IntechOpen

Home > Books > Advances in the Molecular Understanding of Colorectal Cancer

Open access peer-reviewed chapter

Predictive Biomarkers for Monoclonal Antibody Therapies Targeting EGFR (Cetuximab, Panitumumab) in the Treatment of Metastatic Colorectal Cancer

Written By

Anuratha Sakthianandeswaren, Polly Sabljak, Meg J. Elliott, Michelle Palmieri and Oliver M. Sieber

Submitted: 27 July 2018 Reviewed: 03 August 2018 Published: 05 November 2018

DOI: 10.5772/intechopen.80690

Advances in the Molecular Understanding of Colorectal Cancer IntechOpen
Advances in the Molecular Understanding of Colorectal Cancer Edited by Eva Segelov

From the Edited Volume

Advances in the Molecular Understanding of Colorectal Cancer

Edited by Eva Segelov

Book Details Order Print

Chapter metrics overview

1,464 Chapter Downloads

View Full Metrics
Advertisement

Abstract

The treatment for patients with metastatic colorectal cancer has progressively improved over the past few decades with the development of more effective anti-cancer drugs and multi-disciplinary management approaches that combine sequential lines of non-cross-resistant drugs and increased use of potentially curative surgery for metastases of the liver and lung. In this setting, the introduction of monoclonal antibody therapies that target the epidermal growth factor receptor (EGFR) (cetuximab and panitumumab) has made an important contribution to improved patient outcomes. However, the efficacy of therapies is generally limited to a small proportion of patients and associated with toxicity and high cost. There is an urgent clinical need for robust predictive biomarkers to guide the effective use of therapy options. In this chapter we review clinical and molecular predictive markers of primary therapy response for metastatic colorectal cancer, focusing on anti-EGFR antibody therapies, discussing both currently approved and emerging biomarkers.

Keywords

  • metastatic colorectal cancer
  • epidermal growth factor receptor (EGFR)
  • cetuximab
  • panitumumab
  • predictive biomarkers

1. Introduction

Metastatic colorectal cancer (mCRC) remains a major contributor to cancer-related morbidity and mortality worldwide. Among patients diagnosed with colorectal cancer, approximately 20–25% present with distant metastases, while another 20–35% develop metastases following curative-intent treatment for early-stage cancer [1]. The median overall survival for mCRC has improved significantly over the past few decades, increasing from 10 to 12 months for 5-fluorouracil plus leucovorin to currently beyond 30 months [2]. Improvements have been driven by advancements in surgery for metastatic disease, the expansion of chemotherapy options and the introduction of targeted therapies such as monoclonal antibodies against the epidermal growth factor receptor (EGFR) or the vascular endothelial growth factor A (VEGFA) [2]. Presently, there are 11 therapeutics approved by the United States Food and Drug Administration (FDA) for the treatment of mCRC, including 5-fluorouracil, irinotecan, capecitabine, oxaliplatin, bevacizumab, cetuximab, panitumumab, ziv-aflibercept, regorafenib, ramucirumab, and trifluridine-tipiracil. The expansion of treatment options has resulted in an increased clinical need for predictive biomarkers to guide the effective use of therapy. Only a small proportion of patients will respond to any given therapy, and treatments are associated with significant toxicities and often with high financial costs.

Predictive biomarkers for anti-cancer agents are best developed prospectively as companion diagnostics during the drug development process. However, these can also be developed retrospectively through analysis of samples and data from previously conducted randomized clinical trials. Another avenue for marker discovery are longitudinal studies of patients analyzing the emergence of drug resistant tumor clones, although mechanisms of intrinsic (primary) and acquired (secondary) drug resistance may differ. Predictive markers can provide either drug sensitivity (positive prediction of response) or resistance (negative prediction of response) information depending on the biomarker-drug relationship.

There are many challenges in the biomarker development process, such as the choice of analyte (e.g. urine, blood, tissue), cancer sampling procedures (e.g. circulating tumor cells, primary cancer, metastatic lesions), technology for marker evaluation (e.g. DNA, RNA or protein) and determination of clinically relevant cut-offs. In this chapter, we review development efforts for predictive biomarkers for patients with mCRC focusing on anti-EGFR antibody therapies. Our discussion will concentrate on markers of primary drug resistance; markers of acquired drug resistance have been summarized in recent reviews [3, 4].

Advertisement

2. Anti-EGFR therapy

EGFR is a tyrosine kinase transmembrane receptor that belongs to the ErbB protein family. EGFR-mediated signaling has important roles in cell proliferation, survival and differentiation, and dysregulation is a central driver in multiple malignancies including colorectal cancer [4, 5, 6]. EGFR interacts with multiple ligands including epidermal growth factor (EGF), transforming growth factor alpha (TGF-α), amphiregulin (AREG), epiregulin (EPR), betacellulin (BTC), heparin-binding EGF (HB-EGF), epigen (EPN), and neuregulin 1-4 (NRG1-4). Activation of EGFR following ligand binding triggers a variety of signaling cascades, including the RAS/MAPK, PI3K/AKT, PLCγ/PKC, SRC tyrosine kinase and STAT pathways. In addition, ligand binding can induce EGFR translocation to the nucleus where EGFR behaves as a co-transcriptional activator regulating key genes such as Aurora Kinase A (AURKA), Cyclin D1 (CCND1), Prostaglandin-Endoperoxide Synthase 2 (PTGS2) and MYB Proto-Oncogene Like 2 (MYBL2).

EGFR is overexpressed in colorectal tumors, with most estimates between 40% and 80% depending on the methods and cut-offs used, highlighting the receptor as a prime drug target in this malignancy [7, 8]. Two monoclonal antibodies targeting EGFR have been clinically approved for the treatment of mCRC including cetuximab (Erbitux®), a chimeric mouse-human IgG1 antibody, and panitumumab (Vectibix®), a humanized IgG2 antibody. Both antibodies bind the extracellular domain of EGFR, inhibiting ligand-induced tyrosine kinase activation and leading to EGFR cellular internalization and degradation, thereby preventing the activation of downstream signaling (Figure 1). Panitumumab has a higher binding affinity for EGFR than cetuximab [9], and cetuximab is thought to additionally lead to activation of the immune response through antibody-dependent cell-mediated cytotoxicity (ADCC) due to the IgG1 chimeric antibody structure [10, 11]. With respect to toxicity, panitumumab treatment is associated with significantly lower occurrence of grade 3–4 infusion reactions (allergic reactions) than cetuximab due to its fully humanized nature [12]. Despite these differences, cetuximab and panitumumab showed clinical equivalence in efficacy in refractory patients [12], and both are approved for use in combination with chemotherapy in the first and second line setting or as monotherapy for refractory disease.

Figure 1.

Targeting of the EGFR signaling pathway with anti-EGFR monoclonal antibodies. EGFR activation is triggered by ligand binding which results in the formation of receptor homo- or hetero-dimers. Receptor autophosphorylation at tyrosine residues within the cytoplasmic tail acts as a docking site for proteins with Src homology2 (SH2) and phosphotyrosine-binding domains (PTB), initiating cellular signaling via the RAS/MAPK, PI3K/AKT, STAT and PLCγ/PKC pathways. Ligand binding can further stimulate EGFR translocation into the nucleus, with nuclear EGFR interacting with transcription factors to drive expression of target genes including NOS2, PTGS2, AURKA, MYBL2 and CCND1. EGFR signaling in tumor cells promotes cell proliferation and survival, and this can be blocked with antibodies against the receptor (cetuximab and panitumumab).

