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Keywords:

  • colorectal cancer;
  • cetuximab;
  • KRAS;
  • p.G13D;
  • meta-analysis

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

BACKGROUND:

The authors conducted a systematic review and meta-analysis to examine whether patients who had metastatic colorectal cancer (mCRC) with the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) p.G13D mutation (an amino acid substitution at position 13 in KRAS from a glycine to an aspartic acid) and received cetuximab treatment had better clinical outcomes than patients who had mCRC tumors with KRAS codon 12 mutations.

METHODS:

Relevant studies were identified by a search of MEDLINE, EMBASE, the Chinese Biomedical Database, and Wan Fang Digital Journals from inception to October 2011. The primary clinical outcomes included the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The pooled relative risk (RR) or hazard ratio (HR) was estimated by using fixed-effects or random-effects models according to heterogeneity between studies.

RESULTS:

Ten studies were considered eligible that included 1487 patients with mCRC. Patients who had tumors with the KRAS p.G13D mutation had a significantly higher ORR (10 studies; RR, 1.642; 95% confidence interval [CI], 1.131-2.384), longer PFS (1 study; HR, 0.54; 95% CI, 0.36-0.81), and longer OS (1 study; HR, 0.52; 95% CI, 0.33-0.80) than patients who had tumors with KRAS codon 12 mutations. Compared with patients who had KRAS wild-type tumors, patients with the p.G13D mutation had a significantly lower ORR (9 studies; RR, 0.540; 95% CI, 0.381-0.765) and nonsignificantly shorter PFS (1 study; HR, 0.99; 95% CI, 0.68-1.45) and OS (1 study; HR, 1.01; 95% CI, 0.66-1.54).

CONCLUSIONS:

Patients who had mCRC with the KRAS p.G13D mutation appeared to benefit more from cetuximab than patients who had tumors with KRAS codon 12 mutations. However, because of the limited sample sizes in the current meta-analysis, these results should be interpreted with caution. Cancer 2013. © 2012 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

The immunoglobulin G1 monoclonal antibody against the epidermal growth factor receptor (EGFR)—cetuximab—has proven effective in combination with chemotherapy or as a single agent for the treatment of patients with metastatic colorectal cancer (mCRC) who are refractory to irinotecan-based treatment.1-4 However, resistance to cetuximab is common, and only 10% to 20% of patients truly benefit from the treatment.4,5 Recently, it has been widely demonstrated that mutations in v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) codons 12 and 13 are major predictive biomarkers for resistance to cetuximab treatment.6-9 With reference to these findings, the European Medicines Agency10 and, subsequently, the US Food and Drug Administration11 have suggested that patients who have mCRC with KRAS codon 12 and codon 13 mutations should be excluded from cetuximab treatment.

However, studies indicate that not all KRAS mutations are equivalent in their biologic characteristics. First, an in vitro study indicated that KRAS codon 13 mutations (mainly the p.G13D mutation) exhibit weaker transforming activity than codon 12 mutations.12 Second, a few patients who have tumors with KRAS mutations occasionally respond to anti-EGFR treatment.1,13,14 The tumors from those responsive patients predominantly harbored codon 13 mutations, and all codon 13 responders have p.G13D mutation. These findings indicate that the KRAS p.G13D mutation and KRAS codon 12 mutations may have a different effect on cetuximab efficacy.

Although, until now, the effect of KRAS mutations as a whole has been reported in several studies, it makes little sense to interpret estimates of the effect of KRAS mutations when codon 12 and codon 13 mutations are considered separately. To date, only 3 studies (1 published full-text article15 and 2 abstracts16,17) have compared the efficacy of cetuximab treatment between patients who have tumors with the KRAS p.G13D mutation and those who have tumors with KRAS codon 12 mutations. Except for those 3 studies,15-17 there also were some other studies from which individual data could be extracted on this topic, although those studies did not compare patients with the p.G13D mutation and patients with codon 12 mutations. Those studies provided us with an opportunity to perform a systematic review and meta-analysis comparing the efficacy of cetuximab treatment among patients who had mCRC with KRAS p.G13D mutations, KRAS codon 12 mutations, and wild-type KRAS. We hope the findings from this study will help clarify the influence of the KRAS p.G13D mutation on clinical outcomes of cetuximab treatment.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

