Abstract
The pathogenesis of colorectal cancer (CRC) is complex with at least two distinct pathways defined by different forms of genomic instability, and with each pathway including multiple sequential genetic and/or epigenetic changes. The treatment of CRC has evolved substantially over the past decade, due in part to a better understanding of the biology of the disease and development of new drugs including molecular-targeted agents. In this chapter we review molecular classification, prognostic markers and predictive markers in CRC. We focus on markers that have a substantial body of literature available to assess their potential role in routine clinical practice. Future strategies including gene-expression array based testing are also discussed.
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1 Introduction
Colorectal cancer (CRC) is a leading cause of cancer related morbidity and mortality. It ranks as the second most common cancer in women (∼570,000 cases in 2008) and the third most common cancer in men (∼663,000 cases) worldwide. CRC incidence shows pronounced geographic variation, with the highest rates observed in Western Europe, Australia and North America, and the lowest rates reported in sub-Saharan Africa. In most regions of the world the incidence of CRC is increasing. About 608,000 deaths from CRC were recorded in 2008, making it the fourth most common cause of death from cancer [1].
Patients presenting with stage I (confined to the bowel wall), stage II (penetrating the bowel wall) or stage III (involvement of lymph nodes) disease can often be cured by surgery, with 5-year survival rates in the United States of approximately 90, 80 and 50%, respectively. However, following resection of the primary tumor there remains a considerable risk for tumor recurrence for patients with stage III and high-risk stage II disease (T4 stage, high grade, lymphovascular invasion, obstruction and/or perforation of the bowel at presentation), with relapse in approximately 50% of patients in the absence of further treatment. In these patients, 5-fluorouracil (5-FU)-based adjuvant chemotherapy after surgery can reduce recurrence risk by approximately 30% [2, 3], and the addition of oxaliplatin further improves outcomes and is the current standard of care (Fig. 5.1a). In clinical practice, many CRC patients receive adjuvant treatment unnecessarily, either because they were cured by surgery or because they will relapse despite treatment. It is therefore critical to identify new prognostic and predictive markers to more appropriately target adjuvant treatment to those patients who will benefit the most.
Patient pathways for colorectal cancer (CRC) for (a) early-stage and (b) metastatic disease including common treatment regimens. The central role for KRAS mutation testing in guiding the use of anti-EGFR antibody therapies for the treatment of metastatic CRC is highlighted. Pre-operative chemoradiotherapy for rectal cancer is omitted from these pathways
In patients with advanced (metastatic, stage IV) disease at presentation or as a result of relapse, prognosis is poor with a 5-year survival rate of only 8%. In such patients, potentially curative surgery is rarely possible. However, the development of combination therapies utilizing 5-FU together with either oxaliplatin or irinotecan has lead to progressive improvements in patient survival. Recently, these combinations have been expanded to include agents that selectively target molecular pathways that drive CRC growth. These include cetuximab and panitumumab, monoclonal antibodies against the epidermal growth factor receptor (EGFR), and bevacizumab, a monoclonal antibody against the vascular endothelial growth factor A (VEGF-A) (Fig. 5.1b). While the addition of these agents to chemotherapy in metastatic disease has led to improvements in both progression-free and overall survival, these targeted agents have not proven to be of benefit in the adjuvant treatment of stage II and III CRC [4, 5]. The introduction of targeted treatments for metastatic CRC has been associated with a very significant increase in healthcare cost and an expanded spectrum of side effects. Given these increasing constraints, novel prognostic and predictive markers are required to guide their use in advanced and early-stage disease with an intense research focus on molecular biomarkers to personalize therapy.
Recent developments in the application of anti-EGFR monoclonal antibodies are an example of how tumor molecular markers can be used to personalize treatment for CRC. In patients with metastatic CRC, response to cetuximab monotherapy in clinical trials has been repeatedly shown to be limited to KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) wild-type tumors (response rate of 13–17%) with very few responses observed in KRAS mutant tumors (response rate of 0–1.2%) [6, 7]. Based on these data, current American Society of Clinical Oncology (ASCO) guidelines recommend the use of anti-EGFR monoclonal antibodies only for patients with KRAS wild-type cancers [8].
2 Molecular Classification of CRC
To date the most intensely studied biomarkers in CRC are somatic (tumor acquired) changes that have been associated with cancer development, including mutations in tumor suppressor and oncogenes, CpG island methylation and global genomic instability status (microsatellite or chromosomal instability). Analyses of germline (inherited) changes have mostly focused on pathways involved in the metabolism and mechanism of action of chemotherapy agents including 5-FU, oxaliplatin and irinotecan.
Sporadic CRC is often considered to develop along two main genetic pathways, a working model which is an oversimplification. The majority of CRCs appear to follow the classical adenoma-carcinoma pathway (Fig. 5.2a), which is frequently associated with mutations of the APC (adenomatous polyposis coli), KRAS, PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide), SMAD4 (SMAD family member 4) and TP53 (tumor protein p53) genes and the acquisition of chromosomal instability [9]. Less frequently, CRCs may arise via the serrated neoplasia pathway (Fig. 5.2b) characterized by mutation in the BRAF (v-raf murine sarcoma viral oncogene homolog B1) gene, CpG island hypermethylation at specific sites and the loss of DNA mismatch repair function resulting in hypermutation detected as microsatellite instability (MSI-H) [10].
The two main pathways of colorectal tumorigenesis. (a) The classical adenoma-carcinoma pathway and (b) the serrated pathway. Histopathological progression is driven by successive genetic and epigenetic changes in tumor suppressor genes and oncogenes and the acquisition of genomic instability
In addition, individual CRCs accumulate a plethora of low frequency genetic and epigenetic aberrations some of which are likely to influence their pathogenesis and biological behavior. Recent development of microarray and next-generation sequencing technologies has paved the way for analysis of such changes, but the evaluation of low frequency alterations as prognostic or predictive markers remains challenging, requiring the analysis of large patient cohorts with detailed clinical and long-term follow-up data and the development of standardized methodologies and standards of reporting.
In this chapter, we discuss molecular markers in CRC that have a substantial body of data evaluating their potential prognostic or predictive value. Currently, few of these markers have reached the level of evidence required for routine clinical application and for many markers there are conflicting results amongst studies. We further introduce recent developments in the application of array technologies to develop “unbiased” biomarker signatures.
3 Prognostic Biomarkers for CRC
3.1 KRAS
The KRAS proto-oncogene is a central component of the RAS/RAF/MEK/ERK/MAPK signaling pathway. Activating mutations in KRAS are common and early events in colorectal tumorigenesis, occurring in codons 12 and 13 (exon 2), 61 (exon 3) and 146 (exon 4) in approximately 37% of cases [9, 11, 12]. Mutations lead to a constitutively active GTP-bound protein that signals to BRAF triggering downstream activation of the MAPK signaling cascade.
Multiple studies have investigated the role of KRAS mutation as a prognostic marker in CRC with varying results. The RASCALII study, combining data on 3,439 patients with stage II to IV CRC, analysed outcome for 12 different mutations identified in codons 12 and 13. In multivariate analysis, only a glycine to valine substitution in codon 12 (present in 8.6% of all patients) was found to be associated with poorer failure-free survival (FFS) and overall survival (OS). This mutation appeared to have a stronger impact on outcome in stage III patients as compared to stage II patients [13]. In the QUASAR trial, amongst 1,583 patients with stage II CRC, presence of KRAS mutation was associated with a decrease in recurrence-free survival (RFS), a difference which appeared more pronounced in rectal cancers [14]. For patients with metastatic CRC (n = 711), the FOCUS trial reported KRAS mutation (codons 12, 13 and 61) as a poor prognostic factor for OS, although no significant relationship was observed between KRAS status and progression-free survival (PFS) [15]. In contrast, other large studies have found no prognostic effect of KRAS mutation on patient outcome. For example, KRAS analysis (codons 12 and 13) in 1,564 patients with resected stage II and III colon cancer from the PETACC-3 trial found no evidence for association with RFS or OS [16]. Similarly, analysis of the best supportive care arms of several phase III studies of anti-EGFR monoclonal antibodies in metastatic CRC failed to identify a significant prognostic value of KRAS mutation status [6, 7, 17]. At present the combined evidence remains insufficient to support the use of KRAS mutation as a prognostic marker in CRC.
3.2 BRAF
The BRAF gene encodes a serine–threonine protein kinase that acts downstream of KRAS in the RAS/RAF/MEK/ERK/MAPK signaling pathway [18]. BRAF mutations occur in approximately 10% of CRCs, with the most common activating change being a valine to glutamic acid substitution at codon 600 (V600E). Presence of BRAF mutation is positively associated with a number of clinical and molecular features including female gender, older age at diagnosis, right-sided tumor location, MSI-H status and the CpG Island Methylator Phenotype (CIMP). BRAF and KRAS mutations tend to be mutually exclusive in tumors [10, 16].
There is emerging evidence to suggest that presence of a BRAF mutation is a predictor of poor prognosis in patients with metastatic CRC. In a retrospective analysis of BRAF V600E mutation status in 519 tumors from the CAIRO2 trial, BRAF-mutated tumors showed significantly shorter PFS and OS [19]. Similarly, the FOCUS (n = 711) and AGITG MAX (n = 315) trials detected a negative association between BRAF mutation and OS, although no difference was apparent for PFS [15]. In addition, the CRYSTAL study (n = 635) reported poorer PFS and OS for BRAF-mutated/KRAS wild-type tumors [15, 20–25], and comparable results have been reported for a number of retrospective non-trial cohorts [15, 20 25].
The prognostic value of BRAF mutation in early-stage disease, on the other hand, remains uncertain. In both the PETACC-3 (n = 1,564, stage II and III) and QUASAR (n = 1,584, stage II) trials BRAF V600E mutation was not associated with RFS, although PETACC-3 reported poorer OS for patients with MSI-low (MSI-L) and stable (MSS) tumors [14, 16]. The latter finding is consistent with results from a retrospective study on 911 stage I to IV colon cancers [26]. In contrast, the Intergroup 0135/NCCTG 91-46-53/NCIC CTG CO.9 trial (n = 533, stage II and III) found no association between BRAF mutation and OS for MSI-L and MSS tumors, but did find worse OS in MSI/BRAF-mutant cancers compared to MSI/BRAF-wild type cancers [14, 27]. Three other large retrospective studies have reported a negative impact of BRAF V600E mutation on outcome in early-stage patients, although this was limited to right-sided cases in one study [28–30].
Taken together, the evidence suggests that BRAF V600E mutation is a marker of poor prognosis in patients with metastatic CRC, although routine testing has not yet been endorsed by current clinical guidelines. The prognostic value of BRAF mutation in the early-stage disease setting – in particular with respect to prediction of recurrence risk – is less certain.
3.3 PIK3CA
Somatic mutation in PIK3CA, the p110 alpha catalytic subunit of phosphatidylinositol 3-kinase (PI3K), have been described in 10–30% of CRCs. The majority of these activating changes are localized in the helical (exon 9) and catalytic (exon 20) domains of PIK3CA [31] and are thought to constitutively activate the PI3K/AKT pathway driving cell proliferation [32].
Despite their considerable prevalence in CRC, data on the prognostic value of PIK3CA exon 9 and 20 mutations are relatively sparse. A retrospective study on 158 patients with stage I to IV CRC reported shorter RFS for stage II/III individuals with PIK3CA-mutated tumors [33], and similar results were reported in a study on 240 patients with stage I to III rectal cancer [34]. An analysis on 450 patients with stage I to III colon cancer further observed reduced cancer-specific survival (CSS), but this appeared limited to persons with KRAS wild-type tumors [35]. Intriguingly, differential effects on patient outcome have been observed between PIK3CA mutations in exons 9 and 20. In a study of 685 patients with stage I to III colon cancer, PIK3CA mutations in exon 20 were found to be a negative prognostic factor for DFS, CSS and OS in stage III tumors (but not in stage I and II tumors). In contrast, PIK3CA exon 9 mutations did not appear to affect survival [36]. Currently, the combined evidence on the prognostic value of PIK3CA status in early-stage disease remains insufficient. Existing data in the metastatic setting do not suggest a prognostic role for PIK3CA mutation [37].
3.4 TP53
The TP53 tumor suppressor gene encodes a transcription factor that is activated in response to a variety of cellular stresses including DNA damage. The activated TP53 protein regulates transcription of downstream target genes to initiate programs of cell cycle arrest, DNA repair, apoptosis and/or angiogenesis. Loss of TP53 function through gene mutation, often accompanied by loss of the wild-type allele, occurs in approximately 50% of CRCs [9, 38].
