined cetuximab and chemotherapy but this remains to be
their prognosis is likely to be favorable. MSI-positive patients confirmed. It is important that the laboratory report indicate
with adverse prognostic features such as pT4 stage or the specific K-RAS mutation analyzed and detected as well
lymphangio-invasion however, should not be excluded from the methodology used. Recommendations for performing K-
receiving chemotherapy.87 RAS gene mutations testing in CRC have recently been
Future work should compare the prognostic impact of published.105
MSI/MMR status in stage II CRC with that of CEA and the Future research should aim to standardize assays for
various multigene profiles currently undergoing evaluation assessing the mutational status of K-RAS in CRC. Research
(see below). Further research is also required to investigate should also focus on the identification and development of
whether the MSI/dMMR status is of value in predicting bene- additional biomarkers in order to increase the positive pre-
fit from other chemotherapeutic drugs such as platinum salts dictive value for response to anti-EGFR antibodies. This
(oxaliplatinum) and topoisomerase inhibitors (irinotecan). should focus on validating preliminary findings suggesting a
predictive or prognostic value for mutations in BRAF,
K-RAS for predicting response to anti-EGFR antibodies PIK3CA and N-RAS, loss of PTEN and levels of EGFR
Cetuximab and panitumumab are monoclonal antibodies that ligands.106–108 Finally, as mentioned above, further work is
bind to the extracellular domain of EGFR, thereby inhibiting necessary to establish which patients with which G13D muta-
downstream signaling and resulting in decreased cell prolifer- tions are likely to benefit from treatment with anti-EGFR
ation and migration.95,96 Early clinical trials using these anti- antibodies.
bodies, either alone or in combination with chemotherapy, to Other therapeutic targets as well as emerging therapeutic
treat unselected patients with advanced CRC gave response targets for the treatment of CRC are listed in Table 4. Apart
rates of only 10–15%.97–100 More recently, retrospective anal- from the anti-EGFR antibodies discussed above, validated
ysis of randomized controlled trials has shown that patients predictive markers are currently unavailable for the drugs
with specific mutations in codons 12 of the K-RAS gene inhibiting these targets.
almost never benefited from treatment with these antibodies.
However, 15–20% of patients with wild-type K-RAS show an Gastric and Gastro-Oesophageal Junction Cancers
objective response with antibody alone and 35–40%, when HER2 for predicting response to trastuzumab
treated with cetuximab and irinotecan.97–101 As with breast cancer, patients with gastric and GOJ cancers
While almost all of the known K-RAS mutations at overexpress HER2 in 10–25% of cases.119 Consistent with this
codons 12 are associated with lack of benefit from cetuximab finding, HER2-positive cell lines are sensitive to trastuzu-
or panitumumab, a specific mutation at codon 13, i.e., G13D mab,120,121 while patients with advanced HER2-positive gas-
may be an exception. Thus, in two trials, administration of tric and GOJ tumors benefit from treatment with the anti-
cetuximab to patients with this mutation was associated with HER2 antibody.122 Based on these findings, EGTM state that
a significantly better outcome than that seen in patients with for patients with advanced gastric or GOJ under considera-
other types of K-RAS mutations.102,103 Indeed, patients with tion for systemic therapy, measurement of HER2 should be

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Table 4. Established and emerging therapeutic targets for the treat- Table 5. Emerging biomarkers for gastrointestinal cancers
ment of colorectal cancer
Marker Cancer Potential use Ref.
Phase of 1
Multigene profiles CRC Determining 140–142
Target Drug Development Ref.
prognosis
EGFR cetuximab, In clinical use 98–101
TIMP-1 CRC Prognosis 143
panitumumab
CA 19-9 CRC Postoperative 144
VEGF Bevacizumab, In clinical use 109–111
surveillance
aflibercept
Stool DNA profiles CRC Screening 145
Multi Regorafenib In clinical use 112,113
kinases1 Septin 9 CRC Screening 146
BRAF Vemutafenib, In development 114 TFAP2E CRC Chemoprediction 147
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(mutant) dabrafenib
CA 242 Gastric Prognosis, 148
MEK Selutmetinib, In development 115,116 monitoring
pimasertib therapy
mTOR Evorilimus In development 116,117 DOG1 GIST Diagnostic aid 149
PI3K LY294002, In development 116,118 1
Amongst the best-validated multigene signatures are the ColoPrint
GDC0941 test (Agendia) (129), 634-geneColDx (Almac) (130), and the Oncotype
1
DX colon cancer assay (Genomic Health) (131).
Regorafenib inhibits VEGFR1, VEGFR2, VEGFR3, PDGFRbeta, Tie-2, Abbreviations: CRC, colorectal cancer; GIST, gastrointestinal cancer.
FGFR1, RET and BRAF.

