Skip to content

Advertisement

  • Research article
  • Open Access
  • Open Peer Review

This article has Open Peer Review reports available.

How does Open Peer Review work?

The impact of KRAS mutations on prognosis in surgically resected colorectal cancer patients with liver and lung metastases: a retrospective analysis

  • Hae Su Kim1, 5,
  • Jin Seok Heo2,
  • Jeeyun Lee1,
  • Ji Yun  Lee1,
  • Min-Young Lee1,
  • Sung Hee Lim1,
  • Woo Yong Lee2,
  • Seok Hyung Kim3,
  • Yoon Ah Park2,
  • Yong Beom Cho2,
  • Seong Hyeon Yun2,
  • Seung Tae Kim1,
  • Joon Oh Park1,
  • Ho Yeong Lim1,
  • Yong Soo Choi4,
  • Woo Il Kwon2,
  • Hee Cheol Kim2Email author and
  • Young Suk Park1Email author
Contributed equally
BMC Cancer201616:120

https://doi.org/10.1186/s12885-016-2141-4

Received: 5 February 2015

Accepted: 8 February 2016

Published: 18 February 2016

Abstract

Background

KRAS mutations are common in colorectal cancer (CRC). The role of KRAS mutation status as a prognostic factor remains controversial, and most large population-based cohorts usually consist of patients with non-metastatic CRC. We evaluated the impact of KRAS mutations on the time to recurrence (TTR) and overall survival (OS) in patients with metastatic CRC who underwent curative surgery with perioperative chemotherapy.

Methods

Patients who underwent curative resection for primary and synchronous metastases were retrospectively collected in a single institution during a 6 year period between January 2008 and June 2014. Patients with positive surgical margins, those with known BRAF mutation, or those with an unknown KRAS mutation status were excluded, and a total of 82 cases were identified. The pathological and clinical features were evaluated. Patients’ outcome with KRAS mutation status for TTR and OS were investigated by univariate and multivariate analysis.

Results

KRAS mutations were identified in 37.8 % of the patients and not associated with TTR or OS between KRAS wild type and KRAS mutation cohorts (log-rank p = 0.425 for TTR; log-rank p = 0.137 for OS). When patients were further subdivided into three groups according to mutation subtype (wild-type vs. KRAS codon 12 mutation vs. KRAS codon 13 mutation) or amino acid missense mutation type (G > A vs. G > T vs. G > C), there were no significant differences in TTR or OS. Mutational frequencies were significantly higher in patients with lung metastases compared with those with liver and ovary/bladder metastases (p = 0.039), however, KRAS mutation status was not associated with an increased risk of relapsed in the lung.

Conclusions

KRAS mutation was not associated with TTR or OS in patients with metastatic CRC who underwent curative surgery with perioperative chemotherapy.

Keywords

Colorectal cancerKRAS mutationPrognosisMetastases

Background

Colorectal cancer (CRC) is the fourth leading cause of cancer-related death worldwide [1]. Although the development of molecular-targeted therapy has improved the survival of patients with metastatic CRC [2, 3], the majority of patients with stage IV CRC who undergo complete resection die from metastatic disease. Nevertheless, a good proportion of patients demonstrate good recurrence-free survival. CRC tumorigenesis is characterized by the accumulation of genetic alterations, and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are an early event in tumorigenesis [4]. KRAS mutations occur in approximately 30 to 40 % of patients with CRC, and 90 % of KRAS mutations occur in codon 12 or 13 [2, 5, 6]. KRAS mutations lead to constitutive activation of downstream pathways, including the Ras/Raf/MAP/MEK/ERK and/or PTEN/PI3K/Akt pathways [710]. KRAS mutations are established biomarkers for predicting the poor efficacy of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies in patients with stage IV CRC [2, 5, 11], but the prognostic relevance of KRAS mutations remains controversial [1216]. Recent studies, in patients with resected stage II and/or III CRC, have highlighted the prognostic value of KRAS codon12 and 13 mutations, showing correlations between mutation subtype, cancer recurrence, and poor overall survival [1315].

Large population-based cohorts usually consist of patients with non-metastatic CRC [12, 14, 16, 17]. The prognostic impact of KRAS mutation in patients with synchronous metastatic CRC who undergo curative resection with perioperative chemotherapy is unknown. The current study investigated the impact of KRAS mutations on the time to recurrence (TTR) and overall survival (OS) in patients with stage IV CRC who underwent curative surgery with perioperative chemotherapy. In addition, the recurrence pattern according to KRAS mutation status after complete resection was evaluated.