Literature Search

A comprehensive computerized literature search of MEDLINE, EMBASE, the Chinese Biomedical Database, and Wan Fang Digital Journals was performed from inception to October 2011. Following search terms were used to identify relevant studies: metastatic colorectal cancer (eg, “metastatic colorectal cancer,” “metastatic colon cancer, ” “metastatic rectal cancer”, “mCRC”), monoclonal antibodies (eg, “monoclonal antibodies,” “MoAb,” “MAbs,” “cetuximab”), KRAS (eg, “KRAS,” “K-RAS,” “G13D”). All eligible studies were retrieved, and their bibliographies were checked for further relevant publications. If the same patient population was used in more than 1 publication, then only the publication with the most relevant data was used in this systematic review.

Inclusion Criteria

Studies that met all of the following 4 criteria were considered eligible: 1) the patients studied had mCRC; 2) treatment consisted of cetuximab monotherapy or cetuximab in combination with other agents for any line of treatment; 3) KRAS was used as a biomarker; and 4) the outcomes included at least 1 of following stratified according to KRAS mutations status (p.G13D mutation and codon 12 mutations): objective response (the sum of complete responses and partial responses), progression-free survival (PFS), and overall survival (OS).

Data Extraction

Data extraction was performed independently by 2 researchers, and disagreements were resolved by discussion between them. Unsettled disagreements were settled by a third researcher, whose opinions were final. The following data were collected from each study: first author's name; year of publication; study design; demographic characteristics of patients; number of patients with the KRAS p.G13D mutation, KRAS codon 12 mutations, and wild-type KRAS; methods for detection of KRAS mutations status; lines of treatment; study treatment regimen; response criteria; overall response rate (ORR); PFS; OS; and hazard ratio (HR) with 95% confidence interval (CI) for the comparison of PFS and OS. Data on ORR, PFS, and OS were extracted separately according to KRAS mutation status (KRAS p.G13D mutation, KRAS codon 12 mutations, and wild-type KRAS, if possible).

Aggregate data were extracted from 3 studies15-17 that compared the efficacy of cetuximab treatment patients with p.G13D mutations and codon 12 mutations. Individual data were extracted from 7 studies6,13,14,18-21 that included the available data for ORR but did not perform a comparison between 2 groups of patients.

Quality Assessment

The quality of each study was assessed independently by 2 reviewers using the Newcastle-Ottawa Scale (NOS).22 The NOS consists of 3 parameters for the quality of cohort study: selection, comparability, and outcome. The NOS assigns a maximum of 4 points for selection, 2 points for comparability, and 3 points for outcome. Studies with NOS scores >6 were consider high quality. Any discrepancies between 2 reviewers were settled by a third reviewer.

Statistical Methods

The primary endpoints in the current analysis included ORR, PFS, and OS. The association between KRAS p.G13D mutations and the ORR was expressed as the relative risk (RR) of patients with p.G13D mutations versus patients with KRAS codon 12 mutations. The association of the KRAS p.G13D mutation with PFS and OS was expressed as a hazard ratio (HR) for patients with p.G13D mutations over patients with KRAS codon 12 mutations. In addition, we compared the efficacy of cetuximab treatment between patients who had tumors with the KRAS p.G13D mutation versus those who had wild-type KRAS tumors.