Numerous studies have evaluated TP53 status as a prognostic marker in CRC with contradictory results. A particular challenge in assessing these data has been the use of different methodologies to determine TP53 status including mutation screening and immunohistochemistry (IHC) for protein expression. A meta-analysis of 168 eligible studies comprising all stages of disease found an increased risk of death for patients with abnormal TP53 based on both IHC (n = 12,257, relative risk (RR) 1.32, 95% confidence interval (CI) 1.23–1.42) and mutation analysis (n = 6,645, RR 1.31, 95% CI 1.19–1.45), although suboptimal study design of component studies, publication bias and study heterogeneity were evident. The adverse impact of abnormal TP53 appeared to be greater in patients with a lower baseline risk of dying [39]. In contrast, the TP53 CRC International Collaborative Study, analyzing TP53 mutation data on 3,583 stage I to IV patients, found no significant prognostic value of TP53 status for the overall cohort, but some evidence of inferior prognosis was reported for certain types of mutations, particularly for distal colon tumors [40, 41]. Further analysis of this cohort, classifying TP53 mutations according to functional status for transactivation based on reporter assays, suggested that such loss of function mutations were more frequent in stage IV CRC and associated with worse prognosis in this stage of disease [42]. Given these heterogeneous results, the prognostic value of TP53 remains uncertain.
3.5 Chromosome 18q LOH/DCC Protein Loss
One of the most common cytogenetic abnormalities in CRC is deletion of the long arm of chromosome 18q present in up to 70% of cases [9, 43]. The DCC (deleted in colorectal carcinoma) gene was initially suggested as the primary target of 18q loss, but SMAD4 has since emerged as the more likely candidate supported by the identification of frequent somatic mutations [44–46]. SMAD4 is a central effector of the transforming growth factor-β (TGF-β) signaling pathway. TGF-β is an important growth inhibitor of epithelial cells, and loss of sensitivity to this cytokine as a result of SMAD4 inactivation is thought to contribute to uncontrolled cell proliferation [47].
The prognostic value of chromosome 18q deletion has been evaluated using different methodologies, either directly using DNA-based loss of heterozygosity (LOH) analysis or indirectly using the level of DCC protein expression as a surrogate. Several studies have suggested an inferior prognosis for patients with stage II and III cancers harboring 18q LOH or loss of DCC protein [43, 48–50], but others have found no association including an analysis of 955 DNA mismatch repair proficient stage II and III colon cancers from the CALGB 9581 and 89803 trials [51–55]. A meta-analysis of 17 retrospective studies (2,189 patients, stages I to IV), demonstrated worse OS for patients with 18q LOH/DCC protein loss compared to those with intact 18q/DCC protein expression (hazard ratio (HR) 2.00, 95% CI 1.49–2.69), although there was evidence of study heterogeneity and publication bias [56]. Other investigators have analyzed SMAD4 protein loss and reported a negative prognostic effect in early stage [57, 58] and metastatic CRC [59].
Currently, the prognostic value of chromosome 18q status remains to be fully elucidated. In particular, chromosome 18q deletion is strongly correlated with the presence of overall chromosomal instability (CIN), another potential prognostic marker [60]. Despite these limitations, one ongoing adjuvant study (ECOG5202/NCT00217737) is currently stratifying completely resected stage II colon cancer patients for treatment in part based on the LOH status of chromosome 18q (http://www.cancer.gov/clinicaltrials/search).
3.6 Defective DNA Mismatch Repair/Microsatellite Instability
DNA mismatch repair (MMR) is integral to the correction of base-base mismatches generated during normal DNA replication, recombination or as a result of DNA damage. Germline mutations in MMR genes underlie the syndrome of hereditary non-polyposis colorectal cancer (HNPCC), and somatic inactivation of MMR is found in approximately 15% of sporadic CRCs [61]. The most common mechanism of MMR inactivation in sporadic CRC is transcriptional silencing of the MLH1 (human mutL homolog 1) gene by promoter methylation [62, 63]. Cells defective for MMR (dMMR) accumulate mutations at an increased rate including insertions/deletions at nucleotide repeat sequences, a phenotype called microsatellite instability (MSI). Cancer MSI status can be determined using PCR-based techniques in which the length of microsatellite repeats is compared between tumor and matched normal DNA (Fig. 5.3a). A consensus panel of five microsatellite markers is commonly used, with cancers having instability detected at two or more markers considered to have MSI-high (MSI-H) [64]. MMR deficiency may also be reliably detected by immunohistochemical analysis for the mismatch repair proteins MLH1, MSH2, MSH6 and PMS2 (Fig. 5.3b). dMMR/MSI-H is associated with right-sided cancer location, mucinous histology, poor differentiation, female gender and older age [65]. dMMR/MSI-H prevalence appears to decrease with advanced tumor stage, with low frequencies reported for metastatic CRC [66]. Strong positive associations exists with BRAF mutation [10, 67] and the CpG Island Methylator Phenotype (CIMP) [10].
The two main methodologies for detecting DNA mismatch repair deficiency in colorectal cancer. (a) Microsatellite instability testing using the Bethesda panel of markers (BAT25, BAT26, D17S250, D2S123 and D5S346). The tumor sample shows the acquisition of novel alleles of different size as compared to the matched normal sample. Cases with instability demonstrated in two or more of the five markers are considered to have microsatellite instability. (b) Immunohistochemistry for the DNA mismatch repair proteins MLH1, MSH2, MSH6 and PMS2. In the sporadic case shown, there is loss of MLH1 and PMS2 protein from carcinoma cells, indicating loss DNA mismatch repair function. Non-neoplastic stromal cells provide an internal positive control
Evidence from the majority of published studies suggests that dMMR/MSI-H status is associated with improved prognosis in CRC [14, 53, 68–71]. In a meta-analysis of 32 eligible reports (7,642 patients, stages I to IV) the combined HR estimate for overall survival associated with MSI-H was 0.65 (95% CI 0.59–0.71) [71]. In the PETACC-3 study (n = 1,564), the prognostic value of MSI status was found to be stronger in patients with stage II as compared to stage III colon cancer [72], and the QUASAR study (n = 1,584) identified both loss of MMR protein expression and T4 stage as independent prognostic factors for stage II CRC [14]. Similarly, an analysis of 1,852 stage II and III colon cancer patients from the CALGB 9581 and 89803 studies reported improved DFS and OS in patients with dMMR tumors [55].
Based on the weight of the currently available evidence supporting the prognostic value of dMMR/MSI-H status in the adjuvant setting, and data suggesting that dMMR/MSI-H cancers may not benefit from 5-FU-based chemotherapy (see below), it may be reasonable to forego adjuvant chemotherapy in moderate and high-risk stage II patients with a dMMR/MSI-H phenotype. This has been implemented as a criterion for treatment stratification in the ongoing ECOG5202/NCT00217737 trial.
3.7 CpG Island Methylator Phenotype
The term CpG Island Methylator Phenotype (CIMP) refers to a subset of CRCs that exhibit concurrent cancer-specific (or ‘type C’) hypermethylation at a high proportion of defined CpG islands within gene promoters, frequently associated with MSI-H, BRAF mutation and tumor location in the proximal colon [10, 73]. ‘Type C’ DNA hypermethylation affects multiple loci and several CIMP marker panels have been proposed. One of the most widely used panels is NEUROG1, IGF2, SOCS1, CACNA1G, and RUNX3, and cancers are termed CIMP-high (CIMP-H) if four or more of these loci are methylated in tumor DNA [10]. Given the strong association of the CIMP phenotype with MSI-H status and BRAF mutation, the prognostic impact of CIMP-H must be considered in the context of these variables.
Inconsistent data exist for the effect of CIMP status on CRC outcome, with the use of variable marker panels causing some difficulty in the comparison between studies. Some investigators have suggested an improved CSS for persons with CIMP-H stage I to IV colon cancer (n = 649) independent of MSI and BRAF mutation [30], whereas others have reported a detriment in DFS for proximal stage III colon cancer (n = 161), but not for distal stage III colon cancer [74, 75]. The E2290 trial on 188 patients with metastatic CRC found an association with shortened OS, but BRAF mutation status was not considered [74, 75]. Several authors have observed a negative prognostic impact for CIMP-H on OS or CSS in stage I to IV CRCs, but only in cases with MSS [76–79]. However, in two of these studies with available BRAF data, poor outcomes appeared to be largely related to the presence of BRAF mutation [76–79]. Taken together, the independent prognostic value of CIMP-H status in CRC remains uncertain.
3.8 Chromosomal Instability
Aneuploidy is present in 60–70% of CRCs and is often attributed to the presence of some underlying form of chromosomal instability (CIN). CIN may have multiple causes, including perturbation of processes controlling mitotic spindle or kinetochore function, mutations in genes involved in DNA double-strand break repair, or progressive erosion of telomeres triggering the breakage-bridge-fusion cycle. Alternatively, CIN may result as a by-product of inactivation of cell cycle checkpoint genes. For CRC, genes proposed to directly or indirectly cause CIN include APC [80–82], TP53 [83], BUB1 [84], BUBR1 [85] and FBXW1/CDC4 [86]. CIN and MSI tend to be mutually exclusive, although a small proportion of cancers exist that show evidence of both of these forms of genomic instability [87, 88].
The majority of studies evaluating the prognostic impact of CIN have used flow or image cytometric measurements of DNA content which provide a basic indication as to the presence of aneuploidy. Higher-resolution technologies, such as comparative genomic hybridisation (CGH) or single nucleotide polymorphism (SNP) arrays exist, but their application to large patient series has been limited. Data from 63 flow-cytometry studies reporting outcomes for 10,126 patients with stage I to IV CRC have recently been assessed in a meta-analysis [89]. Overall, 60% of patients had CIN+ cancers, and presence of CIN was associated with inferior prognosis (HR 1.45, 95% CI 1.35–1.55). Poorer PFS and OS could be demonstrated for patients with stage II and III disease, but data for stage I and IV patients were insufficient for conclusive evaluation.
While the combined evidence is consistent with CIN+ status as a predictor of poor prognosis in CRC, the relationship with MSI status remains unclear. To date, only one major published study on 528 patients with stage II and III CRCs has evaluated both MSI and CIN in multivariate analysis and found that the effect of MSI on survival was not independent to that of CIN [70].
4 Predictive Biomarkers for Cytotoxic Chemotherapies
4.1 5-Flourouracil (5-FU) and Capecitabine
The antimetabolite drug 5-FU is a pyrimidine analogue which primarily acts through irreversible inhibition of the enzyme thymidylate synthetase (TS or TYMS). TS normally methylates deoxyuridine monophosphate (dUMP) into thymidine monophosphate (dTMP) which is subsequently phosphorylated to thymidine triphosphate, a nucleotide required for DNA synthesis and repair. Inhibition of the action of TS results in a deficiency of dTMP, triggering apoptosis in dividing cells [90]. 5-FU is administered intravenously by bolus injection or infusion, generally with leucovorin to enhance activity. Capecitabine is a 5-FU prodrug which can be administered orally.
4.1.1 Thymidylate Synthetase
The level of intratumoral TS expression has been suggested to predict response to 5-FU-based chemotherapy. Preclinical studies in human colon cancer cell lines found that high levels of TS activity were correlated with intrinsic or acquired resistance to 5-FU [91–94], and higher levels of TS mRNA were observed to be associated with resistance to 5-FU treatment in patients with metastatic CRC [95–98]. With the development of robust antibodies against TS, an increasing number of studies have evaluated the association between intratumoral TS expression and 5-FU response using IHC. In both the adjuvant and palliative treatment setting, such studies have produced evidence that a high level of TS protein expression is associated with reduced benefit from 5-FU chemotherapy [99–102], although some investigators have reported contradictory findings [103–106]. In a meta-analysis of 13 studies on advanced CRC (n = 997) and seven studies on localized CRC (n = 2,610), higher TS expression was associated with inferior survival in both groups. The combined HR for OS was 1.74 (95% CI 1.34–2.26) and 1.35 (95% CI 1.07–1.80) in the advanced and adjuvant settings, respectively. However, evidence of heterogeneity and possible publication bias was observed [107].
Two main polymorphisms have been identified that influence the level of TS expression: A 6 base pair (bp) insertion and deletion variant in the 3′-untranslated region of TS that alters mRNA stability and is associated with low TS expression [108]; a 28-bp sequence within the promoter region of TS which occurs in two (2R), three (3R) or rarely more repeats that correlates with increasing TS expression, probably due to increased efficiency of mRNA translation for longer alleles [109, 110]. In addition, a SNP present within the second repeat of the 3R allele may further increase mRNA expression [111]. Several studies have analysed the predictive value of the tandem 28-bp repeat polymorphism, with conflicting results. Some studies have shown a lack of benefit from 5-FU treatment for persons with the 3R/3R genotype [112–115], while others have found no effect [116–119].