Methods

Patients

In this retrospective study, patients who underwent curative resection for primary and synchronous metastases at our institution between January 2008 and June 2014 were identified from the hospital records. Patients who underwent separate colorectal resection and metastasectomy were excluded if the duration between the two procedures exceeded 2 months. Patients with positive surgical margins, those with known v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutations, or those with an unknown KRAS mutation status were also excluded. All patients included in the study were administered 5-FU with/without oxaliplatin or irinotecan-based chemotherapy. Clinical and pathological data including sex, patient age, tumor location, resection site, staging at surgery (performed in accordance with the classification of the 6th Edition of the American Joint Committee on Cancer guidelines), BRAF mutation status, perioperative chemotherapy regimens, use of molecular targeting agents including cetuximab and bevacizumab, were collected. The study protocol was reviewed and approved by the SMC institutional review board.

Perioperative chemotherapy regimens

Oxaliplatin based chemotherapy was FOLFOX (oxaliplatin 85 mg/m2 on day 1, infused during 2 h; LV 200 mg/m2, infused during 2 h, followed by 5-FU as a 400 mg/m2 intravenous bolus then a 1200 mg/m2 infusion during 22 h on days 1 and 2) in 2 week treatment cycles or XELOX(oxaliplatin 130 mg/m2 on day 1 followed by oral capecitabine 1000 mg/m2 twice daily (day 1 to 14) in 3 week treatment cycles. Irinotecan based chemotherapy was FORFIRI (irinotecan 180 mg/m2 on day 1, infused during 2 h; LV 200 mg/m2, infused during 2 h, followed by 5-FU as a 400 mg/m2 intravenous bolus then a 1200 mg/m2 infusion during 22 h on days 1 and 2) in 2 week treatment cycles or XELIRI (irinotecan 250 mg/m2 on day 1 followed by oral capecitabine 1000 mg/m2 twice daily (day 1 to 14) in 3 week treatment cycles. If bevacizumab or cetuximab was used, patients received cetuximab (initial dose 400 mg/m2 infused during 2 h, and 250 mg/m2 weekly) or bevacizumab (5 mg/kg) followed by FOLFOX or FOLFIRI.

DNA extraction and mutation analysis

DNA was isolated from 10-μm formalin-fixed, paraffin-embedded tumor specimens using FFPE-DNA isolation kit (Qiagen, Hilden, Germany). A Qiagen the rascreen KRAS mutation kit was used to detect the seven most common KRAS codon 12 and 13 mutations. Specifically, the mutation was detected by real-time polymerase chain reaction based on amplification-refractory mutation system and Scorpion probes (Gly12Asp [GGT > GAT] G12D, Gly12Val [GGT > GAC] G12V, Gly12Cys [GGT > TGT] G12C, Gly12Ser [GGT > AGT] G12S, Gly12Ala [GGT > GCT] G12A, Gly12Arg [GGT > CGT] G12R, Gly13Asp [GGC > GAC] G13D).

Statistical analyses

Patients were subdivided into wild-type KRAS and mutant KRAS cohorts. The primary objective was to investigate the effect of KRAS mutation on the TTR. TTR was defined as the time from the date of operation to the date of local or metastatic recurrence. As of November 2014, overall survival data are not yet available for the mutant KRAS group. Data from recurrence-free patients were censored at the date of the last follow-up.

To compare baseline characteristics, categorical outcomes were analyzed using the chi-square test or Fisher’s exact test. Continuous variables are presented as medians and ranges. TTR and OS were calculated using the Kaplan-Meier method, and data was compared using the log-rank test. The Cox proportional hazard model was used to assess hazard ratios (HRs) of prognostic factor. All factors of statistical significance (p < 0.10) in univariate analysis were included in the multivariate analysis. Two-sided p values of <0.05 were considered as statistically significant. All statistical analyses were performed using the SPSS statistical software version 21 (IBM, Armonk, NY. USA).

Results

Patient characteristics

Between January 2008 and June 2014, 82 patients who were diagnosed with synchronous metastatic CRC and underwent curative resection of primary and metastatic lesions with perioperative chemotherapy were included in the analyses. Table 1 summarizes the patient characteristics according to KRAS mutation status. There was no significant difference in clinicopathologic features between the two groups. Baseline characteristics including age, sex, tumor location, tumor grade, T stage, N stage, synchronous metastasectomy site, and recurrence site were similar between the KRAS wild type and KRAS mutation cohorts. Regarding BRAF mutation status, all of the tested cases (76.8 %) were BRAF wild type.
Table 1

Baseline characteristics according to KRAS mutation status

Characteristics

No. of patients

KRAS

wild-type

mutant

p-value

(n = 82)

(n = 51)

(n = 31)

Age, year, Median (range)

55.8 (25–77)

58.8 (25–77)

55.5 (29–77)

0.565

≥65 years

17 (21 %)

12 (24 %)

5 (16 %)

0.423

Sex

   

0.867

 Male

44 (54 %)

27 (53 %)

17 (55 %)

 Female

38 (46 %)

24 (47 %)

14 (45 %)

Location

   