Before combining data, heterogeneity was assessed using a Cochran Q test with degrees of freedom equal to the number of analyzed studies minus 1.23,24 If the P value for the Cochran Q test was >0.10, which suggested that the variation in the results may have arisen purely from chance, the pooled RR or HR would be estimated by using a fixed-effects model (the Mantel-Haenszel method).25 Otherwise, heterogeneity was deemed significant; and a random-effects model (the DerSimonian and Laird method) would be used.26

Subgroup analyses were performed according to the line of treatment (first-line treatment vs second-line or subsequent treatment) and treatment regime (monotherapy vs combined therapy). Sensitivity analyses were performed to determine whether ethnicity, sample-size, methodologic quality, or response criteria would affect the final results. Begg funnel plots and Egger linear regression tests were used to assess the possible presence of publication bias.27 If publication bias existed, then the Duval and Tweedie nonparametric “trim-and-fill” method was used to estimate the “unbiased” effect.28 All statistical tests that were used in our systematic review were conducted using MetaAnalyst Beta 3.13 statistical software (Tufts Medical Center, Boston, Mass).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

Search Results

Figure 1 illustrates the process of identifying eligible articles for the analysis. The search in bibliographic databases yielded 1046 citations. After a review of titles and abstracts, we excluded 943 nonrelevant citations. The 103 remaining citations were classified as potentially relevant and were subjected to full-text assessment. We excluded 93 more articles that did not meet our inclusion criteria. Thus, 10 studies (2 abstracts16,17 and 8 full-text articles6,13-15,18-21) were included in the final analysis, of which 10 articles6,13-21 were included in the analyses of ORR and 3 articles15-17 were included in the analyses of PFS or OS.

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Figure 1. This is a flow chart of study selection for the current analysis. KRAS indicates v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; mCRC, metastatic colorectal cancer.

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Characteristics of the Included Studies

Table 1 lists the main characteristics of the 10 included articles, all of which were retrospective cohort studies. The articles were published between 2005 and 2011. Three studies6,19,20 were conducted in France, 3 studies13,18,21 were conducted in Italy, 1 study14 was conducted in Switzerland, 1 study17 was conducted in Belgium, 1 study15 was conducted in both Canada and Australia, and 1 study16 was conducted in Japan. Sample sizes ranged from 21 to 689 patients. Cetuximab was received as first-line treatment in 1 study17 and as first-line or subsequent treatment in 9 studies.6,13-16,18-21 Patients received cetuximab plus chemotherapy in 5 studies14,16,17,19,21and cetuximab-based treatment (cetuximab monotherapy or cetuximab plus chemotherapy) in the remaining 5 studies.6,13,15,18,20

Table 1. Main Characteristics of Studies Included in the Meta-Analysis
    No. of Patients (%)  
ReferenceCountryNo. of Patients AssessedAge: Median [Range], yMenMonotherapyFirst-Line TreatmentKRAS p.G13D MutationKRAS Codon 12 MutationsKRAS Wild TypeMutation Analysis MethodsResponse Criteria
  1. Abbreviations: DS, direct sequencing; KRAS, v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; NA, not available; p.G13D, an amino acid substitution at position 13 in KRAS from a glycine to an aspartic acid; RECIST, Response Evaluation Criteria in Solid Tumors; WHO, World Health Organization criteria.

Moroni 200513Italy2172 [41-85]17 (81)12 (57)11 (52)1 (5)4 (19)16(76)DSRECIST
Lievre 20066France3062 [41-78]19 (63)1 (3)3 (10)3 (10)10 (33)17(57)DSRECIST
Benvenuti 200718Italy2268 [39-84]17 (77)12 (55)11 (50)1 (5)4 (18)17(77)DSRECIST
Frattini 200714Switzerland2767 [29-84]18 (67)0 (0)4 (15)3 (11)7 (26)17(63)DSRECIST
Goncalves 200819France3260 [37-81]16 (50)0 (0)2 (6)4 (13)10 (31)18(56)DSWHO
Perrone 200921Italy2958 [36-78]18 (62)0 (0)0 (0)2 (7)4 (14)23(79)DSRECIST
De Roock 201015Canada/ Australia565NA [26-89]NA245 (43)0 (0)32 (6)188 (33)345(61)DSRECIST
Perkins 201020France4260 [44-78]24 (57)3 (7)1 (2)4 (10)15 (36)23(55)DSRECIST
Bando 201116Japan30NANA0 (0)0 (0)7 (23)23 (77)NANANA
Tejpar 201117Belgium689NANA0 (0)689 (100)42 (6)249 (36)398(58)NANA

Quality-Assessment Results

One study15 had an NOS score of 9, 7 studies6,13,14,18-21 had an NOS score of 7, and 2 studies16,17 had an NOS score of 6. Eight studies6,13-15,18-21 (80%) were of high quality (NOS score >6), and the average NOS score was 7. The most common bias was observed in the comparability of cohorts. Most of the included studies did not control for potential confounders in design and analysis.