The clinical value of TS genotype, mRNA and/or protein levels for guiding the use of 5-FU-based chemotherapy remains uncertain given the current evidence.
4.1.2 Defective DNA Mismatch Repair/Microsatellite Instability
There is evidence from in vitro and clinical studies to suggest that persons with dMMR/MSI-H CRC do not benefit from 5-FU-based chemotherapy. In a study of 77 CRC cell lines tested for sensitivity to 5-FU, MSI-H status was found to be the strongest molecular predictor of reduced response [120]. A retrospective study on 570 patients with stage II and III colon cancer from five clinical trials of adjuvant 5-FU-based chemotherapy revealed superior OS for patients with MSI-H tumors in the no-treatment group, but no difference in outcome for patients in the chemotherapy group. Adjuvant chemotherapy significantly improved OS among patients with MSS/MSI-L tumors, but not in patients with MSI-H tumors [69]. Further data by the same group on an additional 467 patients confirmed the lack of efficacy of 5-FU-based adjuvant chemotherapy in MSI-H colon cancer [121], and similar results have been reported in a large study on non-trial patients (n = 754) [122] and a meta-analysis [71]. In contrast, other retrospective data and results from the QUASAR study suggest that patients with dMMR/MSI-H CRC do benefit from adjuvant 5-FU administration [14, 123]. The value of dMMR/MSI-H status as a predictive marker of adjuvant 5-FU-based therapy warrants further investigation.
4.2 Oxaliplatin
Oxaliplatin is a platinum-based cytotoxic drug that acts by preventing DNA replication through the formation of intra- and inter-strand platinum-DNA adducts. It lacks efficacy as a single agent, but is administered in combination with 5-FU in the treatment of early-stage and metastatic CRC.
4.2.1 Glutathione-S-transferase P (GSTP1)
GSTP1 is thought to be the primary enzyme for the detoxification of oxaliplatin, causing inactivation and excretion of the drug by conjugation with glutathione. Two coding polymorphisms in GSTP1 (Ile105Val and Ala114Val) show a relationship with reduced enzyme activity [124]. The Ile105Val variant was associated with differential response and survival in one retrospective study on 106 metastatic CRC patients who received second-line oxaliplatin and 5-FU treatment, with the valine allele more common in patients with better outcomes [125]. However, a number of other studies found no effect on survival in metastatic CRC patients [126–129]. Contradictory results have also been reported for the Ile105Val variant with respect to neurotoxicity [126, 129, 130]. Similarly, limited existing data on the predictive value of GTSP1 polymorphisms in the adjuvant setting do not suggest any major effect [128, 131].
4.2.2 Nucleotide Excision Repair Genes
ERCC1 and ERCC2 (excision repair cross-complementing rodent repair deficiency, complementation group 1 and 2) encode two rate-limiting enzymes of the nucleotide excision repair pathway which act in the repair of platinum-DNA adducts. Two functional polymorphisms with these genes, ERCC1 Asn118Asn (G > A) and ERCC2 Lys751Gln (T > G), have been repeatedly studied as potential markers for response and outcome to oxaliplatin treatment. The former variant affects ERCC1 mRNA expression [132], whereas the latter is associated with reduced ERCC2 DNA repair capacity [133]. A recent meta-analysis has summarized published studies on metastatic CRC, comprising eight studies on the ERCC1 (n = 993) and seven studies on the ERCC2 polymorphism (n = 858) [134]. Assuming a dominant model, the ERCC1 T/T genotype was not associated with objective response, PFS or OS for all patients, whereas the ERCC2 G/G genotype was associated with reduced objective response (OR 0.52, 95% CI 0.35–0.77) and inferior outcomes for PFS (HR 1.50, 95% CI 1.11–2.02) and OS (HR1.77, 95% CI 1.11–2.84). Significant study heterogeneity was evident. In a pooled analysis with metastatic gastric cancer, ethnic differences between Asian and Caucasian individuals were suggested, but a sub-analysis for CRC was not presented. One small study of stage III CRCs (n = 98) found no evidence that ERCC1 and ERCC2 polymorphisms predict response to oxaliplatin in the adjuvant setting [131]. Presently, the existing evidence is insufficient to support ERCC1 and ERCC2 genotyping as a predictive marker for oxaliplatin response, with larger prospective studies required to confirm previous findings.
4.3 Irinotecan
Irinotecan is an inhibitor of topoisomerase I, an enzyme that is essential for DNA replication. For the treatment of metastatic CRC, it may be given as a single agent or in combination with 5-FU.
4.3.1 UDP-Glucuronosyltransferase (UGT1A1)
The active metabolite of the topoisomerase I inhibitor irinotecan, SN-38, is detoxified primarily by the enzyme UGT1A1. A TA-repeat polymorphism within the TATA promoter element of the UGT1A1 gene affects the level of enzyme expression and activity [135, 136]. Persons who are heterozygous (6/7) or homozygous (7/7 or UGT1A1*28) for the 7-repeat allele show reduced clearance of SN-38 and have an increasing risk of suffering severe toxicity in the form of grade 3 or 4 neutropenia. Reports determining the size of this effect have shown variable results, and a meta-analysis has shown that the incidence of toxicity in UGT1A1*28 patients is positively correlated with the drug dose used [137]. Genetic testing for this polymorphism to avoid life-threatening neutropenia has been approved by the US Food and Drug Administration and is recommended to guide irinotecan dosing. However, in clinical practice this test has found limited use largely because improved scheduling with lower, more frequent dosing has reduced the incidence of haemotological toxicity.
5 Predictive Biomarkers for Targeted Biological Agents
5.1 Anti-EGFR Monoclonal Antibodies
Binding of ligand to EGFR stimulates cellular signaling via the RAS/RAF/MEK/ MAPK and PI3K/AKT pathways which are of central importance to colorectal tumourigenesis. Two monoclonal antibodies against EGFR, cetuximab (chimeric IgG1) and panitumumab (fully humnised IgG2), have been demonstrated to have activity in metastatic CRC in first and second line therapy when combined with chemotherapy and as a single agent in third line therapy [23, 138, 139].
5.1.1 EGFR
Studies evaluating EGFR protein expression and somatic mutations as predictive markers for the response to anti-EGFR targeted therapy have failed to demonstrate reliable clinical value in CRC [138, 140–144]. However, evidence from a number of investigators suggests that EGFR amplification may be a negative predictive marker of response with small retrospective studies using monotherapy and combination therapy showing a lack of efficacy in EGFR amplified tumors [145–149]. Some difficulty remains with assay reproducibility and there is no agreed standard threshold for reporting of increased copy-number.
5.1.2 Amphiregulin and Epiregulin
Gene expression of the stimulatory EGFR ligands amphiregulin (AREG) and epiregulin (EREG) has been suggested as a potential marker of sensitivity to anti-EGFR antibodies in a small number of reports, including two studies on primary tumor and metastatic biopsy tissues from patients with advanced CRC receiving cetuximab monotherapy [150, 151], and one study on primary tumor tissues from patients receiving cetuximab in combination with chemotherapy [152]. However, AREG and EREG expression have not yet been studied in a large validation trial including a non-treated patient arm and the optimal cut-off for guiding use of anti-EGFR therapy has not yet been determined.
5.1.3 KRAS
Mutations in the KRAS gene are thought to activate the EGFR signaling pathway independently of ligand stimulation of the receptor, thus bypassing the efficacy of anti-EGFR therapy. Accordingly, multiple studies in metastatic CRC patients have demonstrated KRAS tumor mutations in codons 12 and 13 to be predictive of a lack of response to cetuximab and panitumumab. These include single-arm studies [150, 153, 154], and large randomized studies in the first-line setting [155, 156] and in pre-treated mCRC patients [6, 7, 23, 157, 158]. Similarly KRAS mutations in codons 61 and 146 may be associated with anti-EGFR therapy resistance, although data are more limited [6, 7, 23, 157, 158]. There is some evidence to suggest that not all tumors with mutated KRAS are resistant to anti-EGFR therapy, and one study has proposed that patients with a glycine to aspartate substitution at codon 13 (G13D) may respond to such treatment [159]. Confirmation of these latter findings will require further study. Some studies have further suggested a detrimental effect of anti-EGFR monoclonal antibodies when used to treat KRAS mutant cancer [160, 161].
Based on these results, ASCO, ESMO and NCCN (category 2A) presently recommend the use of monoclonal antibodies against EGFR only in metastatic CRC patients with wild-type KRAS status. Current NCCN testing recommendations are for KRAS codons 12 and 13 in CLIA-88 (Clinical Laboratories Improvement Amendments of 1988)-certified laboratories. No formal recommendations exist regarding testing for KRAS codons 61 and 146.
5.1.4 BRAF
The presence of BRAF V600E mutation has been postulated to be a predictive biomarker for anti-EGFR therapy response in cancers with KRAS wild-type status, but this has been challenging to assess given the strong prognostic impact of this mutation in metastatic CRC. Recently, a retrospective analysis of a European consortium on 773 metastatic CRC patients treated with cetuximab between 2001 and 2008 reported a lower objective RR to cetuximab in BRAF-mutated/KRAS wild-type tumors. Data on untreated individuals were not available, but it was suggested that a measure of objective response was a good estimate of treatment effect which was not confounded by the prognostic impact of the mutation [162]. In contrast, analysis of KRAS wild-type CRCs from the CAIRO2 trail of chemotherapy and bevacizumab with or without cetuximab did not find an association between BRAF mutation and PFS according to anti-EGFR therapy [163].
5.1.5 PIK3CA
A number of studies have investigated activating mutations in PIK3CA exons 9 and 20 as a predictive marker for anti-EGFR therapy. One study in 110 metastatic CRC patients receiving various anti-EGFR therapy regimes in first- or subsequent-line settings found a lack of response in patients with PIK3KCA-mutated/KRAS wild-type tumors [164]. In contrast, another study on 200 patients with chemotherapy refractory metastatic colorectal cancers treated with cetuximab in monotherapy or in combination with irinotecan found no evidence for a strong predictive role of PIK3CA status [165]. Subsequently, a European retrospective consortium analysis on 773 metastatic CRC patients treated with cetuximab observed that lack of response in the KRAS wild-type population was limited to patients with PIK3CA exon 20 mutation (ORR, PFS and OS), and proposed that this may explain the previous conflicting results [162]. Further validation of these findings in studies including a non-treated patient arm is required.
5.2 Anti-VEGF Monoclonal Antibodies
Bevacizumab is a humanized monoclonal antibody that inhibits VEGF-A, a growth factor that stimulates neo-angiogenesis in cancer. This anti-angiogenic agent is used in the treatment of metastatic CRC and increases response rates and overall survival in combination with 5-FU alone or with irinotecan or oxaliplatin plus 5-FU.
No effective and reliable biomarkers for bevacizumab response have been discovered to date. Suggested biomarkers include angiopoietin-2 levels [166], polymorphisms in VEGF [167, 168] and VEGFR-1 [167, 168], baseline levels of soluble VEGFR1, VEGF, placental-derived growth factor (PlGF), interleukin 6 (IL-6) and IL-8 during treatment [169, 170], and tumor and/or stromal expression of VEGF and thrombospondin-2 [171]. Although some of these studies show promise validation data are limited and there are currently no biomarkers for bevacizumab response in clinical use.
6 Unbiased Molecular Signatures
Besides the targeted approaches described above, high-throughput PCR-based assays and microarrays for evaluating mRNA expression, SNPs, DNA copy number and methylation are increasingly being utilized for large-scale hypothesis-driven and unbiased genome-wide marker discovery. In addition, next-generation sequencing approaches are beginning to play an important role, although their implementation for large cohort studies is currently hampered by cost and technology constraints. To date, most development effort has been invested in the area of prognostic mRNA expression signatures with significant industry involvement. One prognostic test (Oncotype DX Colon Cancer, Genomic Health Inc) is now commercially available for patients with stage II colon cancer, and a second test (ColoPrint, Agendia) is in the final stage of development for patients with stage II and III disease.
6.1 Prognostic Gene Expression Signatures
Multiple studies have evaluated gene expression profiles derived from RT-PCR or microarray analysis for potential prognostic value in CRC [172–179]. Although sample sizes have often been small, patient populations heterogeneous and external validation limited these studies have indicated promise for expression signatures to discriminate recurrence risk in patients with early-stage disease. A meta-analysis of studies of various gene expression assays including 271 patients from eight cohorts with stage II CRC showed a prognostic likelihood ratio of 4.7 (95% CI, 3.2–6.8) for recurrence or death within 3 years, with an average accuracy, sensitivity, and specificity of approximately 82%, 76%, and 85% [180].