0.246

 Colon

54 (66 %)

36 (71 %)

18 (58 %)

 Rectum

28 (34 %)

15 (29 %)

13 (42 %)

Neoadjuvant Chemotherapy

21 (26 %)

11 (22 %)

10 (32 %)

0.282

Resection site

   

0.039

 Liver

57 (69 %)

39 (76 %)

18 (58 %)

 Lung

13 (16 %)

4 (8 %)

9 (29 %)

 Others (ovary, bladder)

12 (15 %)

8 (16 %)

4 (13 %)

Tumor grade

   

0.432

 Well

10 (12 %)

7 (14 %)

3 (10 %)

 Moderate/Poor

72 (78 %)

44 (86 %)

28 (90 %)

T stage

   

0.265

 T1

1 (1 %)

1 (2 %)

0 (0 %)

 T2

2 (2 %)

2 (4 %)

0 (0 %)

 T3

47 (57 %)

30 (59 %)

17 (55 %)

 T4

30 (37 %)

18 (35 %)

12 (39 %)

 Tx

2 (2 %)

0 (0 %)

2 (6 %)

N stage

   

0.824

 N0

12 (15 %)

8 (16 %)

4 (13 %)

 N1

31 (38 %)

18 (35 %)

13 (42 %)

 N2

39 (47 %)

25 (49 %)

14 (45 %)

1st Adjuvant Chemo-Regimen

   

0.923

 Oxaliplatin-based

70 (86 %)

44 (86 %)

26 (84 %)

 Irinotecan-based

10 (12 %)

6 (12 %)

4 (13 %)

 Only 5-FU

2 (2 %)

1 (2 %)

1 (3 %)

Use of Cetuximab at 1st post-operative chemotherapy

4 (5 %)

4 (8 %)

0 (0 %)

NA

Use of Becavizumab at 1st post-operativechemotherapy

13 (16 %)

6 (12 %)

7 (23 %)

0.194

Ever use of Cetuximab

16 (20 %)

16 (31 %)

0 (0 %)

NA

Ever use of Bevacizumab

23 (28 %)

10 (20 %)

13 (42 %)

0.029

Recurrence pattern (n = 57)

   

0.616

 Primary site

3 (5 %)

1 (2 %)

2 (8 %)

 Metastasectomy site

27 (47 %)

15 (46 %)

12 (50 %)

 New distant sites

27 (47 %)

17 (52 %)

10 (42 %)

Duration of follow up month, median (range)

25 (4–74)

25 (4–74)

34 (9–63)

0.763

Abbreviations: CI confidence interval, A.A amino acid

Subtype of KRAS mutations

Of 82 patients, KRAS mutations were detected in 31 (37.8 %) patients. Eighteen (58 %) patients harbored codon 12 mutations including 9 with c.35G > A (p.G12D, codon 12 GGT > GAT), 5 with c.35G > T (pG12V, codon 12 GGT > GTT), 2 with c.35G > C (p.G12A, codon 12 GGT > GCT), and 2 with c.34G > A (p.G12S, codon 12 GGT > AGT). For the 13 (42 %) patients with codon 13 mutations, all had the c.38G > A (p.G13D, codon 13 GGC > GAC) mutation. KRAS amino acid mutations were also analyzed. The G > A missense mutation was the most frequently observed mutation, followed by the G > T and G > C mutations.

The impact of KRAS mutations on TTR and OS

The median follow-up durations were 25 months (range, 4–74) and 34 months (range, 9–63) for patients with KRAS wild type and KRAS mutation status, respectively. During follow-up in surviving participants, there were 57 events for TTR analysis and 25 events for OS analysis. There were no significant differences in survival time distributions according to KRAS wild type and KRAS mutation status (log-rank p = 0.425 for TTR; log-rank p = 0.137 for OS, Fig. 1). In univariate and multivariate analyses, there were no significant differences in TTR or OS between KRAS wild type and KRAS mutation cohorts (Tables 2, 3 and 4). When patients were further subdivided into three groups according to mutation subtype (wild-type vs. KRAS codon 12 mutation vs. KRAS codon 13 mutation) or amino acid missense mutation type (G > A vs. G > T vs. G > C), there were no significant differences in TTR or OS.
Figure 1
Fig. 1

Time to recurrence (a) and overall survival (b) according to KRAS status. KRAS mutation status had no impact on time to recurrence (p = 0.425) and overall survival (p = 0.137)

Table 2

Univariate analysis for time to recurrence

Characteristics

Hazard ratio (95 % CI)

p-value

Location of primary tumor (rectum vs colon)

0.956 (0.548–1.669)

0.875

Age (≥65 vs <65)

0.856 (0.418–1.755)

0.671

Sex (female vs male)

0.678 (0.399–1.150)

0.150

Neoadjuvant chemotherapy (Yes vs No)

1.040 (0.563–1.923)