In unselected patient populations, the response rate to anti-EGFR therapy is typically less than 30% [13], and for patients who initially respond to treatment most tumors become refractory within 3–12 months [14]. The need to identify biomarkers predictive of EGFR response is therefore vital, and numerous studies have explored resistance mechanisms to EGFR blockade. Findings have unraveled a variety of biomarkers and pathways that are associated with resistance to anti-EGFR therapy. As discussed below, this work has led to the endorsement of predictive testing for tumor RAS (KRAS and NRAS) mutation status and consideration of primary tumor location to guide the use of anti-EGFR therapy. Efforts to discover and validate additional biomarkers is ongoing to further refine treatment delivery are ongoing.

2.1 Current predictive biomarkers for anti-EGFR therapy

2.1.1 KRAS and NRAS mutations

Genes of the RAS type GTPase family, comprising KRAS, NRAS and HRAS, are principal downstream mediators of activated EGFR signaling [15]. In colorectal cancer, KRAS and NRAS are major oncogenes, with activating mutations found in approximately 40% and 3–5% of cases, respectively [16]. Constitutive downstream signaling through oncogenic RAS proteins activates processes contributing to tumor progression and metastasis, independent of EGFR and other cell surface receptor kinases [15]. As anticipated from the biological mechanism, mutations in KRAS and NRAS genes have been found to render tumors insensitive to anti-EGFR therapy.

The majority of KRAS mutations (85–90%) in colorectal cancer occur in exon 2 at codons 12 and 13 [16]. Analyses of clinical trials of cetuximab or panitumumab over the last decade have provided conclusive evidence that patients with KRAS mutations in exon 2 do not benefit from anti-EGFR therapy when given as a single agent or combined with chemotherapy (Table 1) [17, 18, 19, 20, 21, 22, 23, 24]. Retrospective analyses of the randomized phase III CO.17 and 20020408 studies which evaluated cetuximab or panitumumab plus best supportive care (BSC) vs BSC alone in patients with chemotherapy-refractory mCRC, respectively, found a significant improvement in outcomes for patients with wild-type KRAS exon 2 tumors, but no benefit of anti-EGFR therapy in patients who had mutant KRAS exon 2 tumors [19, 22]. Similar results for the first-line setting were subsequently reported for both retrospective and prospective analyses of several randomized clinical trials, including the phase II OPUS and phase III PRIME studies which examined cetuximab or panitumumab plus oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) vs FOLFOX4 alone, respectively [23, 25], and the phase III CRYSTAL study which assessed the addition of cetuximab to irinotecan, infusional fluorouracil, and leucovorin (FOLFIRI) [18]. Prospective analysis of the randomized phase III 20050181 study which evaluated panitumumab plus FOLFIRI in the second-line setting further confirmed the predictive value of KRAS exon 2 mutation status [24].

StudyTreatment armsNumber of patientsPFS (months)HR PFS95% CIp-Value
RAS wild-type
CRYSTALFOLFIRI + C17811.40.560.41–0.76p < 0.001
FOLFIRI1898.4
FIRE-3FOLFIRI + C19910.30.970.88–1.990.77
FOLFIRI +B20110.2
OPUSFOLFOX + C38120.530.27–1.040.0615
FOLFOX495.8
PEAKFOLFOX + P50130.650.44–0.960.029
FOLFOX + B609.5
PRIMEFOLFOX + P25910.10.720.58–0.900.004
FOLFOX2537.9
20050181FOLFIRI + P2086.40.70.54–0.900.007
FOLFIRI2134.6
20020408P + BCS10712.3 wks0.450.34–0.59p < 0.001
BSC1107.3 wks
CO.17C + BSC1173.70.40.3–0.54p < 0.001
BSC1131.9
RAS mutant
CRYSTALFOLFIRI + C2467.41.10.85–1.420.47
FOLFIRI2147.5
FIRE-3FOLFIRI + Cn.an.an.an.an.a
FOLFIRI +Bn.an.a
OPUSFOLFOX + C925.61.541.04–2.290.0309
FOLFOX757.8
PEAKFOLFOX + Pn.an.an.an.an.a
FOLFOX + Bn.an.a
PRIMEFOLFOX + P2727.31.31.07–1.60p < 0.001
FOLFOX2768.7
20050181FOLFIRI + P2994.80.860.71–1.050.14
FOLFIRI2944
20020408P + BCS767.4 wks0.990.73–1.36n.r.
BSC957.3 wks
CO.17C + BSC811.80.990.73–1.350.96
BSC831.8

Table 1.

Summary of clinical trials and treatment effects within subgroups defined by RAS status in patients with metastatic colorectal cancer.

Abbreviations: PFS, progression-free survival; HR, hazard ratio; CI, confidence interval; FOL, folinic acid; F, fluorouracil; IRI, irinotecan; OX, oxaliplatin; B, bevacizumab; C, cetuximab; P, panitumumab; n.r., not reported; BSC, best supportive care.

There is evidence that KRAS codon 12 and 13 mutations may exhibit differential biological effects, including variable ratios of these codon mutations between tumor types [16] and weaker in vitro transforming activity for KRAS codon 13 as compared to codon 12 mutant proteins [26]. Accordingly, some studies have suggested that patients with KRAS glycine (G)-to-aspartate (D) transitions at codon 13 (G13D), the most common codon 13 variant in colorectal cancer, might derive some benefit from anti-EGFR therapy [27, 28]. A retrospective consortium analysis assessing patients with chemotherapy-refractory mCRC treated with cetuximab who participated in multiple clinical trials (CO.17, BOND, MABEL, EMR202600, EVEREST, BABEL and SALVAGE) or who received off-study treatment reported longer overall and progression-free survival among individuals with KRAS G13D-mutated tumors than with other KRAS-mutated tumors [27]. An analysis of the updated pooled data sets from the CRYSTAL and OPUS studies also reported that addition of cetuximab to first-line chemotherapy appeared to benefit patients with KRAS G13D-mutant tumors [28]. In contrast, a retrospective analysis of 110 patients treated with cetuximab, found that patients with KRAS G13D mutations were unlikely to respond to therapy [29], and similar findings were reported for a retrospective pooled analysis of three randomized phase III trials evaluating panitumumab therapy (20050203, first line; 20050181, second line; and 20020408, monotherapy) [30]. To resolve this controversy, the randomized phase II ICECREAM study prospectively assessed cetuximab monotherapy and cetuximab plus irinotecan in patients with KRAS G13D-mutated chemotherapy-refractory mCRC. In this study, no statistically significant improvement in disease control was observed for patients with this rare molecular subtype [31].

More recently, several retrospective analyses have indicated that not only KRAS exon 2 mutations but also KRAS exons 3 and 4 and NRAS exons 2, 3, and 4 mutations are negative predictive markers for anti-EGFR therapy [23, 32, 33, 34, 35, 36]. These additional mutations are observed in approximately 15–20% of wild-type KRAS exon 2 tumors [23, 32]. Reassessment of the randomized OPUS and PRIME studies of cetuximab or panitumumab plus FOLFOX4 vs FOLFOX4 alone in the first-line setting found that additional RAS mutations predicted a lack of response [23, 34], and corresponding observations were reported for the CRYSTAL study of cetuximab plus FOLFIRI [32]. Accordingly, analyses of single arms of the phase III FIRE-3 study evaluating cetuximab plus FOLFIRI and the phase II PEAK study evaluating panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) in the first-line setting reported a more pronounced survival advantage for the wild-type RAS population as compared to the wild-type KRAS exon 2 population [36, 37]. Retrospective analysis of the randomized 20050181 study of panitumumab plus FOLFIRI in the second-line setting further found no benefit of panitumumab addition in patients with RAS mutations beyond KRAS exon 2 [35]. Low response rates for additional RAS mutations were also reported by a European consortium analyzing tumor samples from a large cohort of patients with chemotherapy-refractory mCRC treated with cetuximab and chemotherapy [38].