Overall Response Rate

All studies provided data on the ORR for patients with the KRAS p.G13D mutation versus patients with KRAS codon 12 mutations and for patients with the KRAS p.G13D mutation versus patients with wild-type KRAS. In total, there were 1487 patients in the final analysis, including 99 patients with the KRAS p.G13D mutation, 514 patients with KRAS codon 12 mutations, and 874 patients with wild-type KRAS. The association between the KRAS p.G13D mutation and the ORR is analyzed in Table 2.

Table 2. Meta-Analysis of the Association Between KRAS Status and Overall Response Rate
  ORR (%)Test of AssociationTest of Heterogeneity
Mutation StatusNo. of Studiesp.G13DCodon 12 or Wild-Type KRASRR (95%CI)PQPI2, %
  1. Abbreviations: CI, confidence interval; KRAS, v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; p.G13D, an amino acid substitution at position 13 in KRAS from a glycine to an aspartic acid; ORR, objective response rate; RR, relative risk.

All studies        
KRAS p.G13D vs codon 12 mutations1022/99 (22)80/514 (16)1.642 (1.131-2.384).0094.175.9000
KRAS p.G13D vs wild type921/92 (23)381/874 (44)0.540 (0.381-0.765).0014.040.8540
Studies with first-line treatment        
KRAS p.G13D vs codon 12 mutations418/43 (42)76/255 (30)1.378 (0.927-2.048).1130.865.8340
KRAS p.G13D vs wild type618/43 (42)237/422 (56) 0.757 (0.536-1.070).1153.010.699
Studies with second-line or subsequent treatment        
KRAS p.G13D vs codon 12 mutations84/52 (8)4/244 (2)2.822 (1.078-7.388).0351.479.9830
KRAS p.G13D vs wild type73/45 (7)132/429 (31)0.313 (0.140-0.700).0051.067.9830
Studies with cetuximab monotherapy        
KRAS p.G13D vs codon 12 mutations30/10 (0)2/95 (2)2.637 (0.434-16.031).2920.218.8970
KRAS p.G13D vs wild type40/10 (0)30/165 (18)0.616 (0.171-2.214).4581.118.7730
Studies with cetuximab combined treatment        
KRAS p.G13D vs codon 12 mutations922/85 (26)78/404 (19)1.610 (1.106-2.343).0135.060.7510
KRAS p.G13D vs wild type821/78 (27)339/686 (49)0.572 (0.404-0.809).0022.865.8970

Among patients who received cetuximab-based treatment, patients with the KRAS p.G13D mutation had a higher ORR than patients with KRAS codon 12 mutations (22% vs 16%; RR, 1.642; 95% CI, 1.131-2.384; P = .009) (Fig. 2), with no heterogeneity (I2 = 0%) between studies and with significant publication bias (t = 3.86; P = .005). The trim-and-fill method was used to adjust for publication bias, which would not have altered our results.

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Figure 2. The overall response rate (ORR) is compared between patients with metastatic colorectal cancer who had the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) p.G13D mutation (an amino acid substitution at position 13 in KRAS from a glycine to an aspartic acid) and patients who had metastatic colorectal cancer with codon 12 KRAS mutations. RR indicates relative risk; CI, confidence interval; I2, test for heterogeneity.

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Compared with patients who had wild-type KRAS tumors, patients who had tumors with the p.G13D mutation had a lower ORR (23% vs 44%; RR, 0.540; 95% CI, 0.381-0.765; P = .001) (Fig. 3), with no heterogeneity (I2 = 0%) and with no significant publication bias (t = 2.32; P = .053).