Two commercial assays, Oncotype DX Colon Cancer and ColoPrint, have been developed as prognostic markers for recurrence risk in stage II and III colon cancers, with clinical validation studies ongoing. The Oncotype DX Colon Cancer test is a quantitative, multigene RT-PCR assay for use on formalin-fixed paraffin-embedded tissue. The assay has been developed based on the analysis of 761 selected candidate genes with putative significance in colon cancer in 1,851 specimens from four adjuvant trials (NSABP C-01/C-02, Cleveland Clinic Foundation, NSABP C-04, and NSABP C-06) [181]. A total of 48 genes were identified as significantly associated with recurrence risk and 66 genes as significantly associated with treatment benefit. The final assay incorporated the seven genes most strongly associated with recurrence, the six genes most strongly identified with treatment benefit, and five reference genes for standardization. The assay was evaluated in 1,436 patients with stage II colon cancer from the QUASAR clinical trial. In multivariate analyses, the classifier retained prognostic significance independent of conventional prognostic factors including mismatch repair status, tumor T stage, number of lymph nodes examined, grade, and presence of lymphovascular invasion. However, the classifier was not confirmed to be predictive of treatment benefit in the 725 patients treated with fluorouracil and leucovorin [182].
The ColoPrint assay is an 18-gene signature developed in fresh-frozen tumor specimens from 188 patients with stage I to IV CRC using high density Agilent 44K oligonucleotide arrays, with subsequent validation in 206 patients with stage I to III colon cancer. In the validation cohort, the signature classified 60% of samples as low risk and 40% as high risk, with an HR for RFS of 2.69 between groups. RFS at 5 years was 87.6% in the low-risk group as compared to 67.2% in the high-risk group. The signature was a predictor of outcome when applied separately to stage II and stage III patients, and to individuals treated with or without adjuvant chemotherapy [183]. The PARSC trial, a prospective study for the assessment of recurrence risk in stage II colon cancer (CC) patients using ColoPrint is ongoing [184].
7 Conclusions
The successful improvements in treatment of CRC over the past decade and our increasing understanding of the molecular biology of the disease have driven substantial efforts to identify biomarkers of prognosis and therapy response. These efforts have been fraught with difficulties with many markers supported by insufficient data and failing to demonstrate clinical utility. Small sample size, limited clinical and follow-up data, differences in patient selection and therapies employed, low frequency of candidate marker alteration, heterogeneous screening methodologies and lack of standardization of reporting account for much of the conflict. Many of these deficiencies are beginning to be addressed, and a number of comprehensive biomarkers studies are currently underway. Despite these challenges, encouraging progress has recently been made with the recognition of the importance of KRAS mutation status for selection of EGFR-specific therapy.
With improving technology, evaluation of large panels of markers – perhaps tailored to interrogate particular pathways – or genome-wide analyses will become feasible. The ongoing commercial development of prognostic gene expression signatures utilizing microarrays is an early example of this. The development of such global biomarker signatures will require large well-planned studies including cooperative national and international consortia.
References
Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2010) GLOBOCAN 2008 v1.2, Cancer incidence and mortality worldwide: IARC CancerBase No. 10. International Agency for Research on Cancer, Lyon. http://globocan.iarc.fr. Accessed 29 July 2011
Wolmark N, Rockette H, Fisher B, Wickerham DL, Redmond C, Fisher ER, Jones J, Mamounas EP, Ore L, Petrelli NJ et al (1993) The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol 11(10):1879–1887
Wolmark N, Rockette H, Mamounas E, Jones J, Wieand S, Wickerham DL, Bear HD, Atkins JN, Dimitrov NV, Glass AG, Fisher ER, Fisher B (1999) Clinical trial to assess the relative efficacy of fluorouracil and leucovorin, fluorouracil and levamisole, and fluorouracil, leucovorin, and levamisole in patients with Dukes’ B and C carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project C-04. J Clin Oncol 17(11):3553–3559
Allegra CJ, Yothers G, O’Connell MJ, Sharif S, Petrelli NJ, Colangelo LH, Atkins JN, Seay TE, Fehrenbacher L, Goldberg RM, O’Reilly S, Chu L, Azar CA, Lopa S, Wolmark N (2011) Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J Clin Oncol 29(1):11–16. doi:10.1200/JCO.2010.30.0855
Alberts S, Sargent D, Smyrk T, Shields E (2010) Adjuvant mFOLFOX6 with or without cetuxiumab (Cmab) in KRAS wild-type (WT) patients (pts) with resected stage III colon cancer (CC): results from NCCTG Intergroup Phase III Trial N0147. J Clin Oncol 28:18s
Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore MJ, Zalcberg JR (2008) K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359(17):1757–1765
Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, Juan T, Sikorski R, Suggs S, Radinsky R, Patterson SD, Chang DD (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26:1626–1634
Allegra CJ, Jessup JM, Somerfield MR, Hamilton SR, Hammond EH, Hayes DF, McAllister PK, Morton RF, Schilsky RL (2009) American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol 27(12):2091–2096. doi:10.1200/JCO.2009.21.9170
Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Nakamura Y, White R, Smits AM, Bos JL (1988) Genetic alterations during colorectal-tumor development. N Engl J Med 319(9):525–532. doi:10.1056/NEJM198809013190901
Weisenberger DJ, Siegmund KD, Campan M, Young J, Long TI, Faasse MA, Kang GH, Widschwendter M, Weener D, Buchanan D, Koh H, Simms L, Barker M, Leggett B, Levine J, Kim M, French AJ, Thibodeau SN, Jass J, Haile R, Laird PW (2006) CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 38(7):787–793
Andreyev HJ, Norman AR, Cunningham D, Oates JR, Clarke PA (1998) Kirsten ras mutations in patients with colorectal cancer: the multicenter “RASCAL” study. J Natl Cancer Inst 90(9):675–684
Vaughn CP, Zobell SD, Furtado LV, Baker CL, Samowitz WS (2011) Frequency of KRAS, BRAF, and NRAS mutations in colorectal cancer. Genes Chromosomes Cancer 50(5):307–312. doi:10.1002/gcc.20854
Andreyev HJ, Norman AR, Cunningham D, Oates J, Dix BR, Iacopetta BJ, Young J, Walsh T, Ward R, Hawkins N, Beranek M, Jandik P, Benamouzig R, Jullian E, Laurent-Puig P, Olschwang S, Muller O, Hoffmann I, Rabes HM, Zietz C, Troungos C, Valavanis C, Yuen ST, Ho JW, Croke CT, O’Donoghue DP, Giaretti W, Rapallo A, Russo A, Bazan V, Tanaka M, Omura K, Azuma T, Ohkusa T, Fujimori T, Ono Y, Pauly M, Faber C, Glaesener R, de Goeij AF, Arends JW, Andersen SN, Lovig T, Breivik J, Gaudernack G, Clausen OP, De Angelis PD, Meling GI, Rognum TO, Smith R, Goh HS, Font A, Rosell R, Sun XF, Zhang H, Benhattar J, Losi L, Lee JQ, Wang ST, Clarke PA, Bell S, Quirke P, Bubb VJ, Piris J, Cruickshank NR, Morton D, Fox JC, Al-Mulla F, Lees N, Hall CN, Snary D, Wilkinson K, Dillon D, Costa J, Pricolo VE, Finkelstein SD, Thebo JS, Senagore AJ, Halter SA, Wadler S, Malik S, Krtolica K, Urosevic N (2001) Kirsten ras mutations in patients with colorectal cancer: the ‘RASCAL II’ study. Br J Cancer 85(5):692–696. doi:10.1054/bjoc.2001.1964
Hutchins G, Southward K, Handley K, Magill L, Beaumont C, Stahlschmidt J, Richman S, Chambers P, Seymour M, Kerr D, Gray R, Quirke P (2011) Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer. J Clin Oncol 29(10):1261–1270. doi:10.1200/JCO.2010.30.1366
Richman SD, Seymour MT, Chambers P, Elliott F, Daly CL, Meade AM, Taylor G, Barrett JH, Quirke P (2009) KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial. J Clin Oncol 27(35):5931–5937. doi:10.1200/JCO.2009.22.4295
Roth AD, Tejpar S, Delorenzi M, Yan P, Fiocca R, Klingbiel D, Dietrich D, Biesmans B, Bodoky G, Barone C, Aranda E, Nordlinger B, Cisar L, Labianca R, Cunningham D, Van Cutsem E, Bosman F (2010) Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60–00 trial. J Clin Oncol 28(3):466–474. doi:10.1200/JCO.2009.23.3452
Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, Canon JL, Van Laethem JL, Maurel J, Richardson G, Wolf M, Amado RG (2007) Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25(13):1658–1664
Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE (2002) Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature 418(6901):934. doi:10.1038/418934a
Tol J, Nagtegaal ID, Punt CJ (2009) BRAF mutation in metastatic colorectal cancer. N Engl J Med 361(1):98–99. doi:10.1056/NEJMc0904160
Samowitz WS, Albertsen H, Herrick J, Levin TR, Sweeney C, Murtaugh MA, Wolff RK, Slattery ML (2005) Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer. Gastroenterology 129(3):837–845. doi:10.1053/j.gastro.2005.06.020
Tie J, Gibbs P, Lipton L, Christie M, Jorissen RN, Burgess AW, Croxford M, Jones I, Langland R, Kosmider S, McKay D, Bollag G, Nolop K, Sieber OM, Desai J (2011) Optimizing targeted therapeutic development: analysis of a colorectal cancer patient population with the BRAF(V600E) mutation. Int J Cancer 128(9):2075–2084
Price TJ, Hardingham JE, Lee CK, Weickhardt A, Townsend AR, Wrin JW, Chua A, Shivasami A, Cummins MM, Murone C, Tebbutt NC (2011) Impact of KRAS and BRAF gene mutation status on outcomes from the phase III AGITG MAX trial of capecitabine alone or in combination with bevacizumab and mitomycin in advanced colorectal cancer. J Clin Oncol 29(19):2675–2682. doi:10.1200/JCO.2010.34.5520
Van Cutsem E, Kohne CH, Lang I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, Schlichting M, Zubel A, Celik I, Rougier P, Ciardiello F (2011) Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 29(15):2011–2019. doi:10.1200/JCO.2010.33.5091
Yokota T, Ura T, Shibata N, Takahari D, Shitara K, Nomura M, Kondo C, Mizota A, Utsunomiya S, Muro K, Yatabe Y (2011) BRAF mutation is a powerful prognostic factor in advanced and recurrent colorectal cancer. Br J Cancer 104(5):856–862. doi:10.1038/bjc.2011.19
Saridaki Z, Papadatos-Pastos D, Tzardi M, Mavroudis D, Bairaktari E, Arvanity H, Stathopoulos E, Georgoulias V, Souglakos J (2010) BRAF mutations, microsatellite instability status and cyclin D1 expression predict metastatic colorectal patients’ outcome. Br J Cancer 102(12):1762–1768. doi:10.1038/sj.bjc.6605694
Samowitz WS, Sweeney C, Herrick J, Albertsen H, Levin TR, Murtaugh MA, Wolff RK, Slattery ML (2005) Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer Res 65(14):6063–6069