A systematic review and meta-analysis of nine randomized controlled trials for anti-EGFR therapy comprising a total of 5948 participants evaluated for RAS mutations has confirmed tumors without any RAS mutations to have significantly superior progression-free (PFS) and overall survival (OS) as compared to tumors with RAS mutations. No difference in PFS or OS benefit was evident between tumors with KRAS exon 2 mutations and tumors with other RAS mutations [33]. Treatment guidelines for mCRC now recommend RAS testing prior to start of anti-EGFR antibody therapy to exclude patients with mutated RAS [2, 21]. However, RAS mutations only account for approximately 35–50% of nonresponsive patients, and the search for additional biomarkers that predict resistance continues to be an active area of research as surveyed below.

2.1.2 Primary tumor location

Colorectal cancers can be broadly grouped by their primary tumor location within the colon [39]. The left-sided colon, comprising the distal third of the transverse colon, splenic flexure, descending colon, sigmoid colon and rectum, are derived from the embryonic hindgut. The right-sided colon, comprising the proximal two-thirds of the transverse colon, ascending colon and caecum, is derived from the embryonic midgut. Baseline differences exist along the colorectal tract such as cell composition and function of the epithelium, the microbiome and gene expression. Strong evidence for the prognostic effect of primary tumor location is available from clinical studies in patients with mCRC, with right-sided tumors exhibiting a worse prognosis [40, 41]. Right- and left-sided cancers differ in their clinical and molecular characteristics: right-sided colon cancers are more likely to be diploid and have high-grade or mucinous histology, DNA mismatch-repair deficiency and microsatellite instability, CpG island methylation, BRAF, TGFBR2 and PIK3CA mutations [41, 42], while left-sided cancers often show chromosome instability, APC, KRAS, SMAD4 and TP53 mutations [43]. Right-sided tumors have also been associated with more frequent overexpression of the EGFR ligands, EREG and AREG, and amplification of EGFR and human epidermal growth factor receptor 2 (HER2) [44, 45]. In cohort studies, the classification of tumor sidedness is variable, with right-sided tumors commonly defined as comprising the region from the ceacum to the splenic flexure.

Clinically, primary tumor location was not considered of particular interest in metastatic patients treated with anti-EGFR therapy, until the importance of sidedness as a biomarker was recognized. Retrospective surveys of clinical trials have indicated that while anti-EGFR therapy provides clinical benefit to patients with RAS wild-type mCRC, this benefit is specific to patients with left-sided tumors (Table 2). In the CRYSTAL and FIRE-3 studies of cetuximab in the first-line setting, patients with RAS wild-type left-sided tumors had better outcomes compared to the respective comparators (FOLFIRI alone and FOLFIRI plus bevacizumab), while limited efficacy was observed in patients with RAS wild-type right-sided tumors [46]. Benefit from cetuximab treatment specific to patients with KRAS wild-type left-sided tumors was further observed for the randomized phase III CALGB/SWOG 80405 study of cetuximab or bevacizumab with either irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) [47]. Similar results for patients with RAS wild-type left-sided as compared to right-sided tumors were reported for panitumumab for analyses of the PRIME (comparator: FOLFOX alone) and PEAK studies (comparator: FOLFOX plus bevacizumab) [48]. A meta-analysis integrating these data for the first-line setting is available [49]. For the second-line setting, a retrospective analysis of FIRE-3 study also found evidence of better outcomes for cetuximab treatment in patients with KRAS wild-type left-sided tumors as compared to right-sided tumors (comparator: bevacizumab) [50]. Similar results for panitumumab were reported in a preliminary efficacy analysis of the 20050181 study for RAS/BRAF wild-type patients (comparator FOLFIRI) [51]. A retrospective analysis of the CO.17 study in the treatment-refractory setting further observed that only individuals with KRAS wild-type left-sided tumors appeared to benefit from cetuximab as compared to BSC [52].

StudyTreatment armsNumber of patientsPFS (months)HR PFS95% CIp-Value
Left-sided colorectal cancer
CRYSTALFOLFIRI1388.90.50.34–0.72<0.001
FOLFIRI + C14212
PRIMEFOLFOX1599.20.720.57–0.90n.r.
FOLFOX + P16912.9
CALGB/SWOG 80405FOLFOX/FOLFIRI + B15211.20.840.66–1.060.15
FOLFOX/FOLFIRI + C17312.7
FIRE-3FOLFIRI + B14910.70.90.71–1.140.38
FOLFIRI + C15710.7
PEAKFOLFOX + P5314.60.650.21–2.0n.r.
FOLFOX + B5411.5
Right-sided colorectal cancer
CRYSTALFOLFIRI517.10.870.47–1.620.66
FOLFIRI + C338.1
PRIMEFOLFOX4970.80.50–1.26n.r.
FOLFOX + P397.5
CALGB/SWOG 80405FOLFOX/FOLFIRI + B7810.21.641.15–2.360.006
FOLFOX/FOLFIRI + C717.5
FIRE-3FOLFIRI + B5091.440.92–2.260.11
FOLFIRI + C387.6
PEAKFOLFOX + P228.70.840.18–3.79n.r.
FOLFOX + B1412.6

Table 2.

Summary of clinical trials and treatment effects within subgroups defined by primary tumor location in patients with metastatic colorectal cancer.

Abbreviations: PFS, progression-free survival; HR, hazard ratio; CI, confidence interval; FOL, folinic acid; F, fluorouracil; IRI, irinotecan; OX, oxaliplatin; B, bevacizumab; C, cetuximab; P, panitumumab; n.r., not reported; BSC, best supportive care.

Given the above evidence, NCCN guidelines now recommend the use of anti-EGFR antibody therapies for the treatment of RAS wild-type left-sided colon cancers only [53].

2.2 Future predictive biomarkers for anti-EGFR therapy

2.2.1 Skin toxicity

Dermatological toxicities such as papulopustular rash (acneiform eruption), erythema, and skin fissures are common side effects of treatment with anti-EGFR antibodies, as EGFR is involved in the normal development and physiology of the epidermis [54]. Both undifferentiated and proliferating keratinocytes in the basal and suprabasal layers of the epidermis express EGFR, and keratinocytes depend on EGFR to regulate proliferation, differentiation, migration, and survival [55]. The emergence of skin toxicity has therefore been investigated as an on-target marker for anti-EGFR therapy efficacy in patients with mCRC.

Subset analyses of outcomes by skin toxicity severity suggest that improvements in outcome are associated with a higher grade of severity for patients treated with either panitumumab or cetuximab. For example, in the CRYSTAL trial of cetuximab as a first-line therapy, PFS was 11.3 months compared with 5.4 months in patients with G3 and G0-1 skin reactions, respectively [56]. Similarly, the randomized phase III EPIC study of cetuximab plus irinotecan vs irinotecan after fluoropyrimidine and oxaliplatin failure in patients with EGFR-expressing mCRC observed a median PFS of 15.6 months for patients who developed G3-4 rash compared to 5.8 months for those with no rash [57]. In the PRIME study of panitumumab plus FOLFOX4 (first line) and 20050181 study of panitumumab plus FOLFIRI (second line) the addition of a targeted agent even appeared detrimental for outcomes in patients with G0-1 skin toxicity as compared to the control arms [58, 59]. Better outcomes in patients with higher-grade skin toxicity were further noted for both arms in a randomized trial of cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer [60]. A meta-analysis by Petrelli et al of 14 studies including a total of 3833 patients, found that the occurrence of skin toxicity was a predictive factor for survival (HR 0.51; 95% CI 0.40–0.64) and progression (HR 0.58; 95% CI 0.49–0.68). However, 12 of the studies included patients with either KRAS wild-type or mutated tumors, and data on skin toxicity by KRAS mutation status remains limited.