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Figure 3. The overall response rate (ORR) is compared between patients with metastatic colorectal cancer who had the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) p.G13D mutation (an amino acid substitution at position 13 in KRAS from a glycine to an aspartic acid) and patients who had metastatic colorectal cancer with wild-type KRAS. RR indicates relative risk; CI, confidence interval; I2, test for heterogeneity.

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Progression-Free Survival and Overall Survival

Information concerning KRAS p.G13D mutation status and survival (PFS and OS) were reported in 3 studies (Table 3).15-17 Only 1 study14 presented data on the HR with 95% CI for PFS and OS. Therefore, the results could not be reasonably combined in a meta-analysis. Among the patients who received cetuximab-based treatment, 3 studies15-17 reported a longer median PFS and OS in patients who had tumors with the p.G13D mutation than in patients who had tumors with KRAS codon 12 mutations, although statistical significance was reached in only 1 study (OS, 7.6 months vs 5.7 months [HR, 0.52; 95% CI, 0.33-0.80]; P = .003]; PFS, 4.0 months vs 1.9 months [HR, 0.54; 95% CI, 0.36-0.81]; P = .020).15

Table 3. Overall Survival and Progression-Free Survival According to KRAS Mutation Status
 Progression-Free SurvivalOverall Survival
Mutation StatusMedian (95% CI), moNo. of PatientsUnivariate HR (95% CI)Median (95% CI), moNo. of PatientsUnivariate HR (95% CI)
  1. Abbreviations: CI, confidence interval; HR, hazard ratio; KRAS, v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; NA, not available; p.G13D, an amino acid substitution at position 13 in KRAS from a glycine to an aspartic acid; Ref, referent category.

Patients who received any cetuximab-based treatment
De Roock 201015      
KRAS p.G13D4.0 (1.9-6.2)321.00: Ref7.6 (5.7-20.5)321: Ref
Codon 12 mutations1.9 (1.8-2.8)1940.54 (0.36-0.81)5.7 (4.9-6.8)1950.52 (0.33-0.80)
KRAS wild type4.2 (3.9-5.4)3470.99 (0.68-1.45)10.1 (9.4-11.3)3451.01 (0.66-1.54)
Patients who received cetuximab monotherapy
De Roock 201015      
KRAS p.G13D1.8 (1.7-11.0)101: Ref6.7 (3.3-20.5)101: Ref
Codon 12 mutations1.8 (1.8-1.9)910.49 (0.23-1.03)4.8 (4.0-5.9)910.66 (0.32-1.38)
KRAS wild type3.7 (2.8-4.1)1460.72 (0.35-1.48)9.4 (7.7-10.3)1460.86 (0.41-1.78)
Patients who received cetuximab plus chemotherapy
De Roock 201015      
KRAS p.G13D4.1 (2.8-6.9)221: Ref10.6 (5.7-24.6)221: Ref
Codon 12 mutations2.8 (2.5-3.7)1030.63 (0.39-1.03)7.4 (5.5-9.0)1040.50 (0.29-0.88)
KRAS wild type5.5 (4.2-5.5)2011.23 (0.79-1.94)11.3 (9.9-13.6)1991.06 (0.62-1.81)
Bando 201116      
KRAS p.G13D4.5 (1.7-)71: Ref9.3 (8.5-11.8)71: Ref
Codon 12 mutations2.3 (1.9-4.3)23NA7.4 (4.5-9.4)23NA
KRAS wild type4.6 (3.5-6.5)63NA12.2 (8.7-19.8)63NA
Tejpar 201117      
KRAS p.G13D7.4 (NA)421: Ref15.4 (NA)421: Ref
Codon 12 mutations6.4 (NA)249NA15.5 (NA)249NA
KRAS wild type9.6 (NA)398NA23.5 (NA)398NA

Compared with patients who had KRAS wild-type tumors, 3 studies15-17 reported a shorter median PFS and OS in patients who had tumors with the KRAS p.G13D mutation, but the results were not statistically significant. De Rook et al15 reported a median PFS of 4.0 months versus 4.2 months (HR, 0.99; 95% CI, 0.68-1.45; P = .970) and a median OS of 7.6 months versus 10.1 months (HR, 1.01; 95% CI, 0.66-1.54; P = .980) for patients with KRAS wild-type tumors and patients with the KRAS p.G13D mutation, respectively.