French AJ, Sargent DJ, Burgart LJ, Foster NR, Kabat BF, Goldberg R, Shepherd L, Windschitl HE, Thibodeau SN (2008) Prognostic significance of defective mismatch repair and BRAF V600E in patients with colon cancer. Clin Cancer Res 14(11):3408–3415. doi:10.1158/1078-0432.CCR-07-1489
Farina-Sarasqueta A, van Lijnschoten G, Moerland E, Creemers GJ, Lemmens VE, Rutten HJ, van den Brule AJ (2010) The BRAF V600E mutation is an independent prognostic factor for survival in stage II and stage III colon cancer patients. Ann Oncol 21(12):2396–2402. doi:10.1093/annonc/mdq258
Zlobec I, Kovac M, Erzberger P, Molinari F, Bihl MP, Rufle A, Foerster A, Frattini M, Terracciano L, Heinimann K, Lugli A (2010) Combined analysis of specific KRAS mutation, BRAF and microsatellite instability identifies prognostic subgroups of sporadic and hereditary colorectal cancer. Int J Cancer 127(11):2569–2575. doi:10.1002/ijc.25265
Ogino S, Nosho K, Kirkner GJ, Kawasaki T, Meyerhardt JA, Loda M, Giovannucci EL, Fuchs CS (2009) CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer. Gut 58(1):90–96
Samuels Y, Velculescu VE (2004) Oncogenic mutations of PIK3CA in human cancers. Cell Cycle 3(10):1221–1224
Oda K, Okada J, Timmerman L, Rodriguez-Viciana P, Stokoe D, Shoji K, Taketani Y, Kuramoto H, Knight ZA, Shokat KM, McCormick F (2008) PIK3CA cooperates with other phosphatidylinositol 3′-kinase pathway mutations to effect oncogenic transformation. Cancer Res 68(19):8127–8136. doi:10.1158/0008-5472.CAN-08-0755
Kato S, Iida S, Higuchi T, Ishikawa T, Takagi Y, Yasuno M, Enomoto M, Uetake H, Sugihara K (2007) PIK3CA mutation is predictive of poor survival in patients with colorectal cancer. Int J Cancer 121(8):1771–1778
He Y, Van’t Veer LJ, Mikolajewska-Hanclich I, van Velthuysen ML, Zeestraten EC, Nagtegaal ID, van de Velde CJ, Marijnen CA (2009) PIK3CA mutations predict local recurrences in rectal cancer patients. Clin Cancer Res 15(22):6956–6962. doi:10.1158/1078-0432.CCR-09-1165
Ogino S, Nosho K, Kirkner GJ, Shima K, Irahara N, Kure S, Chan AT, Engelman JA, Kraft P, Cantley LC, Giovannucci EL, Fuchs CS (2009) PIK3CA mutation is associated with poor prognosis among patients with curatively resected colon cancer. J Clin Oncol 27(9):1477–1484
Farina Sarasqueta A, Zeestraten EC, van Wezel T, van Lijnschoten G, van Eijk R, Dekker JW, Kuppen PJ, Goossens-Beumer IJ, Lemmens VE, van de Velde CJ, Rutten HJ, Morreau H, van den Brule AJ (2011) PIK3CA kinase domain mutation identifies a subgroup of stage III colon cancer patients with poor prognosis. Cell Oncol 34:523–531. doi:10.1007/s13402-011-0054-4
Sartore-Bianchi A, Di Nicolantonio F, Nichelatti M, Molinari F, De Dosso S, Saletti P, Martini M, Cipani T, Marrapese G, Mazzucchelli L, Lamba S, Veronese S, Frattini M, Bardelli A, Siena S (2009) Multi-determinants analysis of molecular alterations for predicting clinical benefit to EGFR-targeted monoclonal antibodies in colorectal cancer. PLoS One 4(10):e7287. doi:10.1371/journal.pone.0007287
Ilyas M, Tomlinson IP (1996) Genetic pathways in colorectal cancer. Histopathology 28(5):389–399
Munro AJ, Lain S, Lane DP (2005) P53 abnormalities and outcomes in colorectal cancer: a systematic review. Br J Cancer 92(3):434–444. doi:10.1038/sj.bjc.6602358
Soong R, Powell B, Elsaleh H, Gnanasampanthan G, Smith DR, Goh HS, Joseph D, Iacopetta B (2000) Prognostic significance of TP53 gene mutation in 995 cases of colorectal carcinoma. Influence of tumour site, stage, adjuvant chemotherapy and type of mutation. Eur J Cancer 36(16):2053–2060
Russo A, Bazan V, Iacopetta B, Kerr D, Soussi T, Gebbia N (2005) The TP53 colorectal cancer international collaborative study on the prognostic and predictive significance of p53 mutation: influence of tumor site, type of mutation, and adjuvant treatment. J Clin Oncol 23(30):7518–7528. doi:10.1200/JCO.2005.00.471
Iacopetta B, Russo A, Bazan V, Dardanoni G, Gebbia N, Soussi T, Kerr D, Elsaleh H, Soong R, Kandioler D, Janschek E, Kappel S, Lung M, Leung CS, Ko JM, Yuen S, Ho J, Leung SY, Crapez E, Duffour J, Ychou M, Leahy DT, O’Donoghue DP, Agnese V, Cascio S, Di Fede G, Chieco-Bianchi L, Bertorelle R, Belluco C, Giaretti W, Castagnola P, Ricevuto E, Ficorella C, Bosari S, Arizzi CD, Miyaki M, Onda M, Kampman E, Diergaarde B, Royds J, Lothe RA, Diep CB, Meling GI, Ostrowski J, Trzeciak L, Guzinska-Ustymowicz K, Zalewski B, Capella GM, Moreno V, Peinado MA, Lonnroth C, Lundholm K, Sun XF, Jansson A, Bouzourene H, Hsieh LL, Tang R, Smith DR, Allen-Mersh TG, Khan ZA, Shorthouse AJ, Silverman ML, Kato S, Ishioka C (2006) Functional categories of TP53 mutation in colorectal cancer: results of an International Collaborative Study. Ann Oncol 17(5):842–847. doi:10.1093/annonc/mdl035
Jen J, Kim H, Piantadosi S, Liu ZF, Levitt RC, Sistonen P, Kinzler KW, Vogelstein B, Hamilton SR (1994) Allelic loss of chromosome 18q and prognosis in colorectal cancer. N Engl J Med 331(4):213–221. doi:10.1056/NEJM199407283310401
Fearon ER, Cho KR, Nigro JM, Kern SE, Simons JW, Ruppert JM, Hamilton SR, Preisinger AC, Thomas G, Kinzler KW et al (1990) Identification of a chromosome 18q gene that is altered in colorectal cancers. Science 247(4938):49–56
Kinzler KW, Vogelstein B (1996) Lessons from hereditary colorectal cancer. Cell 87(2):159–170
Eppert K, Scherer SW, Ozcelik H, Pirone R, Hoodless P, Kim H, Tsui LC, Bapat B, Gallinger S, Andrulis IL, Thomsen GH, Wrana JL, Attisano L (1996) MADR2 maps to 18q21 and encodes a TGFbeta-regulated MAD-related protein that is functionally mutated in colorectal carcinoma. Cell 86(4):543–552
Derynck R, Akhurst RJ, Balmain A (2001) TGF-beta signaling in tumor suppression and cancer progression. Nat Genet 29(2):117–129. doi:10.1038/ng1001-117
Watanabe T, Wu TT, Catalano PJ, Ueki T, Satriano R, Haller DG, Benson AB 3rd, Hamilton SR (2001) Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N Engl J Med 344(16):1196–1206. doi:10.1056/NEJM200104193441603
Shibata D, Reale MA, Lavin P, Silverman M, Fearon ER, Steele G Jr, Jessup JM, Loda M, Summerhayes IC (1996) The DCC protein and prognosis in colorectal cancer. N Engl J Med 335(23):1727–1732. doi:10.1056/NEJM199612053352303
Ogunbiyi OA, Goodfellow PJ, Herfarth K, Gagliardi G, Swanson PE, Birnbaum EH, Read TE, Fleshman JW, Kodner IJ, Moley JF (1998) Confirmation that chromosome 18q allelic loss in colon cancer is a prognostic indicator. J Clin Oncol 16(2):427–433
Carethers JM, Hawn MT, Greenson JK, Hitchcock CL, Boland CR (1998) Prognostic significance of allelic lost at chromosome 18q21 for stage II colorectal cancer. Gastroenterology 114(6):1188–1195
Ogino S, Nosho K, Irahara N, Shima K, Baba Y, Kirkner GJ, Meyerhardt JA, Fuchs CS (2009) Prognostic significance and molecular associations of 18q loss of heterozygosity: a cohort study of microsatellite stable colorectal cancers. J Clin Oncol 27(27):4591–4598
Halling KC, French AJ, McDonnell SK, Burgart LJ, Schaid DJ, Peterson BJ, Moon-Tasson L, Mahoney MR, Sargent DJ, O’Connell MJ, Witzig TE, Farr GH Jr, Goldberg RM, Thibodeau SN (1999) Microsatellite instability and 8p allelic imbalance in stage B2 and C colorectal cancers. J Natl Cancer Inst 91(15):1295–1303
Popat S, Zhao D, Chen Z, Pan H, Shao Y, Chandler I, Houlston RS (2007) Relationship between chromosome 18q status and colorectal cancer prognosis: a prospective, blinded analysis of 280 patients. Anticancer Res 27(1B):627–633
Bertagnolli MM, Redston M, Compton CC, Niedzwiecki D, Mayer RJ, Goldberg RM, Colacchio TA, Saltz LB, Warren RS (2011) Microsatellite instability and loss of heterozygosity at chromosomal location 18q: prospective evaluation of biomarkers for stages II and III colon cancer–a study of CALGB 9581 and 89803. J Clin Oncol 29(23):3153–3162. doi:10.1200/JCO.2010.33.0092
Popat S, Houlston RS (2005) A systematic review and meta-analysis of the relationship between chromosome 18q genotype, DCC status and colorectal cancer prognosis. Eur J Cancer 41(14):2060–2070
Isaksson-Mettavainio M, Palmqvist R, Forssell J, Stenling R, Oberg A (2006) SMAD4/DPC4 expression and prognosis in human colorectal cancer. Anticancer Res 26(1B):507–510
Alazzouzi H, Alhopuro P, Salovaara R, Sammalkorpi H, Jarvinen H, Mecklin JP, Hemminki A, Schwartz S Jr, Aaltonen LA, Arango D (2005) SMAD4 as a prognostic marker in colorectal cancer. Clin Cancer Res 11(7):2606–2611. doi:10.1158/1078-0432.CCR-04-1458
Baraniskin A, Munding J, Schulmann K, Meier D, Porschen R, Arkenau HT, Graeven U, Schmiegel W, Tannapfel A, Reinacher-Schick A (2011) Prognostic value of reduced SMAD4 expression in patients with metastatic colorectal cancer under oxaliplatin-containing chemotherapy: a translational study of the AIO colorectal study group. Clin Colorectal Cancer 10(1):24–29. doi:10.3816/CCC.2011.n.003
Offerhaus GJ, De Feyter EP, Cornelisse CJ, Tersmette KW, Floyd J, Kern SE, Vogelstein B, Hamilton SR (1992) The relationship of DNA aneuploidy to molecular genetic alterations in colorectal carcinoma. Gastroenterology 102(5):1612–1619
Lindor NM, Burgart LJ, Leontovich O, Goldberg RM, Cunningham JM, Sargent DJ, Walsh-Vockley C, Petersen GM, Walsh MD, Leggett BA, Young JP, Barker MA, Jass JR, Hopper J, Gallinger S, Bapat B, Redston M, Thibodeau SN (2002) Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. J Clin Oncol 20(4):1043–1048
Esteller M, Levine R, Baylin SB, Ellenson LH, Herman JG (1998) MLH1 promoter hypermethylation is associated with the microsatellite instability phenotype in sporadic endometrial carcinomas. Oncogene 17(18):2413–2417
Herman JG, Umar A, Polyak K, Graff JR, Ahuja N, Issa JP, Markowitz S, Willson JK, Hamilton SR, Kinzler KW, Kane MF, Kolodner RD, Vogelstein B, Kunkel TA, Baylin SB (1998) Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA 95(12):6870–6875
Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, Meltzer SJ, Rodriguez-Bigas MA, Fodde R, Ranzani GN, Srivastava S (1998) A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 58(22):5248–5257
Jass JR (2001) Microsatellite unstable colorectal cancer. J Clin Pathol 54(7):573–574
Koopman M, Kortman GA, Mekenkamp L, Ligtenberg MJ, Hoogerbrugge N, Antonini NF, Punt CJ, van Krieken JH (2009) Deficient mismatch repair system in patients with sporadic advanced colorectal cancer. Br J Cancer 100(2):266–273. doi:10.1038/sj.bjc.6604867
Tie J, Gibbs P, Lipton L, Christie M, Jorissen RN, Burgess AW, Croxford M, Jones I, Langland R, Kosmider S, McKay D, Bollag G, Nolop K, Sieber OM, Desai J (2011) Optimizing targeted therapeutic development: analysis of a colorectal cancer patient population with the BRAF(V600E) mutation. Int J Cancer 128(9):2075–2084
Gryfe R, Kim H, Hsieh ET, Aronson MD, Holowaty EJ, Bull SB, Redston M, Gallinger S (2000) Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med 342(2):69–77. doi:10.1056/NEJM200001133420201
Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, Hamilton SR, Laurent-Puig P, Gryfe R, Shepherd LE, Tu D, Redston M, Gallinger S (2003) Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 349(3):247–257. doi:10.1056/NEJMoa022289
Sinicrope FA, Rego RL, Halling KC, Foster N, Sargent DJ, La Plant B, French AJ, Laurie JA, Goldberg RM, Thibodeau SN, Witzig TE (2006) Prognostic impact of microsatellite instability and DNA ploidy in human colon carcinoma patients. Gastroenterology 131(3):729–737. doi:10.1053/j.gastro.2006.06.005
Popat S, Hubner R, Houlston RS (2005) Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 23(3):609–618
Tejpar S, Bosman F, Delorenzi M, Fiocca R, Roth RK (2009) Microsatellite instability (MSI) in stage II and III colon cancer treated with 5FU-LV or 5FU-LV and irinotecan (PETACC 3-EORTC 40993-SAKK 60/00 trial). J Clin Oncol 27(suppl):15s; abstr 4001
Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP (1999) CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci USA 96(15):8681–8686
Ahn JB, Chung WB, Maeda O, Shin SJ, Kim HS, Chung HC, Kim NK, Issa JP (2011) DNA methylation predicts recurrence from resected stage III proximal colon cancer. Cancer 117(9):1847–1854. doi:10.1002/cncr.25737
Shen L, Catalano PJ, Benson AB 3rd, O’Dwyer P, Hamilton SR, Issa JP (2007) Association between DNA methylation and shortened survival in patients with advanced colorectal cancer treated with 5-fluorouracil based chemotherapy. Clin Cancer Res 13(20):6093–6098. doi:10.1158/1078-0432.CCR-07-1011
Ward RL, Cheong K, Ku SL, Meagher A, O’Connor T, Hawkins NJ (2003) Adverse prognostic effect of methylation in colorectal cancer is reversed by microsatellite instability. J Clin Oncol 21(20):3729–3736. doi:10.1200/JCO.2003.03.123
Dahlin AM, Palmqvist R, Henriksson ML, Jacobsson M, Eklof V, Rutegard J, Oberg A, Van Guelpen BR (2010) The role of the CpG island methylator phenotype in colorectal cancer prognosis depends on microsatellite instability screening status. Clin Cancer Res 16(6):1845–1855. doi:10.1158/1078-0432.CCR-09-2594
Kim JH, Shin SH, Kwon HJ, Cho NY, Kang GH (2009) Prognostic implications of CpG island hypermethylator phenotype in colorectal cancers. Virchows Arch 455(6):485–494. doi:10.1007/s00428-009-0857-0
Lee S, Cho NY, Choi M, Yoo EJ, Kim JH, Kang GH (2008) Clinicopathological features of CpG island methylator phenotype-positive colorectal cancer and its adverse prognosis in relation to KRAS/BRAF mutation. Pathol Int 58(2):104–113. doi:10.1111/j.1440-1827.2007.02197.x
Delhanty JD, Cooke HM (1989) Increased chromosome breakage by N-methyl-N1-nitro-N-nitrosoguanidine in patients with adenomatous polyposis coli. Cancer Genet Cytogenet 42(2):263–271
Abal M, Obrador-Hevia A, Janssen KP, Casadome L, Menendez M, Carpentier S, Barillot E, Wagner M, Ansorge W, Moeslein G, Fsihi H, Bezrookove V, Reventos J, Louvard D, Capella G, Robine S (2007) APC inactivation associates with abnormal mitosis completion and concomitant BUB1B/MAD2L1 up-regulation. Gastroenterology 132(7):2448–2458. doi:10.1053/j.gastro.2007.03.027
Alberici P, de Pater E, Cardoso J, Bevelander M, Molenaar L, Jonkers J, Fodde R (2007) Aneuploidy arises at early stages of Apc-driven intestinal tumorigenesis and pinpoints conserved chromosomal loci of allelic imbalance between mouse and human. Am J Pathol 170(1):377–387. doi:10.2353/ajpath.2007.060853
Kahlenberg MS, Stoler DL, Basik M, Petrelli NJ, Rodriguez-Bigas M, Anderson GR (1996) p53 tumor suppressor gene status and the degree of genomic instability in sporadic colorectal cancers. J Natl Cancer Inst 88(22):1665–1670
Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JK, Markowitz SD, Kinzler KW, Vogelstein B (1998) Mutations of mitotic checkpoint genes in human cancers. Nature 392(6673):300–303. doi:10.1038/32688
Menssen A, Epanchintsev A, Lodygin D, Rezaei N, Jung P, Verdoodt B, Diebold J, Hermeking H (2007) c-MYC delays prometaphase by direct transactivation of MAD2 and BubR1: identification of mechanisms underlying c-MYC-induced DNA damage and chromosomal instability. Cell Cycle 6(3):339–352
Michor F, Iwasa Y, Rajagopalan H, Lengauer C, Nowak MA (2004) Linear model of colon cancer initiation. Cell Cycle 3(3):358–362
Goel A, Arnold CN, Niedzwiecki D, Chang DK, Ricciardiello L, Carethers JM, Dowell JM, Wasserman L, Compton C, Mayer RJ, Bertagnolli MM, Boland CR (2003) Characterization of sporadic colon cancer by patterns of genomic instability. Cancer Res 63(7):1608–1614
Jones AM, Douglas EJ, Halford SE, Fiegler H, Gorman PA, Roylance RR, Carter NP, Tomlinson IP (2005) Array-CGH analysis of microsatellite-stable, near-diploid bowel cancers and comparison with other types of colorectal carcinoma. Oncogene 24(1):118–129. doi:10.1038/sj.onc.1208194
Walther A, Houlston R, Tomlinson I (2008) Association between chromosomal instability and prognosis in colorectal cancer: a meta-analysis. Gut 57(7):941–950. doi:10.1136/gut.2007.135004
Longley DB, Harkin DP, Johnston PG (2003) 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 3(5):330–338. doi:10.1038/nrc1074
Berger SH, Jenh CH, Johnson LF, Berger FG (1985) Thymidylate synthase overproduction and gene amplification in fluorodeoxyuridine-resistant human cells. Mol Pharmacol 28(5):461–467
Longo GS, Izzo J, Gorlick R, Banerjee D, Jhanwar SC, Bertino JR (2001) Characterization and drug sensitivity of four newly established colon adenocarcinoma cell lines to antifolate inhibitors of thymidylate synthase. Oncol Res 12(8):309–314
Backus HH, Pinedo HM, Wouters D, Padron JM, Molders N, van Der Wilt CL, van Groeningen CJ, Jansen G, Peters GJ (2000) Folate depletion increases sensitivity of solid tumor cell lines to 5-fluorouracil and antifolates. Int J Cancer 87(6):771–778
van Triest B, Pinedo HM, van Hensbergen Y, Smid K, Telleman F, Schoenmakers PS, van der Wilt CL, van Laar JA, Noordhuis P, Jansen G, Peters GJ (1999) Thymidylate synthase level as the main predictive parameter for sensitivity to 5-fluorouracil, but not for folate-based thymidylate synthase inhibitors, in 13 nonselected colon cancer cell lines. Clin Cancer Res 5(3):643–654
Leichman CG (1998) Thymidylate synthase as a predictor of response. Oncology 12(8 Suppl 6):43–47
Shirota Y, Stoehlmacher J, Brabender J, Xiong YP, Uetake H, Danenberg KD, Groshen S, Tsao-Wei DD, Danenberg PV, Lenz HJ (2001) ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy. J Clin Oncol 19(23):4298–4304
Lenz HJ, Hayashi K, Salonga D, Danenberg KD, Danenberg PV, Metzger R, Banerjee D, Bertino JR, Groshen S, Leichman LP, Leichman CG (1998) p53 point mutations and thymidylate synthase messenger RNA levels in disseminated colorectal cancer: an analysis of response and survival. Clin Cancer Res 4(5):1243–1250
Leichman CG, Lenz HJ, Leichman L, Danenberg K, Baranda J, Groshen S, Boswell W, Metzger R, Tan M, Danenberg PV (1997) Quantitation of intratumoral thymidylate synthase expression predicts for disseminated colorectal cancer response and resistance to protracted-infusion fluorouracil and weekly leucovorin. J Clin Oncol 15(10):3223–3229
Aschele C, Debernardis D, Casazza S, Antonelli G, Tunesi G, Baldo C, Lionetto R, Maley F, Sobrero A (1999) Immunohistochemical quantitation of thymidylate synthase expression in colorectal cancer metastases predicts for clinical outcome to fluorouracil-based chemotherapy. J Clin Oncol 17(6):1760–1770
Paradiso A, Simone G, Petroni S, Leone B, Vallejo C, Lacava J, Romero A, Machiavelli M, De Lena M, Allegra CJ, Johnston PG (2000) Thymidilate synthase and p53 primary tumour expression as predictive factors for advanced colorectal cancer patients. Br J Cancer 82(3):560–567. doi:10.1054/bjoc.1999.0964
Bendardaf R, Lamlum H, Elzagheid A, Ristamaki R, Pyrhonen S (2005) Thymidylate synthase expression levels: a prognostic and predictive role in advanced colorectal cancer. Oncol Rep 14(3):657–662
Ciaparrone M, Quirino M, Schinzari G, Zannoni G, Corsi DC, Vecchio FM, Cassano A, La Torre G, Barone C (2006) Predictive role of thymidylate synthase, dihydropyrimidine dehydrogenase and thymidine phosphorylase expression in colorectal cancer patients receiving adjuvant 5-fluorouracil. Oncology 70(5):366–377. doi:10.1159/000098110
Edler D, Glimelius B, Hallstrom M, Jakobsen A, Johnston PG, Magnusson I, Ragnhammar P, Blomgren H (2002) Thymidylate synthase expression in colorectal cancer: a prognostic and predictive marker of benefit from adjuvant fluorouracil-based chemotherapy. J Clin Oncol 20(7):1721–1728
Takenoue T, Nagawa H, Matsuda K, Fujii S, Nita ME, Hatano K, Kitayama J, Tsuruo T, Muto T (2000) Relation between thymidylate synthase expression and survival in colon carcinoma, and determination of appropriate application of 5-fluorouracil by immunohistochemical method. Ann Surg Oncol 7(3):193–198
Kornmann M, Schwabe W, Sander S, Kron M, Strater J, Polat S, Kettner E, Weiser HF, Baumann W, Schramm H, Hausler P, Ott K, Behnke D, Staib L, Beger HG, Link KH (2003) Thymidylate synthase and dihydropyrimidine dehydrogenase mRNA expression levels: predictors for survival in colorectal cancer patients receiving adjuvant 5-fluorouracil. Clin Cancer Res 9(11):4116–4124
Aguiar S Jr, Lopes A, Soares FA, Rossi BM, Ferreira FO, Nakagawa WT, Carvalho AL, Filho WJ (2005) Prognostic and predictive value of the thymidylate synthase expression in patients with non-metastatic colorectal cancer. Eur J Surg Oncol 31(8):863–868. doi:10.1016/j.ejso.2005.03.014
Popat S, Matakidou A, Houlston RS (2004) Thymidylate synthase expression and prognosis in colorectal cancer: a systematic review and meta-analysis. J Clin Oncol 22(3):529–536. doi:10.1200/JCO.2004.05.064
Mandola MV, Stoehlmacher J, Zhang W, Groshen S, Yu MC, Iqbal S, Lenz HJ, Ladner RD (2004) A 6 bp polymorphism in the thymidylate synthase gene causes message instability and is associated with decreased intratumoral TS mRNA levels. Pharmacogenetics 14(5):319–327
Kawakami K, Salonga D, Park JM, Danenberg KD, Uetake H, Brabender J, Omura K, Watanabe G, Danenberg PV (2001) Different lengths of a polymorphic repeat sequence in the thymidylate synthase gene affect translational efficiency but not its gene expression. Clin Cancer Res 7(12):4096–4101
Yu KH, Wang WX, Ding YM, Li H, Wang ZS (2008) Polymorphism of thymidylate synthase gene associated with its protein expression in human colon cancer. World J Gastroenterol 14(4):617–621
Mandola MV, Stoehlmacher J, Muller-Weeks S, Cesarone G, Yu MC, Lenz HJ, Ladner RD (2003) A novel single nucleotide polymorphism within the 5′ tandem repeat polymorphism of the thymidylate synthase gene abolishes USF-1 binding and alters transcriptional activity. Cancer Res 63(11):2898–2904