Analysis of skin toxicity in the randomized phase III ASPECCT study of panitumumab vs cetuximab in chemorefractory wild-type KRAS exon 2 mCRC observed improved outcomes in patients with higher grade of severity for both antibodies, although patients with higher-grade skin toxicity had longer median duration of treatment [61]. Two retrospective trial analyses (PRIME and AIO CRC-0104 [cetuximab with CAPOX or CAPIRI, first-line]) suggest that the relationship between skin toxicity and outcome may not only apply to patients with wild-type RAS tumors, but perhaps also to patients mutant RAS tumors [62, 63]. A recent meta-analysis of skin toxicity identified seven and five studies that reported information on PFS and OS stratified by KRAS mutation status, respectively [64]. Improved clinical outcome in the presence of higher grade severity was observed for both patients with wild-type KRAS tumors and those with mutant KRAS tumors (PFS for wild-type KRAS, HR = 0.60, 95% CI (0.51, 0.70); mutant KRAS, HR = 0.60, 95% CI (0.45, 0.80), OS for wild-type KRAS, HR = 0.54, 95% CI (0.46, 0.65), mutant KRAS, HR = 0.64, 95% CI (0.50, 0.81), P < 0.001]. However, only mCRC patients with wild-type KRAS tumors who suffered grade 2+ skin toxicity derived absolute benefit from anti-EGFR treatment additional to best BSC or chemotherapy (PFS HR = 0.58, 95% CI (0.41, 0.82), OS HR = 0.73, 95% CI (0.61, 0.88)).

These data raise the question whether wild-type RAS patients receiving anti-EGFR therapy who do not develop skin toxicity should receive a dose escalation to induce skin toxicity or whether treatment should be discontinued. Further prospective data are needed to establish the clinical value of skin toxicity as a predictive biomarker.

2.2.2 EGFR gene copy number

EGFR is localized on chromosome 7p11.2 which exhibits DNA copy number gain in approximately 35% of colorectal cancers [65]. Based on this observation, EGFR gene copy number has been investigated as a predictive biomarker for anti-EGFR therapy in multiple post hoc analyses. Study results have been aggregated in three meta-analyses [66-68], which broadly concurred in identifying gain of EGFR gene copy number as associated with improved outcomes among patients receiving cetuximab or panitumumab treatment. This association was found to be retained in subgroup analyses for patients with KRAS wild-type tumors, with one meta-analysis suggesting that this difference was not present in patients with KRAS mutated tumors [69]. However, the methodologies and criteria used for scoring increased EGFR gene copy number were highly inconsistent across different studies, and more research is required to clarify the predictive potential of this biomarker.

2.2.3 Amphiregulin (AREG) and epiregulin (EREG) expression

The EGFR ligands AREG and EREG are overexpressed in colorectal cancer at both the mRNA and protein levels [70, 71], and suppression of AREG or EREG gene expression reduces the therapeutic efficacy of cetuximab in tumor cell lines [72]. Accordingly, multiple studies have found evidence that the extent of expression of these ligands is related to efficacy of anti-EGFR therapy [71, 73, 74, 75, 76, 77, 78, 79].

For example, in the randomized phase III PICCOLO study of panitumumab and irinotecan vs irinotecan alone in fluorouracil-resistant mCRC, high messenger RNA (mRNA) expression of EREG or AREG (defined as either EREG or AREG in the top tertile for mRNA level) was a predictive marker for anti-EGFR therapy benefit in patients with wild-type RAS tumors. In contrast, patients with mutant RAS tumors gained no panitumumab therapy benefit regardless of ligand status [80]. Similarly, in the CO.17 study of cetuximab in chemotherapy-refractory mCRC, wild-type KRAS patients with high EREG gene expression obtained benefit from cetuximab therapy, while no benefit was observed in patients with low EREG expression; patients with mutant KRAS tumors showed no improvement on anti-EGFR therapy irrespective of EREG expression levels [76]. A retrospective analysis of the single-arm phase II NCT 00508404 study of first-line panitumumab plus FOLFIRI similarly also found a higher overall response rate for patients with wild-type RAS tumors and high vs low AREG expression [81]. A meta-analysis including eight studies that used anti-EGFR therapy alone or in combination with chemotherapy reported that AREG/EREG mRNA overexpression was associated with longer overall survival in patients with wild-type RAS tumors who received cetuximab or panitumumab treatment; AREG overexpression was further associated with longer PFS. In contrast, AREG and EREG was found not to have predictive value in patients with mutant KRAS tumors [82]. Given these encouraging data, further examination of these ligands in prospective controlled trials appears warranted.

2.2.4 BRAF mutation

The BRAF gene encodes a serine-threonine protein kinase that is an integral member of the RAS/MAPK signaling pathway. Approximately 10% of colorectal cancers harbor activating mutations in BRAF, with a valine (V) to a glutamic acid (E) substitution at codon 600 (V600E) accounting for more than 95% of alterations [16]. Mutations in BRAF are mutually exclusive with KRAS mutations in CRC [83]. Patients with mCRC who possess a BRAF mutation have significantly poorer prognosis as measured by PFS and OS, and mutational analysis is recommended for prognostic stratification in guidelines from the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology [84]. The relatively low mutation prevalence and strong association with prognosis in the metastatic setting have hampered conclusive evaluation of BRAF status as a predictive biomarker for anti-EGFR therapy in individual trials.

Two meta-analyses of randomized studies of anti-EGFR antibodies have been conducted with inconsistent findings. The first meta-analysis of eight randomized controlled trials published in seven studies concluded that there was insufficient evidence to demonstrate that mCRC patients with wild-type RAS/mutant BRAF tumors attain a different treatment benefit from anti-EGFR therapy as compared to patients with wild-type RAS/wild-type BRAF tumors [85]. However, the second meta-analysis of 10 randomized controlled trials from nine reports focusing on wild-type RAS/mutant BRAF tumors reported that anti-EGFR therapy provided no benefit in these patients, indicating presence of mutation as a marker of drug resistance. Based on these uncertain data, current guidelines for the treatment of mCRC do not recommend BRAF mutations as a biomarker for response to anti-EGFR therapy [84].

2.2.5 PIK3CA mutation

Phosphoinositide 3-kinases (PI3K) are a family of heterodimeric lipid kinases which consist of regulatory (p85) and catalytic (p110) subunits. PI3K is a key signaling mediator downstream of EGFR involved in the regulation of cell metabolism, growth, proliferation and survival. The PIK3CA gene encodes the catalytic subunit, p110α, which, when mutated in cancer, results in constitutively active PI3K signaling. PIK3CA mutations are present in approximately 10–20% of colorectal cancers, with missense mutations in exon 9 (helical domain) and exon 20 (kinase domain) being the most common alterations [86, 87]. Notably, biochemical studies comparing mutant p110α proteins have established that exon 9 and exon 20 substitutions have different mechanisms of action. Exon 9-mutant p110α protein induces cell transformation independently of binding to p85 but requires interaction with RAS-GTP, whereas exon 20-mutant p110α protein is active in the absence of RAS-GTP binding but is dependent on the interaction with p85 [88].

PIK3CA mutations have been investigated as a potential predictor of anti-EGFR therapy efficacy, with studies considering mutation status overall or for exons 9 and 20 separately. Again, conclusive analyses from individual studies have been hampered by the relatively low mutation prevalence, with PIK3CA mutations tending to co-occur with KRAS mutations [87]. A series of meta-analyses have been conducted to consolidate findings, indicating that PIK3CA mutations as a whole are associated with a lack of anti-EGFR therapy response in patients with wild-type RAS tumors [89, 90, 91, 92, 93]. Some studies further suggest that the predictive power may be confined to exon 20 mutations, although sample size remains limited [90, 91, 94]. However, these meta-analyses have included many of the same studies, as well as observed and acknowledged between-study heterogeneity. Further investigations are needed before definitive conclusions regarding the predictive value of PIK3CA mutations for clinical decision making can be drawn, and PIK3CA mutational analysis of colorectal carcinoma tissue for therapy selection outside of a clinical trial is currently not recommended [84].