Subgroup Analyses

The results from subgroup analyses of the ORR according to treatment line and treatment regime are presented in Table 2. A significantly higher ORR was observed among patients who had the KRAS p.G13D mutation compared with those who had KRAS codon 12 mutations in the subgroups that received cetuximab as second-line or subsequent treatment (8% vs 2%; RR, 2.822; 95% CI, 1.078-7.388; P = .035) and combined cetuximab therapy (26% vs 19%; RR, 1.610; 95% CI, 1.106-2.343; P = .013), but not in the subgroups that received cetuximab as first-line treatment (42% vs 30%; RR, 1.378; 95% CI, 0.927-2.048; P = .113) or cetuximab monotherapy (0% vs 2%; RR, 2.637; 95% CI, 0.434-16.031; P = .292). Compared with patients who had wild-type KRAS tumors, patients with the KRAS p.G13D mutation had a significantly lower ORR in the subgroups that received cetuximab as second-line or subsequent treatment (7% vs 31%; RR, 0.313; 95% CI, 0.140-0.700; P = .005) and combined cetuximab therapy (27% vs 49%; RR, 0.572; 95% CI, 0.404-0.809; P = .002), but not in the subgroups that received cetuximab as first-line treatment (42% vs 56%; RR, 0.757; 95% CI, 0.536-1.030; P = .115) or cetuximab monotherapy (0% vs 18%; RR, 0.616; 95% CI, 0.171-2.214; P = .458).

Sensitivity Analyses

Sensitivity analyses were carried out by limiting the meta-analysis to studies that with sample sizes >29 patients, studies in European counties, studies with high quality, and studies that used the Response Evaluation Criteria in Solid Tumors. All results were materially unaltered, and no heterogeneity was observed, both of which suggest that the results were statistically robust (data not shown).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

The results from this systematic review suggest that patients with mCRC who have tumors with the KRAS p.G13D mutation may benefit more from cetuximab treatment than patients who have tumors with KRAS codon 12 mutations. First, our meta-analysis of 10 studies indicated that patients with the p.G13D mutation who received cetuximab had a significantly higher ORR than patients with KRAS codon 12 mutations. In addition, patients with the p.G13D mutation appeared to have longer PFS and OS than those with KRAS codon 12 mutations, although the available data were limited.

Second, among the patients who did not receive cetuximab, patients who had tumors with the KRAS p.G13D mutation appeared to have worse ORR,17 PFS,15 and OS15 than patients who had tumors with KRAS codon 12 mutations. There was significant interaction between KRAS mutation status (p.G13D mutation vs codon 12 mutations) and cetuximab treatment status with regard to ORR,17 PFS,15 and OS.15 Tejpar et al17 observed a significant interaction between KRAS mutation status (p.G13D mutation vs codon 12 mutations) and cetuximab treatment status (with vs without) with regard to the ORR (P < .0001). De Roock et al15 reported a significant interaction between KRAS mutation status and cetuximab treatment status with regard to PFS (P = .050) and OS (P = .003). These results suggest that patients with the p.G13D mutation may benefit more from cetuximab than those with KRAS codon 12 mutations.

Third, although our pooled results from 10 studies indicated that patients who had tumors with the KRAS p.G13D mutation who received cetuximab had a significantly lower ORR than those who had tumors with wild-type KRAS, no significant difference between PFS or OS was observed in any of the 3 studies that included survival data. In addition, De Roock et al15 demonstrated that there was no significant interaction between the KRAS p.G13D mutation versus wild-type KRAS and cetuximab-based treatment versus no cetuximab in terms of PFS (P = .790) and OS (P = .060). These results suggest that the survival benefits from cetuximab may be comparable in both groups of patients.