performed using immunohistochemistry and/or FISH.

include DOG1, CD34, S100, desmin, PS100 and smooth muscle
Patients with HER2-positive disease are candidates for receiv-
actin.125,128 Measurement of markers however, complements but
ing combined trastuzumab and chemotherapy. HER2 staining
does not replace histopathology in the diagnosis of GIST.
and scoring in gastric and GOJ tumors should be performed
A number of expert panels including ESMO,129 a French
and scored as recently recommended.123 Because the expres-
National Consensus Group,130 and NCCN131 recommend
sion of HER2 in gastric and GOJ cancer may be heteroge-
measurement of KIT as an aid for diagnosis of GIST. Both
nous, multiple biopsies are necessary in order to obtain a
the ESMO and NCCN Panels also state that KIT and
reliable indication of the oncoprotein status.124
PDGFRA mutation testing should be considered for KIT
protein-negative tumors that are suspected to be GISTs.129,131
Gastrointestinal Stromal Tumors In agreement with these groups, EGTM recommend that
KIT as a diagnostic aid staining for KIT protein should be used as a diagnostic aid
Gastrointestinal stromal tumors (GISTs) although rare are the for GIST. However, its absence does not exclude GIST. Muta-
most common mesenchymal tumor found in the gastrointestinal tional analysis of KIT or PDGFR genes may be considered, if
tract (for review, see Refs. 125,126). At a molecular level, GISTs sample is KIT protein-negative.
are characterized by the presence of KIT protein and mutations
in the KIT gene. Thus, the KIT protein is found in >95% of KIT in predicting benefit from Imatinib
GISTs, while mutations in the KIT gene are present in 80– Imatinib is a tyrosine kinase inhibitor which blocks KIT and
85% of cases.125,126 Most of the mutations in the KIT gene are PFGFRA as well as BCR-ABL. The use of imatinib has revolu-
found in Exon 11 and consist of point mutations and deletions. tinized the treatment of patients with GISTs in recent years.125
Less frequent mutations are present in Exons 9, 13 and 17. Five Response to imatinib however, depends on the mutational sta-
to 10% of GISTs have mutations in the homologous gene, tus of the KIT gene. Thus, patients with advanced GISTs
PDGFRA.125,126 Mutations in PDGFRA are mostly found in exhibiting mutations in Exon 11 of KIT had a better outcome
Exons 12 and 18 and appear to be mutually exclusively with than those with Exon 9 mutations or those without a detecta-
mutations in KIT. Overall, 80–95% of GISTs have mutations in ble KIT mutation.132–138 Based on the above, several expert
either the KIT or PDGFRA gene. panels currently recommend KIT and PDGFFRA mutational
Because the KIT gene is almost universally expressed and/or analysis prior to prescribing imatinib to patients with GISTs.
mutated in GISTs, it has been extensively investigated as a bio- Although the use of imatinib in patients with GISTs was
marker for this disease125–127 and immunostaining for KIT pro- originally restricted to patients with advanced disease, a
tein is used as a diagnostic aid for GISTs. For the small recent provisional clinical opinion published by a European
proportion of GISTs that fail to express KIT protein (5%), consensus group recommended adjuvant imatinib in patients
mutational analysis of the KIT and PDGFRA genes may confirm with KIT exon 11 mutations. However, adjuvant imatinib
the diagnosis. However, although KIT protein is rarely detected was not recommended for patients with primary GISTs con-
in other abdominal tumors, it may be present in some nonabdo- taining PDGFRA D842V mutations.139
minal tumors, including melanomas, breast cancers, and semi- In agreement with other expert panels,129–131 EGTM state
nomas.125,128 Other markers that may aid the diagnosis of GISTs that mutational analysis of KIT and PDGFRA should be

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Duffy et al. 2519

considered prior to administering imatinib to patients with of gastrointestinal cancers (Table 1). We should point out,
GIST. however, that the guidance published here and elsewhere
should not replace physician judgment in specific patients.
Emerging Markers Furthermore, as new data becomes available, recommenda-
Table 5 lists some promising new biomarkers and multigene tions based on existing evidence may change. It is therefore
profiles for gastrointestinal cancer. None of the listed vital that physicians using these biomarkers and the labora-
markers/profiles however, can currently be recommended for tories performing the assays keep up-to-date with new find-
routine clinical utility. ings. Finally, laboratories performing the recommended
assays should participate in external quality assessment
Conclusion schemes, be accredited by appropriate regulatory organiza-
It is clear from the above that several biomarkers are now tions and be staffed and managed by an appropriately

Mini Review
integral to the management of patients with different types trained work-force.

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