2.2.6 PTEN loss

PTEN is a negative regulator of the PI3K/AKT pathway downstream of EGFR through its lipid phosphatase activity. PTEN is a tumor suppressor gene in colorectal cancer, with inactivating mutations or loss of protein expression observed in approximately 5% and 30% of sporadic colorectal cancers [87, 95, 96].

With respect to response to anti-EGFR therapy, a number of studies have indicated an association with PTEN loss and lack of response to cetuximab and panitumumab [97, 98, 99, 100], although other reports have not identified this relationship [101, 102, 103]. There are also data to suggest that some discordance in PTEN protein expression may exist between primary tumors and metastases [104]. Several meta-analyses have considered published findings, supporting the notion that loss of PTEN protein expression and/or mutation are predictive of worse outcomes in patients with wild-type KRAS tumors treated with anti-EGFR therapy [91, 92, 105]. However, given a high level of variability in methods for assessment of PTEN expression between studies, including IHC scoring algorithms, and the potential inconsistency in expression between primary and metastatic tumor samples, loss of PTEN expression cannot yet be regarded as a reliable predictive biomarker. Further investigation and prospective large randomized clinical trials are still required to fully confirm the role of PTEN in anti-EGFR therapy resistance.

Advertisement

3. Conclusion

The introduction of multiple chemotherapy and biological therapy options for the treatment of CRC over the past few decades have driven an increased need for predictive biomarkers to select the most appropriate therapy for each patient. Biomarker guided treatment selection is critical to improving patient outcomes, reducing exposure to ineffective lines of treatment that are associated with significant toxicities and costs. For the use of the anti-EGFR antibodies cetuximab and panitumumab, current best clinical practice mandates that assessment of all common mutations in KRAS and NRAS be undertaken at the time of diagnosis of mCRC. Sidedness is also an important factor and it is recommended to limit anti-EGFR therapy to cases with left-sided primary tumor location [53].

Mutations and amplifications of several genes other than RAS have been investigated as potential predictive biomarkers of response to anti-EGFR therapy. These include EGFR gene copy number, BRAF and PIK3CA mutation as well as PTEN loss (mutation and loss of protein expression). The individual frequencies of all of these mutations and amplifications are low and methodologies to determine DNA copy number or protein expression have been highly variable across studies, thus whether these alterations are true biomarkers for anti-EGFR therapy resistance remains uncertain. Expression of the EGFR ligands AREG and EREG are an interesting avenue to explore, but current evidence is insufficient to recommend routine testing in clinical practice. Skin toxicity is a potential predictive marker in wild-type RAS patients receiving anti-EGFR therapy, but prospective randomized data are required to demonstrate clinical utility and determine how this information is best used to inform patient management (dose escalation vs treatment discontinuation).

While significant progress has been made in identifying predictive biomarkers for anti-EGFR therapy, with RAS mutation status and tumor sidedness endorsed as clinical diagnostics, many patients treated with cetuximab and panitumumab as selected by these parameters still do not experience treatment benefit. Further basic biology and clinical studies are clearly warranted to improve our understanding of EGFR signaling to identify novel biomarkers predictive of anti-EGFR therapy response and to develop more refined companion diagnostics.

Advertisement

Acknowledgments

O.M.S. is supported by a NHMRC Senior Research Fellowship (APP1136119).

Advertisement

Conflict of interest

The authors declare no conflict of interest.