Fourth, in vitro data15 demonstrated that cells from tumors with the KRAS p.G12V mutation (an amino acid substitution at position 12 in KRAS from a glycine to a valine) were insensitive to cetuximab, whereas cells from tumors with the KRAS p.G13D mutation were nearly as responsive to cetuximab as wild-type cells. These results provide cell-based molecular evidence in support of our results indicating that patients who have tumors with the KRAS p.G13D mutation benefit from cetuximab treatment the same as patients with wild-type KRAS tumors, whereas patients who have KRAS codon 12 mutations do not.

Subgroup analyses of the ORR were performed according to the line of treatment and the treatment regimen. One study17 in the first-line treatment setting with a large sample size reported a higher ORR (40.5%, 30.5%, and 57.3% in patients with the KRAS p.G13D mutation, KRAS codon 12 mutations, and wild-type KRAS, respectively) than other studies, which resulted in a higher pooled ORR for all patients and for the patients who received cetuximab as first-line treatment. It is possible that patients with early stage, chemotherapy-responsive disease may respond better to cetuximab compared with patients who are heavily pretreated and have chemorefractory disease. In the patient subgroups that received cetuximab as first-line treatment and cetuximab monotherapy, the difference in the ORR between patients who had tumors with the p.G13D mutation and tumors with codon 12 mutations was not statistically significant, partially because of the small sample size. However, the direction of the ORR was the same as that for the subgroups of patients who received cetuximab as second-line or higher treatment and patients who received combined cetuximab therapy.

Our study has several strengths. First, we collected individual data on the ORR from 7 studies6,13,14,18-21 that did not perform a comparison between patients with the KRAS p.G13D mutation and KRAS codon 12 mutations, which significantly increased the statistical power of the analysis. Second, except for 2 abstracts,16,17 all full-text studies6,13-15,18-21 were of high quality, with an average NOS score of 7. Third, no heterogeneity was observed in any comparison. This indicated that it may be appropriate to use an overall estimate of the association between the KRAS p.G13D mutation and clinical outcomes after cetuximab treatment.

Several limitations need to be taken into account when interpreting our results. First, although all relevant studies demonstrated a trend toward longer OS and PFS in patients who had tumors with the KRAS p.G13D mutation versus those who had tumors with KRAS codon 12 mutations, only 1 study provided HR data, which limited the quantitative synthesis of evidence. Thus, more studies are needed to further clarify the relation between the KRAS p.G13D mutation and survival. Second, the number of Asian studies was relatively limited, and only 1 study was performed in Japan. Because ethnic differences in response to cetuximab have been observed, more studies conducted in Asian populations are needed to clarify the ethnic differences in the relation between the KRAS p.G13D mutation and clinical outcomes after cetuximab treatment. Third, there was evidence of publication bias with regard to the ORR of patients who had tumors with the p.G13D mutation versus KRAS codon 12 mutations. However, when we used the trim-and-fill method to adjust for publication bias, the results were not altered, indicating that our results were robust.

In conclusion, our systematic review demonstrates that patients who have mCRC with the KRAS p.G13D mutation appear to benefit more from cetuximab than those who have KRAS codon 12 mutations and should be treated differently. However, the number of studies and the number of patients included in the meta-analysis were relatively small. Large, randomized clinical trials will be needed to further confirm these findings and to clarify their clinical implications.

FUNDING SOURCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

No specific funding was disclosed.

CONFLICT OF INTEREST DISCLOSURES

The authors made no disclosures.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES
  • 1
    De Roock W, Piessevaux H, De Schutter J, et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol. 2008; 19: 508-515.
  • 2
    Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004; 351: 337-345.
  • 3
    Meyerhardt JA, Mayer RJ. Systemic therapy for colorectal cancer. N Engl J Med. 2005; 352: 476-487.
  • 4
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