Iacopetta B, Grieu F, Joseph D, Elsaleh H (2001) A polymorphism in the enhancer region of the thymidylate synthase promoter influences the survival of colorectal cancer patients treated with 5-fluorouracil. Br J Cancer 85(6):827–830. doi:10.1054/bjoc.2001.2007
Park DJ, Stoehlmacher J, Zhang W, Tsao-Wei D, Groshen S, Lenz HJ (2002) Thymidylate synthase gene polymorphism predicts response to capecitabine in advanced colorectal cancer. Int J Colorectal Dis 17(1):46–49
Pullarkat ST, Stoehlmacher J, Ghaderi V, Xiong YP, Ingles SA, Sherrod A, Warren R, Tsao-Wei D, Groshen S, Lenz HJ (2001) Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenomics J 1(1):65–70
Prall F, Ostwald C, Schiffmann L, Barten M (2007) Do thymidylate synthase gene promoter polymorphism and the C/G single nucleotide polymorphism predict effectiveness of adjuvant 5-fluorouracil-based chemotherapy in stage III colonic adenocarcinoma? Oncol Rep 18(1):203–209
Vignoli M, Nobili S, Napoli C, Putignano AL, Morganti M, Papi L, Valanzano R, Cianchi F, Tonelli F, Mazzei T, Mini E, Genuardi M (2011) Thymidylate synthase expression and genotype have no major impact on the clinical outcome of colorectal cancer patients treated with 5-fluorouracil. Pharmacol Res 64(3):242–248. doi:10.1016/j.phrs.2011.04.006
Tsuji T, Hidaka S, Sawai T, Nakagoe T, Yano H, Haseba M, Komatsu H, Shindou H, Fukuoka H, Yoshinaga M, Shibasaki S, Nanashima A, Yamaguchi H, Yasutake T, Tagawa Y (2003) Polymorphism in the thymidylate synthase promoter enhancer region is not an efficacious marker for tumor sensitivity to 5-fluorouracil-based oral adjuvant chemotherapy in colorectal cancer. Clin Cancer Res 9(10 Pt 1):3700–3704
Farina-Sarasqueta A, Gosens MJ, Moerland E, van Lijnschoten I, Lemmens VE, Slooter GD, Rutten HJ, van den Brule AJ (2010) TS gene polymorphisms are not good markers of response to 5-FU therapy in stage III colon cancer patients. Anal Cell Pathol (Amst) 33(1):1–11. doi:10.3233/ACP-CLO-2010-0526
Park CM, Lee WY, Chun HK, Cho YB, Yun HR, Heo JS, Yun SH, Kim HC (2010) Relationship of polymorphism of the tandem repeat sequence in the thymidylate synthase gene and the survival of stage III colorectal cancer patients receiving adjuvant 5-flurouracil-based chemotherapy. J Surg Oncol 101(1):22–27. doi:10.1002/jso.21412
Bracht K, Nicholls AM, Liu Y, Bodmer WF (2010) 5-Fluorouracil response in a large panel of colorectal cancer cell lines is associated with mismatch repair deficiency. Br J Cancer 103(3):340–346. doi:10.1038/sj.bjc.6605780
Sargent DJ, Marsoni S, Monges G, Thibodeau SN, Labianca R, Hamilton SR, French AJ, Kabat B, Foster NR, Torri V, Ribic C, Grothey A, Moore M, Zaniboni A, Seitz JF, Sinicrope F, Gallinger S (2010) Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol 28(20):3219–3226. doi:10.1200/JCO.2009.27.1825
Jover R, Zapater P, Castells A, Llor X, Andreu M, Cubiella J, Balaguer F, Sempere L, Xicola RM, Bujanda L, Rene JM, Clofent J, Bessa X, Morillas JD, Nicolas-Perez D, Pons E, Paya A, Alenda C (2009) The efficacy of adjuvant chemotherapy with 5-fluorouracil in colorectal cancer depends on the mismatch repair status. Eur J Cancer 45(3):365–373. doi:10.1016/j.ejca.2008.07.016
Kim GP, Colangelo LH, Wieand HS, Paik S, Kirsch IR, Wolmark N, Allegra CJ (2007) Prognostic and predictive roles of high-degree microsatellite instability in colon cancer: a National Cancer Institute-National Surgical Adjuvant Breast and Bowel Project Collaborative Study. J Clin Oncol 25(7):767–772. doi:10.1200/JCO.2006.05.8172
Stoehlmacher J, Park DJ, Zhang W, Groshen S, Tsao-Wei DD, Yu MC, Lenz HJ (2002) Association between glutathione S-transferase P1, T1, and M1 genetic polymorphism and survival of patients with metastatic colorectal cancer. J Natl Cancer Inst 94(12):936–942
Stoehlmacher J, Park DJ, Zhang W, Yang D, Groshen S, Zahedy S, Lenz HJ (2004) A multivariate analysis of genomic polymorphisms: prediction of clinical outcome to 5-FU/oxaliplatin combination chemotherapy in refractory colorectal cancer. Br J Cancer 91(2):344–354. doi:10.1038/sj.bjc.6601975
Ruzzo A, Graziano F, Loupakis F, Rulli E, Canestrari E, Santini D, Catalano V, Ficarelli R, Maltese P, Bisonni R, Masi G, Schiavon G, Giordani P, Giustini L, Falcone A, Tonini G, Silva R, Mattioli R, Floriani I, Magnani M (2007) Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFOX-4 chemotherapy. J Clin Oncol 25(10):1247–1254. doi:10.1200/JCO.2006.08.1844
Le Morvan V, Smith D, Laurand A, Brouste V, Bellott R, Soubeyran I, Mathoulin-Pelissier S, Robert J (2007) Determination of ERCC2 Lys751Gln and GSTP1 Ile105Val gene polymorphisms in colorectal cancer patients: relationships with treatment outcome. Pharmacogenomics 8(12):1693–1703. doi:10.2217/14622416.8.12.1693
Funke S, Timofeeva M, Risch A, Hoffmeister M, Stegmaier C, Seiler CM, Brenner H, Chang-Claude J (2010) Genetic polymorphisms in GST genes and survival of colorectal cancer patients treated with chemotherapy. Pharmacogenomics 11(1):33–41. doi:10.2217/pgs.09.132
Kweekel DM, Gelderblom H, Antonini NF, Van der Straaten T, Nortier JW, Punt CJ, Guchelaar HJ (2009) Glutathione-S-transferase pi (GSTP1) codon 105 polymorphism is not associated with oxaliplatin efficacy or toxicity in advanced colorectal cancer patients. Eur J Cancer 45(4):572–578. doi:10.1016/j.ejca.2008.10.015
Lecomte T, Landi B, Beaune P, Laurent-Puig P, Loriot MA (2006) Glutathione S-transferase P1 polymorphism (Ile105Val) predicts cumulative neuropathy in patients receiving oxaliplatin-based chemotherapy. Clin Cancer Res 12(10):3050–3056. doi:10.1158/1078-0432.CCR-05-2076
Farina Sarasqueta A, van Lijnschoten G, Lemmens VE, Rutten HJ, van den Brule AJ (2011) Pharmacogenetics of oxaliplatin as adjuvant treatment in colon carcinoma: are single nucleotide polymorphisms in GSTP1, ERCC1, and ERCC2 good predictive markers? Mol Diagn Ther 15(5):277–283. doi:10.2165/11592080-000000000-00000
Yu JJ, Lee KB, Mu C, Li Q, Abernathy TV, Bostick-Bruton F, Reed E (2000) Comparison of two human ovarian carcinoma cell lines (A2780/CP70 and MCAS) that are equally resistant to platinum, but differ at codon 118 of the ERCC1 gene. Int J Oncol 16(3):555–560
Lunn RM, Helzlsouer KJ, Parshad R, Umbach DM, Harris EL, Sanford KK, Bell DA (2000) XPD polymorphisms: effects on DNA repair proficiency. Carcinogenesis 21(4):551–555
Yin M, Yan J, Martinez-Balibrea E, Graziano F, Lenz HJ, Kim HJ, Robert J, Im SA, Wang WS, Etienne-Grimaldi MC, Wei Q (2011) ERCC1 and ERCC2 polymorphisms predict clinical outcomes of oxaliplatin-based chemotherapies in gastric and colorectal cancer: a systemic review and meta-analysis. Clin Cancer Res 17(6):1632–1640. doi:10.1158/1078-0432.CCR-10-2169
Iyer L, Hall D, Das S, Mortell MA, Ramirez J, Kim S, Di Rienzo A, Ratain MJ (1999) Phenotype-genotype correlation of in vitro SN-38 (active metabolite of irinotecan) and bilirubin glucuronidation in human liver tissue with UGT1A1 promoter polymorphism. Clin Pharmacol Ther 65(5):576–582. doi:10.1016/S0009-9236(99)70078-0
Ando Y, Saka H, Asai G, Sugiura S, Shimokata K, Kamataki T (1998) UGT1A1 genotypes and glucuronidation of SN-38, the active metabolite of irinotecan. Ann Oncol 9(8):845–847
Hoskins JM, Goldberg RM, Qu P, Ibrahim JG, McLeod HL (2007) UGT1A1*28 genotype and irinotecan-induced neutropenia: dose matters. J Natl Cancer Inst 99(17):1290–1295. doi:10.1093/jnci/djm115
Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351(4):337–345. doi:10.1056/NEJMoa033025
Jonker DJ, O’Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, Berry SR, Krahn M, Price T, Simes RJ, Tebbutt NC, van Hazel G, Wierzbicki R, Langer C, Moore MJ (2007) Cetuximab for the treatment of colorectal cancer. N Engl J Med 357(20):2040–2048. doi:10.1056/NEJMoa071834
Saltz LB, Meropol NJ, Loehrer PJ Sr, Needle MN, Kopit J, Mayer RJ (2004) Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 22(7):1201–1208. doi:10.1200/JCO.2004.10.182
Chung TD, Broaddus WC (2005) Molecular targeting in radiotherapy: epidermal growth factor receptor. Mol Interv 5(1):15–19. doi:10.1124/mi.5.1.5
Meropol NJ (2005) Epidermal growth factor receptor inhibitors in colorectal cancer: it’s time to get back on target. J Clin Oncol 23(9):1791–1793. doi:10.1200/JCO.2005.10.951
Barber TD, Vogelstein B, Kinzler KW, Velculescu VE (2004) Somatic mutations of EGFR in colorectal cancers and glioblastomas. N Engl J Med 351(27):2883. doi:10.1056/NEJM200412303512724
Tsuchihashi Z, Khambata-Ford S, Hanna N, Janne PA (2005) Responsiveness to cetuximab without mutations in EGFR. N Engl J Med 353(2):208–209. doi:10.1056/NEJM200507143530218
Moroni M, Veronese S, Benvenuti S, Marrapese G, Sartore-Bianchi A, Di Nicolantonio F, Gambacorta M, Siena S, Bardelli A (2005) Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol 6(5):279–286. doi:10.1016/S1470-2045(05)70102-9
Laurent-Puig P, Cayre A, Manceau G, Buc E, Bachet JB, Lecomte T, Rougier P, Lievre A, Landi B, Boige V, Ducreux M, Ychou M, Bibeau F, Bouche O, Reid J, Stone S, Penault-Llorca F (2009) Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol 27(35):5924–5930. doi:10.1200/JCO.2008.21.6796
Cappuzzo F, Varella-Garcia M, Finocchiaro G, Skokan M, Gajapathy S, Carnaghi C, Rimassa L, Rossi E, Ligorio C, Di Tommaso L, Holmes AJ, Toschi L, Tallini G, Destro A, Roncalli M, Santoro A, Janne PA (2008) Primary resistance to cetuximab therapy in EGFR FISH-positive colorectal cancer patients. Br J Cancer 99(1):83–89. doi:10.1038/sj.bjc.6604439
Personeni N, Fieuws S, Piessevaux H, De Hertogh G, De Schutter J, Biesmans B, De Roock W, Capoen A, Debiec-Rychter M, Van Laethem JL, Peeters M, Humblet Y, Van Cutsem E, Tejpar S (2008) Clinical usefulness of EGFR gene copy number as a predictive marker in colorectal cancer patients treated with cetuximab: a fluorescent in situ hybridization study. Clin Cancer Res 14(18):5869–5876. doi:10.1158/1078-0432.CCR-08-0449
Sartore-Bianchi A, Moroni M, Veronese S, Carnaghi C, Bajetta E, Luppi G, Sobrero A, Barone C, Cascinu S, Colucci G, Cortesi E, Nichelatti M, Gambacorta M, Siena S (2007) Epidermal growth factor receptor gene copy number and clinical outcome of metastatic colorectal cancer treated with panitumumab. J Clin Oncol 25(22):3238–3245. doi:10.1200/JCO.2007.11.5956
Khambata-Ford S, Garrett CR, Meropol NJ, Basik M, Harbison CT, Wu S, Wong TW, Huang X, Takimoto CH, Godwin AK, Tan BR, Krishnamurthi SS, Burris HA 3rd, Poplin EA, Hidalgo M, Baselga J, Clark EA, Mauro DJ (2007) Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol 25(22):3230–3237. doi:10.1200/JCO.2006.10.5437
Baker JB, Dutta D, Watson D, Maddala T, Munneke BM, Shak S, Rowinsky EK, Xu LA, Harbison CT, Clark EA, Mauro DJ, Khambata-Ford S (2011) Tumour gene expression predicts response to cetuximab in patients with KRAS wild-type metastatic colorectal cancer. Br J Cancer 104(3):488–495. doi:10.1038/sj.bjc.6606054