References

  1. 1. Surveillance, Epidemiology, and End Results Program SEER Facts and Figures. Colorectal Cancer. National Cancer Institute. 2018. [cited Jul 20, 2018]. Available from: https://seer.cancer.gov/statfacts/html/colorect.html
  2. 2. Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Annals of Oncology. 2016;27(8):1386-1422
  3. 3. Zhao B, Wang L, Qiu H, Zhang M, Sun L, Peng P, et al. Mechanisms of resistance to anti-EGFR therapy in colorectal cancer. Oncotarget. 2017;8(3):3980-4000
  4. 4. Brand TM, Iida M, Wheeler DL. Molecular mechanisms of resistance to the EGFR monoclonal antibody cetuximab. Cancer Biology & Therapy. 2011;11(9):777-792
  5. 5. Tebbutt N, Pedersen MW, Johns TG. Targeting the ERBB family in cancer: couples therapy. Nature Reviews. Cancer. 2013;13(9):663-673
  6. 6. Sigismund S, Avanzato D, Lanzetti L. Emerging functions of the EGFR in cancer. Molecular Oncology. 2018;12(1):3-20
  7. 7. Spano JP, Lagorce C, Atlan D, Milano G, Domont J, Benamouzig R, et al. Impact of EGFR expression on colorectal cancer patient prognosis and survival. Annals of Oncology. 2005;16(1):102-108
  8. 8. Goldstein NS, Armin M. Epidermal growth factor receptor immunohistochemical reactivity in patients with American Joint Committee on Cancer Stage IV colon adenocarcinoma: Implications for a standardized scoring system. Cancer. 2001;92(5):1331-1346
  9. 9. Yang BB, Lum P, Chen A, Arends R, Roskos L, Smith B, et al. Pharmacokinetic and pharmacodynamic perspectives on the clinical drug development of panitumumab. Clinical Pharmacokinetics. 2010;49(11):729-740
  10. 10. Inoue Y, Hazama S, Iwamoto S, Miyake Y, Matsuda C, Tsunedomi R, et al. FcgammaR and EGFR polymorphisms as predictive markers of cetuximab efficacy in metastatic colorectal cancer. Molecular Diagnosis & Therapy. 2014;18(5):541-548
  11. 11. Kurai J, Chikumi H, Hashimoto K, Yamaguchi K, Yamasaki A, Sako T, et al. Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines. Clinical Cancer Research. 2007;13(5):1552-1561
  12. 12. Price TJ, Peeters M, Kim TW, Li J, Cascinu S, Ruff P, et al. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): A randomised, multicentre, open-label, non-inferiority phase 3 study. The Lancet Oncology. 2014;15(6):569-579
  13. 13. Linardou H, Briasoulis E, Dahabreh IJ, Mountzios G, Papadimitriou C, Papadopoulos S, et al. All about KRAS for clinical oncology practice: Gene profile, clinical implications and laboratory recommendations for somatic mutational testing in colorectal cancer. Cancer Treatment Reviews. 2011;37(3):221-233
  14. 14. Van Emburgh BO, Sartore-Bianchi A, Di Nicolantonio F, Siena S, Bardelli A. Acquired resistance to EGFR-targeted therapies in colorectal cancer. Molecular Oncology. 2014;8(6):1084-1094
  15. 15. Malumbres M, Barbacid M. RAS oncogenes: the first 30 years. Nature Reviews. Cancer. 2003;3(6):459-465
  16. 16. Catalogue of Somatic Mutations in Cancer. Wellcome Trust Sanger Institute. 2018 [cited Jul 20, 2018]. Available from: http://www.sanger.ac.uk/genetics/CGP/cosmic/
  17. 17. Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A, et al. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Annals of Oncology. 2011;22(7):1535-1546
  18. 18. Van Cutsem E, Kohne CH, Lang I, Folprecht G, Nowacki MP, Cascinu S, et al. 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. Journal of Clinical Oncology. 2011;29(15):2011-2019
  19. 19. Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. Journal of Clinical Oncology. 2008;26(10):1626-1634
  20. 20. Allegra CJ, Jessup JM, Somerfield MR, Hamilton SR, Hammond EH, Hayes DF, et al. 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. Journal of Clinical Oncology. 2009;27(12):2091-2096
  21. 21. Allegra CJ, Rumble RB, Hamilton SR, Mangu PB, Roach N, Hantel A, et al. Extended RAS gene mutation testing in metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy: American Society of Clinical Oncology Provisional Clinical Opinion Update 2015. Journal of Clinical Oncology. 2016;34(2):179-185
  22. 22. Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. The New England Journal of Medicine. 2008;359(17):1757-1765
  23. 23. Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. The New England Journal of Medicine. 2013;369(11):1023-1034
  24. 24. Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, et al. Final results from a randomized phase 3 study of FOLFIRI {+/−} panitumumab for second-line treatment of metastatic colorectal cancer. Annals of Oncology. 2014;25(1):107-116
  25. 25. Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. Journal of Clinical Oncology. 2009;27(5):663-671
  26. 26. Guerrero S, Casanova I, Farre L, Mazo A, Capella G, Mangues R. K-ras codon 12 mutation induces higher level of resistance to apoptosis and predisposition to anchorage-independent growth than codon 13 mutation or proto-oncogene overexpression. Cancer Research. 2000;60(23):6750-6756
  27. 27. De Roock W, Jonker DJ, Di Nicolantonio F, Sartore-Bianchi A, Tu D, Siena S, et al. Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. Journal of the American Medical Association. 2010;304(16):1812-1820
  28. 28. Tejpar S, Celik I, Schlichting M, Sartorius U, Bokemeyer C, Van Cutsem E. Association of KRAS G13D tumor mutations with outcome in patients with metastatic colorectal cancer treated with first-line chemotherapy with or without cetuximab. Journal of Clinical Oncology. 2012;30(29):3570-3577
  29. 29. Gajate P, Sastre J, Bando I, Alonso T, Cillero L, Sanz J, et al. Influence of KRAS p.G13D mutation in patients with metastatic colorectal cancer treated with cetuximab. Clinical Colorectal Cancer. 2012;11(4):291-296
  30. 30. Peeters M, Douillard JY, Van Cutsem E, Siena S, Zhang K, Williams R, et al. Mutant KRAS codon 12 and 13 alleles in patients with metastatic colorectal cancer: Assessment as prognostic and predictive biomarkers of response to panitumumab. Journal of Clinical Oncology. 2013;31(6):759-765
  31. 31. Segelov E, Thavaneswaran S, Waring PM, Desai J, Robledo KP, Gebski VJ, et al. Response to cetuximab with or without irinotecan in patients with refractory metastatic colorectal cancer harboring the KRAS G13D mutation: Australasian gastro-intestinal trials group ICECREAM study. Journal of Clinical Oncology. 2016;34(19):2258-2264
  32. 32. Van Cutsem E, Lenz HJ, Kohne CH, Heinemann V, Tejpar S, Melezinek I, et al. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. Journal of Clinical Oncology. 2015;33(7):692-700
  33. 33. Sorich MJ, Wiese MD, Rowland A, Kichenadasse G, McKinnon RA, Karapetis CS. Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials. Annals of Oncology. 2015;26(1):13-21
  34. 34. Bokemeyer C, Kohne CH, Ciardiello F, Lenz HJ, Heinemann V, Klinkhardt U, et al. FOLFOX4 plus cetuximab treatment and RAS mutations in colorectal cancer. European Journal of Cancer. 2015;51(10):1243-1252
  35. 35. Peeters M, Oliner KS, Price TJ, Cervantes A, Sobrero AF, Ducreux M, et al. Analysis of KRAS/NRAS mutations in a phase III study of panitumumab with FOLFIRI compared with FOLFIRI alone as second-line treatment for metastatic colorectal cancer. Clinical Cancer Research. 2015;21(24):5469-5479
  36. 36. Schwartzberg LS, Rivera F, Karthaus M, Fasola G, Canon JL, Hecht JR, et al. PEAK: A randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. Journal of Clinical Oncology. 2014;32(21):2240-2247
  37. 37. Stintzing S, Modest DP, Rossius L, Lerch MM, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): A post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial. The Lancet Oncology. 2016;17(10):1426-1434
  38. 38. De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G, et al. 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. The Lancet Oncology. 2010;11(8):753-762
  39. 39. Stintzing S, Tejpar S, Gibbs P, Thiebach L, Lenz HJ. Understanding the role of primary tumour localisation in colorectal cancer treatment and outcomes. European Journal of Cancer. 2017;84:69-80
  40. 40. Loupakis F, Yang D, Yau L, Feng S, Cremolini C, Zhang W, et al. Primary tumor location as a prognostic factor in metastatic colorectal cancer. Journal of the National Cancer Institute. 2015;107(3):dju427
  41. 41. Nitsche U, Stogbauer F, Spath C, Haller B, Wilhelm D, Friess H, et al. Right sided colon cancer as a distinct histopathological subtype with reduced prognosis. Digestive Surgery. 2016;33(2):157-163
  42. 42. Sinicrope FA, Mahoney MR, Yoon HH, Smyrk TC, Thibodeau SN, Goldberg RM, et al. Analysis of molecular markers by anatomic tumor site in stage III colon carcinomas from adjuvant chemotherapy trial NCCTG N0147 (alliance). Clinical Cancer Research. 2015;21(23):5294-5304
  43. 43. Rowan A, Halford S, Gaasenbeek M, Kemp Z, Sieber O, Volikos E, et al. Refining molecular analysis in the pathways of colorectal carcinogenesis. Clinical Gastroenterology and Hepatology. 2005;3(11):1115-1123
  44. 44. Missiaglia E, Jacobs B, D'Ario G, Di Narzo AF, Soneson C, Budinska E, et al. Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features. Annals of Oncology. 2014;25(10):1995-2001
  45. 45. Lee MS, McGuffey EJ, Morris JS, Manyam G, Baladandayuthapani V, Wei W, et al. Association of CpG island methylator phenotype and EREG/AREG methylation and expression in colorectal cancer. British Journal of Cancer. 2016;114(12):1352-1361
  46. 46. Tejpar S, Stintzing S, Ciardiello F, Tabernero J, Van Cutsem E, Beier F, et al. Prognostic and predictive relevance of primary tumor location in patients with RAS wild-type metastatic colorectal cancer: Retrospective analyses of the CRYSTAL and FIRE-3 trials. JAMA Oncology. 2017;3(2):194-201
  47. 47. Venook A, Niedzwiecki D, Innocenti F, Fruth B, Greene C, O'Neil B, et al. Impact of primary (1°) tumor location on overall survival (OS) and progression free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analysis of CALGB/SWOG 80405 (Alliance). Journal of Clinical Oncology. 2016;34:3504
  48. 48. Boeckx N, Koukakis R, Op de Beeck K, Rolfo C, Van Camp G, Siena S, et al. Primary tumor sidedness has an impact on prognosis and treatment outcome in metastatic colorectal cancer: results from two randomized first-line panitumumab studies. Annals of Oncology. 2017;28(8):1862-1868
  49. 49. Holch JW, Ricard I, Stintzing S, Modest DP, Heinemann V. The relevance of primary tumour location in patients with metastatic colorectal cancer: A meta-analysis of first-line clinical trials. European Journal of Cancer. 2017;70:87-98
  50. 50. Modest DP, Stintzing S, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, et al. Exploring the effect of primary tumor sidedness on therapeutic efficacy across treatment lines in patients with metastatic colorectal cancer: analysis of FIRE-3 (AIOKRK0306). Oncotarget. 2017;8(62):105749-105760
  51. 51. Boeckx AT N, Op de Beeck K, Kafatos G, Deschoolmeester V, Rolfo C, et al. Primary tumor sidedness impacts on prognosis and treatment outcome: results from three randomized studies of panitumumab plus chemotherapy versus chemotherapy or chemotherapy plus bevacizumab in 1st and 2nd line RAS/BRAF WT mCRC Ann Oncol. 2016;27(suppl 6):vi15-vi42
  52. 52. Brule SY, Jonker DJ, Karapetis CS, O'Callaghan CJ, Moore MJ, Wong R, et al. Location of colon cancer (right-sided versus left-sided) as a prognostic factor and a predictor of benefit from cetuximab in NCIC CO.17. European Journal of Cancer. 2015;51(11):1405-1414
  53. 53. Clinical Practice Guidelines in Oncology Colon cancer: National Comprehensive Cancer Network (NCCN). 2018. [cited Jul 20, 2018]. Available from: https://www.nccn.org
  54. 54. Petrelli F, Ardito R, Ghidini A, Zaniboni A, Ghidini M, Barni S, et al. Different toxicity of cetuximab and panitumumab in metastatic colorectal cancer treatment: A systematic review and meta-analysis. Oncology. 2018;94(4):191-199
  55. 55. Lacouture ME. Mechanisms of cutaneous toxicities to EGFR inhibitors. Nature Reviews. Cancer. 2006;6(10):803-812
  56. 56. AAMPP I. Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC): The CRYSTAL trial. Journal of Clinical Oncology. 2007;25(18S; June 20 suppl)
  57. 57. Sobrero AF, Maurel J, Fehrenbacher L, et al. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. Journal of Clinical Oncology. 2008 May 10;26(14):2311-2319
  58. 58. Sobrero AF, Peeters M, Price TJ, et al. Final results from study 181: Randomized phase III study of FOLFIRI with or without panitumumab (pmab) for the treatment of second-line metastatic colorectal cancer (mCRC). Journal of Clinical Oncology. 2012;30(suppl 4):387
  59. 59. Douillard YJSS, Tabernero J, et al. Final skin toxicity (ST) and patient-reported outcomes (PRO) results from PRIME: A randomized phase III study of panitumumab (pmab) plus FOLFOX4 (CT) for first-line metastatic colorectal cancer (mCRC). Journal of Clinical Oncology. 2012;30(suppl 4):531
  60. 60. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. The New England Journal of Medicine. 2004;351(4):337-345
  61. 61. Price T, Kim TW, Li J, Cascinu S, Ruff P, Suresh AS, et al. Final results and outcomes by prior bevacizumab exposure, skin toxicity, and hypomagnesaemia from ASPECCT: randomized phase 3 non-inferiority study of panitumumab versus cetuximab in chemorefractory wild-type KRAS exon 2 metastatic colorectal cancer. European Journal of Cancer. 2016;68:51-59
  62. 62. Douillard JY, Rong A, Sidhu R. RAS mutations in colorectal cancer. The New England Journal of Medicine. 2013;369(22):2159-2160
  63. 63. Stintzing SKC, Laubender RP, et al. Cetuximab-related skin toxicity in metastatic colorectal cancer (mCRC) patients and its correlation with molecular markers: Results from the German AIO CRC 0104 trial. Journal of Clinical Oncology. 2102;30(suppl 4):491
  64. 64. Hu J, Zhang Z, Zheng R, Cheng L, Yang M, Li L, et al. On-treatment markers as predictors to guide anti-EGFR MoAb treatment in metastatic colorectal cancer: a systematic review with meta-analysis. Cancer Chemotherapy and Pharmacology. 2017;79(2):275-285
  65. 65. Mouradov D, Sloggett C, Jorissen RN, Love CG, Li S, Burgess AW, et al. Colorectal cancer cell lines are representative models of the main molecular subtypes of primary cancer. Cancer Research. 2014;74(12):3238-3247
  66. 66. Shen WD, Chen HL, Liu PF. EGFR gene copy number as a predictive biomarker for resistance to anti-EGFR monoclonal antibodies in metastatic colorectal cancer treatment: A meta-analysis. Chinese Journal of Cancer Research. 2014;26(1):59-71
  67. 67. Ketzer S, Schimmel K, Koopman M, Guchelaar HJ. Clinical pharmacokinetics and pharmacodynamics of the epidermal growth factor receptor inhibitor panitumumab in the treatment of colorectal cancer. Clinical Pharmacokinetics. 2018;57(4):455-473
  68. 68. Jiang Z, Li C, Li F, Wang X. EGFR gene copy number as a prognostic marker in colorectal cancer patients treated with cetuximab or panitumumab: A systematic review and meta-analysis. PLoS One. 2013;8(2):e56205
  69. 69. Yang ZY, Shen WX, Hu XF, Zheng DY, Wu XY, Huang YF, et al. EGFR gene copy number as a predictive biomarker for the treatment of metastatic colorectal cancer with anti-EGFR monoclonal antibodies: A meta-analysis. Journal of Hematology & Oncology. 2012;5:52
  70. 70. Li XD, Miao SY, Wang GL, Yang L, Shu YQ Yin YM. Amphiregulin and epiregulin expression in colorectal carcinoma and the correlation with clinicopathological characteristics. Onkologie. 2010;33(7):353-358
  71. 71. Khambata-Ford S, Garrett CR, Meropol NJ, Basik M, Harbison CT, Wu S, et al. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. Journal of Clinical Oncology. 2007;25(22):3230-3237
  72. 72. Oliveras-Ferraros C, Cufi S, Queralt B, Vazquez-Martin A, Martin-Castillo B, de Llorens R, et al. Cross-suppression of EGFR ligands amphiregulin and epiregulin and de-repression of FGFR3 signalling contribute to cetuximab resistance in wild-type KRAS tumour cells. British Journal of Cancer. 2012;106(8):1406-1414
  73. 73. Yoshida M, Shimura T, Sato M, Ebi M, Nakazawa T, Takeyama H, et al. A novel predictive strategy by immunohistochemical analysis of four EGFR ligands in metastatic colorectal cancer treated with anti-EGFR antibodies. Journal of Cancer Research and Clinical Oncology. 2013;139(3):367-378
  74. 74. Baker JB, Dutta D, Watson D, Maddala T, Munneke BM, Shak S, et al. Tumour gene expression predicts response to cetuximab in patients with KRAS wild-type metastatic colorectal cancer. British Journal of Cancer. 2011;104(3):488-495
  75. 75. Jacobs B, De Roock W, Piessevaux H, Van Oirbeek R, Biesmans B, De Schutter J, et al. Amphiregulin and epiregulin mRNA expression in primary tumors predicts outcome in metastatic colorectal cancer treated with cetuximab. Journal of Clinical Oncology. 2009;27(30):5068-5074