Jacobs B, De Roock W, Piessevaux H, Van Oirbeek R, Biesmans B, De Schutter J, Fieuws S, Vandesompele J, Peeters M, Van Laethem JL, Humblet Y, Penault-Llorca F, De Hertogh G, Laurent-Puig P, Van Cutsem E, Tejpar S (2009) Amphiregulin and epiregulin mRNA expression in primary tumors predicts outcome in metastatic colorectal cancer treated with cetuximab. J Clin Oncol 27(30):5068–5074. doi:10.1200/JCO.2008.21.3744
Lievre A, Bachet JB, Boige V, Cayre A, Le Corre D, Buc E, Ychou M, Bouche O, Landi B, Louvet C, Andre T, Bibeau F, Diebold MD, Rougier P, Ducreux M, Tomasic G, Emile JF, Penault-Llorca F, Laurent-Puig P (2008) KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 26(3):374–379. doi:10.1200/JCO.2007.12.5906
De Roock W, Piessevaux H, De Schutter J, Janssens M, De Hertogh G, Personeni N, Biesmans B, Van Laethem JL, Peeters M, Humblet Y, Van Cutsem E, Tejpar S (2008) KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol 19(3):508–515. doi:10.1093/annonc/mdm496
Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D’Haens G, Pinter T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P (2009) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360(14):1408–1417. doi:10.1056/NEJMoa0805019
Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P (2009) Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 27(5):663–671. doi:10.1200/JCO.2008.20.8397
Lievre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, Cote JF, Tomasic G, Penna C, Ducreux M, Rougier P, Penault-Llorca F, Laurent-Puig P (2006) KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66(8):3992–3995
Loupakis F, Ruzzo A, Cremolini C, Vincenzi B, Salvatore L, Santini D, Masi G, Stasi I, Canestrari E, Rulli E, Floriani I, Bencardino K, Galluccio N, Catalano V, Tonini G, Magnani M, Fontanini G, Basolo F, Falcone A, Graziano F (2009) KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer. Br J Cancer 101(4):715–721. doi:10.1038/sj.bjc.6605177
De Roock W, Jonker DJ, Di Nicolantonio F, Sartore-Bianchi A, Tu D, Siena S, Lamba S, Arena S, Frattini M, Piessevaux H, Van Cutsem E, O’Callaghan CJ, Khambata-Ford S, Zalcberg JR, Simes J, Karapetis CS, Bardelli A, Tejpar S (2010) Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA 304(16):1812–1820. doi:10.1001/jama.2010.1535
Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJ, Schrama JG, Erdkamp FL, Vos AH, van Groeningen CJ, Sinnige HA, Richel DJ, Voest EE, Dijkstra JR, Vink-Borger ME, Antonini NF, Mol L, van Krieken JH, Dalesio O, Punt CJ (2009) Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med 360(6):563–572. doi:10.1056/NEJMoa0808268
Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocakova I, Ruff P, Blasinska-Morawiec M, Smakal M, Canon JL, Rother M, Oliner KS, Wolf M, Gansert J (2010) Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 28(31):4697–4705. doi:10.1200/JCO.2009.27.4860
De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G, Kalogeras KT, Kotoula V, Papamichael D, Laurent-Puig P, Penault-Llorca F, Rougier P, Vincenzi B, Santini D, Tonini G, Cappuzzo F, Frattini M, Molinari F, Saletti P, De Dosso S, Martini M, Bardelli A, Siena S, Sartore-Bianchi A, Tabernero J, Macarulla T, Di Fiore F, Gangloff AO, Ciardiello F, Pfeiffer P, Qvortrup C, Hansen TP, Van Cutsem E, Piessevaux H, Lambrechts D, Delorenzi M, Tejpar S (2010) Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol 11(8):753–762. doi:10.1016/S1470-2045(10)70130-3
Tol J, Dijkstra JR, Klomp M, Teerenstra S, Dommerholt M, Vink-Borger ME, van Cleef PH, van Krieken JH, Punt CJ, Nagtegaal ID (2010) Markers for EGFR pathway activation as predictor of outcome in metastatic colorectal cancer patients treated with or without cetuximab. Eur J Cancer 46(11):1997–2009. doi:10.1016/j.ejca.2010.03.036
Sartore-Bianchi A, Martini M, Molinari F, Veronese S, Nichelatti M, Artale S, Di Nicolantonio F, Saletti P, De Dosso S, Mazzucchelli L, Frattini M, Siena S, Bardelli A (2009) PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res 69(5):1851–1857
Prenen H, De Schutter J, Jacobs B, De Roock W, Biesmans B, Claes B, Lambrechts D, Van Cutsem E, Tejpar S (2009) PIK3CA mutations are not a major determinant of resistance to the epidermal growth factor receptor inhibitor cetuximab in metastatic colorectal cancer. Clin Cancer Res 15(9):3184–3188. doi:10.1158/1078-0432.CCR-08-2961
Goede V, Coutelle O, Neuneier J, Reinacher-Schick A, Schnell R, Koslowsky TC, Weihrauch MR, Cremer B, Kashkar H, Odenthal M, Augustin HG, Schmiegel W, Hallek M, Hacker UT (2010) Identification of serum angiopoietin-2 as a biomarker for clinical outcome of colorectal cancer patients treated with bevacizumab-containing therapy. Br J Cancer 103(9):1407–1414. doi:10.1038/sj.bjc.6605925
Hansen TF, Christensen RD, Andersen RF, Spindler KL, Johnsson A, Jakobsen A (2011) The predictive value of single nucleotide polymorphisms in the VEGF system to the efficacy of first-line treatment with bevacizumab plus chemotherapy in patients with metastatic colorectal cancer: results from the Nordic ACT trial. Int J Colorectal Dis. doi:10.1007/s00384-011-1382-6
Koutras AK, Antonacopoulou AG, Eleftheraki AG, Dimitrakopoulos FI, Koumarianou A, Varthalitis I, Fostira F, Sgouros J, Briasoulis E, Bournakis E, Bafaloukos D, Bompolaki I, Galani E, Kalogeras KT, Pectasides D, Fountzilas G, Kalofonos HP (2011) Vascular endothelial growth factor polymorphisms and clinical outcome in colorectal cancer patients treated with irinotecan-based chemotherapy and bevacizumab. Pharmacogenomics J. doi:10.1038/tpj.2011.37
Willett CG, Duda DG, di Tomaso E, Boucher Y, Ancukiewicz M, Sahani DV, Lahdenranta J, Chung DC, Fischman AJ, Lauwers GY, Shellito P, Czito BG, Wong TZ, Paulson E, Poleski M, Vujaskovic Z, Bentley R, Chen HX, Clark JW, Jain RK (2009) Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study. J Clin Oncol 27(18):3020–3026. doi:10.1200/JCO.2008.21.1771
Kopetz S, Hoff PM, Morris JS, Wolff RA, Eng C, Glover KY, Adinin R, Overman MJ, Valero V, Wen S, Lieu C, Yan S, Tran HT, Ellis LM, Abbruzzese JL, Heymach JV (2010) Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol 28(3):453–459. doi:10.1200/JCO.2009.24.8252
Jubb AM, Hurwitz HI, Bai W, Holmgren EB, Tobin P, Guerrero AS, Kabbinavar F, Holden SN, Novotny WF, Frantz GD, Hillan KJ, Koeppen H (2006) Impact of vascular endothelial growth factor-A expression, thrombospondin-2 expression, and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer. J Clin Oncol 24(2):217–227. doi:10.1200/JCO.2005.01.5388
Wang Y, Jatkoe T, Zhang Y, Mutch MG, Talantov D, Jiang J, McLeod HL, Atkins D (2004) Gene expression profiles and molecular markers to predict recurrence of Dukes’ B colon cancer. J Clin Oncol 22(9):1564–1571. doi:10.1200/JCO.2004.08.186
Barrier A, Boelle PY, Roser F, Gregg J, Tse C, Brault D, Lacaine F, Houry S, Huguier M, Franc B, Flahault A, Lemoine A, Dudoit S (2006) Stage II colon cancer prognosis prediction by tumor gene expression profiling. J Clin Oncol 24(29):4685–4691. doi:10.1200/JCO.2005.05.0229
Arango D, Laiho P, Kokko A, Alhopuro P, Sammalkorpi H, Salovaara R, Nicorici D, Hautaniemi S, Alazzouzi H, Mecklin JP, Jarvinen H, Hemminki A, Astola J, Schwartz S Jr, Aaltonen LA (2005) Gene-expression profiling predicts recurrence in Dukes’ C colorectal cancer. Gastroenterology 129(3):874–884
Eschrich S, Yang I, Bloom G, Kwong KY, Boulware D, Cantor A, Coppola D, Kruhoffer M, Aaltonen L, Orntoft TF, Quackenbush J, Yeatman TJ (2005) Molecular staging for survival prediction of colorectal cancer patients. J Clin Oncol 23(15):3526–3535
Lin YH, Friederichs J, Black MA, Mages J, Rosenberg R, Guilford PJ, Phillips V, Thompson-Fawcett M, Kasabov N, Toro T, Merrie AE, van Rij A, Yoon HS, McCall JL, Siewert JR, Holzmann B, Reeve AE (2007) Multiple gene expression classifiers from different array platforms predict poor prognosis of colorectal cancer. Clin Cancer Res 13(2 Pt 1):498–507
Garman KS, Acharya CR, Edelman E, Grade M, Gaedcke J, Sud S, Barry W, Diehl AM, Provenzale D, Ginsburg GS, Ghadimi BM, Ried T, Nevins JR, Mukherjee S, Hsu D, Potti A (2008) A genomic approach to colon cancer risk stratification yields biologic insights into therapeutic opportunities. Proc Natl Acad Sci USA 105(49):19432–19437. doi:10.1073/pnas.0806674105
Jiang Y, Casey G, Lavery IC, Zhang Y, Talantov D, Martin-McGreevy M, Skacel M, Manilich E, Mazumder A, Atkins D, Delaney CP, Wang Y (2008) Development of a clinically feasible molecular assay to predict recurrence of stage II colon cancer. J Mol Diagn 10(4):346–354. doi:10.2353/jmoldx.2008.080011
Koehler A, Bataille F, Schmid C, Ruemmele P, Waldeck A, Blaszyk H, Hartmann A, Hofstaedter F, Dietmaier W (2004) Gene expression profiling of colorectal cancer and metastases divides tumours according to their clinicopathological stage. J Pathol 204(1):65–74. doi:10.1002/path.1606
Lu AT, Salpeter SR, Reeve AE, Eschrich S, Johnston PG, Barrier AJ, Bertucci F, Buckley NS, Salpeter EE, Lin AY (2009) Gene expression profiles as predictors of poor outcomes in stage II colorectal cancer: a systematic review and meta-analysis. Clin Colorectal Cancer 8(4):207–214. doi:10.3816/CCC.2009.n.035
Kerr D, Gray R, Quirke P, Watson D, Yothers G, Lavery IC, Lee M, O’Connell MJ, Shak S, Wolmark N (2009) A quantitative multigene RT-PCR assay for prediction of recurrence in stage II colon cancer: selection of the genes in four large studies and results of the independent, prospectively designed QUASAR validation study. JCO 27(suppl):15s; abstr 4000
Gray RG, Quirke P, Handley K, Lopatin M, Magill L, Baehner FL, Beaumont C, Clark-Langone KM, Yoshizawa CN, Lee M, Watson D, Shak S, Kerr DJ (2011) Validation study of a quantitative multigene reverse transcriptase-polymerase chain reaction assay for assessment of recurrence risk in patients with stage II colon cancer. J Clin Oncol 29(35):4611–4619. doi:10.1200/JCO.2010.32.8732
Salazar R, Roepman P, Capella G, Moreno V, Simon I, Dreezen C, Lopez-Doriga A, Santos C, Marijnen C, Westerga J, Bruin S, Kerr D, Kuppen P, van de Velde C, Morreau H, Van Velthuysen L, Glas AM, Van’t Veer LJ, Tollenaar R (2011) Gene expression signature to improve prognosis prediction of stage II and III colorectal cancer. J Clin Oncol 29(1):17–24. doi:10.1200/JCO.2010.30.1077
Salazar RR, Lutke Holzik M, Marshall J, Van Der Hoeven JJ, Glimelius B, Bibeau F, Stork-Sloots L, Bender RA, Tabernero J (2011) The PARSC trial: a prospective study for the assessment of recurrence risk in stage II colon cancer (CC) patients using ColoPrint. J Clin Oncol 29(suppl 4); abstr 602
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Lipton, L., Christie, M., Sieber, O. (2013). Predictive and Prognostic Biomarkers for Colorectal Cancer. In: Pfeffer, U. (eds) Cancer Genomics. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5842-1_5
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