  76. 76. Jonker DJ, Karapetis CS, Harbison C, O'Callaghan CJ, Tu D, Simes RJ, et al. Epiregulin gene expression as a biomarker of benefit from cetuximab in the treatment of advanced colorectal cancer. British Journal of Cancer. 2014;110(3):648-655
  77. 77. Pentheroudakis G, Kotoula V, De Roock W, Kouvatseas G, Papakostas P, Makatsoris T, et al. Biomarkers of benefit from cetuximab-based therapy in metastatic colorectal cancer: Interaction of EGFR ligand expression with RAS/RAF, PIK3CA genotypes. BMC Cancer. 2013;13:49
  78. 78. Saridaki Z, Tzardi M, Papadaki C, Sfakianaki M, Pega F, Kalikaki A, et al. Impact of KRAS, BRAF, PIK3CA mutations, PTEN, AREG, EREG expression and skin rash in ≥2 line cetuximab-based therapy of colorectal cancer patients. PLoS One. 2011;6(1):e15980
  79. 79. Llovet P, Sastre J, Ortega JS, Bando I, Ferrer M, Garcia-Alfonso P, et al. Prognostic value of BRAF, PI3K, PTEN, EGFR copy number, amphiregulin and epiregulin status in patients with KRAS Codon 12 wild-type metastatic colorectal cancer receiving first-line chemotherapy with anti-EGFR therapy. Molecular Diagnosis & Therapy. 2015;19(6):397-408
  80. 80. Seligmann JF, Elliott F, Richman SD, Jacobs B, Hemmings G, Brown S, et al. Combined epiregulin and amphiregulin expression levels as a predictive biomarker for panitumumab therapy benefit or lack of benefit in patients with RAS wild-type advanced colorectal cancer. JAMA Oncology. 2016
  81. 81. Karthaus M, Hofheinz RD, Mineur L, Letocha H, Greil R, Thaler J, et al. Impact of tumour RAS/BRAF status in a first-line study of panitumumab + FOLFIRI in patients with metastatic colorectal cancer. British Journal of Cancer. 2016;115(10):1215-1222
  82. 82. Jing C, Jin YH, You Z, Qiong Q Jun Z. Prognostic value of amphiregulin and epiregulin mRNA expression in metastatic colorectal cancer patients. Oncotarget. 2016;7(34):55890-55899
  83. 83. Tie J, Gibbs P, Lipton L, Christie M, Jorissen RN, Burgess AW, et al. Optimizing targeted therapeutic development: Analysis of a colorectal cancer patient population with the BRAF(V600E) mutation. International Journal of Cancer. 2011;128(9):2075-2084
  84. 84. Sepulveda AR, Hamilton SR, Allegra CJ, Grody W, Cushman-Vokoun AM, Funkhouser WK, et al. Molecular biomarkers for the evaluation of colorectal cancer: Guideline from the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology. The Journal of Molecular Diagnostics. 2017;19(2):187-225
  85. 85. Rowland A, Dias MM, Wiese MD, Kichenadasse G, McKinnon RA, Karapetis CS, et al. Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer. British Journal of Cancer. 2015;112(12):1888-1894
  86. 86. Nosho K, Kawasaki T, Ohnishi M, Suemoto Y, Kirkner GJ, Zepf D, et al. PIK3CA mutation in colorectal cancer: Relationship with genetic and epigenetic alterations. Neoplasia. 2008;10(6):534-541
  87. 87. Day FL, Jorissen RN, Lipton L, Mouradov D, Sakthianandeswaren A, Christie M, et al. PIK3CA and PTEN gene and exon mutation-specific clinicopathologic and molecular associations in colorectal cancer. Clinical Cancer Research. 2013;19(12):3285-3296
  88. 88. Zhao L, Vogt PK. Helical domain and kinase domain mutations in p110alpha of phosphatidylinositol 3-kinase induce gain of function by different mechanisms. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(7):2652-2657
  89. 89. Wu S, Gan Y, Wang X, Liu J, Li M, Tang Y. PIK3CA mutation is associated with poor survival among patients with metastatic colorectal cancer following anti-EGFR monoclonal antibody therapy: a meta-analysis. Journal of Cancer Research and Clinical Oncology. 2013;139(5):891-900
  90. 90. Huang L, Liu Z, Deng D, Tan A, Liao M, Mo Z, et al. Anti-epidermal growth factor receptor monoclonal antibody-based therapy for metastatic colorectal cancer: A meta-analysis of the effect of PIK3CA mutations in KRAS wild-type patients. Archives of Medical Science. 2014;10(1):1-9
  91. 91. Yang ZY, Wu XY, Huang YF, Di MY, Zheng DY, Chen JZ, et al. Promising biomarkers for predicting the outcomes of patients with KRAS wild-type metastatic colorectal cancer treated with anti-epidermal growth factor receptor monoclonal antibodies: A systematic review with meta-analysis. International Journal of Cancer. 2013;133(8):1914-1925
  92. 92. Therkildsen C, Bergmann TK, Henrichsen-Schnack T, Ladelund S, Nilbert M. The predictive value of KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer: A systematic review and meta-analysis. Acta Oncologica. 2014;53(7):852-864
  93. 93. Mohamed A, Twardy B, AbdAllah N, Akhras A, Ismail H, Zordok M, et al. Clinical impact of PI3K/BRAF mutations in RAS wild metastatic colorectal cancer: Meta-analysis results. Journal of Gastrointestinal Cancer. 2018. DOI: 10.1007/s12029-018-0062-y
  94. 94. Mao C, Yang ZY, Hu XF, Chen Q, Tang JL. PIK3CA exon 20 mutations as a potential biomarker for resistance to anti-EGFR monoclonal antibodies in KRAS wild-type metastatic colorectal cancer: A systematic review and meta-analysis. Annals of Oncology. 2012;23(6):1518-1525
  95. 95. Zhou XP, Loukola A, Salovaara R, Nystrom-Lahti M, Peltomaki P, de la Chapelle A, et al. PTEN mutational spectra, expression levels, and subcellular localization in microsatellite stable and unstable colorectal cancers. The American Journal of Pathology. 2002;161(2):439-447
  96. 96. Goel A, Arnold CN, Niedzwiecki D, Carethers JM, Dowell JM, Wasserman L, et al. Frequent inactivation of PTEN by promoter hypermethylation in microsatellite instability-high sporadic colorectal cancers. Cancer Research. 2004;64(9):3014-3021
  97. 97. Frattini M, Saletti P, Romagnani E, Martin V, Molinari F, Ghisletta M, et al. PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. British Journal of Cancer. 2007;97(8):1139-1145
  98. 98. Perrone F, Lampis A, Orsenigo M, Di Bartolomeo M, Gevorgyan A, Losa M, et al. PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients. Annals of Oncology. 2009;20(1):84-90
  99. 99. Sartore-Bianchi A, Martini M, Molinari F, Veronese S, Nichelatti M, Artale S, et al. PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Research. 2009;69(5):1851-1857
  100. 100. Negri FV, Bozzetti C, Lagrasta CA, Crafa P, Bonasoni MP, Camisa R, et al. PTEN status in advanced colorectal cancer treated with cetuximab. British Journal of Cancer. 2010;102(1):162-164
  101. 101. Laurent-Puig P, Cayre A, Manceau G, Buc E, Bachet JB, Lecomte T, et al. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. Journal of Clinical Oncology. 2009;27(35):5924-5930
  102. 102. Tol J, Dijkstra JR, Klomp M, Teerenstra S, Dommerholt M, Vink-Borger ME, et al. Markers for EGFR pathway activation as predictor of outcome in metastatic colorectal cancer patients treated with or without cetuximab. European Journal of Cancer. 2010;46(11):1997-2009
  103. 103. Ulivi P, Capelli L, Valgiusti M, Zoli W, Scarpi E, Chiadini E, et al. Predictive role of multiple gene alterations in response to cetuximab in metastatic colorectal cancer: a single center study. Journal of Translational Medicine. 2012;10:87
  104. 104. Loupakis F, Pollina L, Stasi I, Ruzzo A, Scartozzi M, Santini D, et al. PTEN expression and KRAS mutations on primary tumors and metastases in the prediction of benefit from cetuximab plus irinotecan for patients with metastatic colorectal cancer. Journal of Clinical Oncology. 2009;27(16):2622-2629
  105. 105. Wang ZH, Gao QY, Fang JY. Loss of PTEN expression as a predictor of resistance to anti-EGFR monoclonal therapy in metastatic colorectal cancer: evidence from retrospective studies. Cancer Chemotherapy and Pharmacology. 2012;69(6):1647-1655

Written By

Anuratha Sakthianandeswaren, Polly Sabljak, Meg J. Elliott, Michelle Palmieri and Oliver M. Sieber

Submitted: 27 July 2018 Reviewed: 03 August 2018 Published: 05 November 2018

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Continue reading from the same book

View All
Chapter 7 Finding Needles in Haystacks: The Use of Quantitat...

By Tiffany Gould, Muhammad Fairuz B. Jamaluddin, Joel...

1313 downloads

Chapter 1 Advances in Molecular Subclassification of Colorec...

By Avani Athauda and Ian Chau

1164 downloads

Chapter 2 Experimental Results Help Shape the Development of...

By Rania B. Georges, Hassan Adwan and Martin R. Berge...

1142 downloads