0.899

Tumor grade (moderate/poor vs well)

1.201 (0.508–2.843)

0.676

T stage (T4 vs T1-3)

1.041 (0.608–1.782)

0.885

N stage (N2 vs N0,1)

1.197 (0.703–2.037)

0.508

Resection site

  

 Liver

1

 

 Lung

0.694 (0.311–1.550)

0.373

 Others (ovary, uterus, bladder)

0.670 (0.299–1.502)

0.331

Use of Cetuximab at 1st post-operative chemotherapy (Yes vs No)

0.589 (0.143–2.425)

0.463

Use of Bevacizumab at 1st post-operative chemotherapy (Yes vs No)

0.582 (0.231–1.469)

0.252

KRAS (mutation vs wild)

1.245 (0.725–2.137)

1.245

KRAS subtype

  

 Wild

1

 

 12th

1.127 (0.599–2.123)

0.710

 13th

1.230 (0.561–2.697)

0.605

A.A Mutation type

  

 Wild (n = 51)

1

 

 Guanine to thymidine (n = 5)

0.737 (0.164–3.315)

0.691

 Guanine to cytosine (n = 2)

1.482 (0.766–2.864)

0.242

 Guanine to adenine (n = 24)

1.029 (0.553–1.931)

0.928

Abbreviations: CI confidence interval, A.A amino acid, HR hazard ratio

Table 3

Univariate analysis for overall survival

Characteristics

HR (95 % CI)

p-value

Location of primary tumor (rectum vs colon)

0.531 (0.212–1.333)

0.178

Age (≥65 vs <65)

7.492 (2.941–9.084)

<0.001

Sex (female vs male)

2.038 (0.908–4.578)

0.085

Neoadjuvant chemotherapy (Yes vs No)

1.114 (0.460–2.698)

0.811

Tumor grade (moderate/poor vs well)

1.332 (0.312–5.693)

0.698

T stage (T4 vs T1-3)

4.324 (1.857–10.068)

0.001

N stage (N2 vs N0,1)

1.906 (0.854–4.251)

0.115

Resection site

  

 Liver

1

 

 Lung

0.311 (0.041–2.335)

0.256

 Others (ovary, uterus, bladder)

1.036 (0.345–3.108)

0.950

Use of Cetuximab at 1st post-operative chemotherapy (Yes vs No)

3.777 (0.850–16.779)

0.081

Use of Bevacizumab at 1st post-operative chemotherapy (Yes vs No)

0.899 (0.267–3.027)

0.863

KRAS (mutation vs mutation)

0.500(0.198–1.267)

0.144

KRAS

  

 Wild

1

 

 12th

0.330 (0.076–1.428)

0.138

 13th

0.675 (0.227–2.010)

0.481

Abbreviations: CI confidence interval, A.A amino acid, HR hazard ratio

Factors of statistical significance (p < 0.10) in univariate analysis presented with boldface

Table 4

Multivariate analysis for overall survival

Characteristics

HR (95 % CI)

p-value

Age (≥65 vs <65)

9.749 (3.404–27.919)

<0.001

Sex (female vs male)

3.070 (1.260–7.478)

0.014

T stage (T4 vs T1-3)

3.511 (1.484–8.307)

0.004

Use of Cetuximab at 1st post-operative chemotherapy (Yes vs No)

1.185 (0.235–5.979)

0.837

Abbreviations: CI confidence interval A.A amino acid; HR, hazard ratio

The effect of KRAS mutation status on the recurrence site

Mutational frequencies were significantly higher in patients with lung metastases compared with those with liver and ovary/bladder metastases (KRAS mutant: lung 9/13 [69 %], liver 18/57 [31 %], ovary/bladder 4/12 [33 %]; p = 0.039). However, KRAS mutation status was not associated with an increased risk of relapse in the lung, and the majority of recurrence occurred at the previous metastasectomy sites (15/33 vs. 24/31 for KRAS wild type vs. KRAS mutation, respectively).

Discussion

The majority of studies evaluating the prognostic impact of KRAS mutational status in CRC have been conducted in patients with stage II/III disease. The QUASAR trial, which mainly evaluated patients with stage II CRC, revealed that KRAS mutations had a detrimental effect on recurrence and OS, despite adjuvant chemotherapy [17]. In contrast, the CALGB 89803 and PETACC-3 trials demonstrated that KRAS mutation status had no significant effect on recurrence or OS in patients with stage II/III colon cancer or CRC treated with adjuvant chemotherapy [12, 16]. However, conflicting findings were reported simultaneously in two large studies conducted by The Kirsten ras in-colorectal-cancer collaborative group, the RASCAL and RASCAL II trials, which were comprised of 2721 and 4268 patients, respectively [18, 19]. Although the first RASCAL study reported an association of KRAS mutations with an increased risk of recurrence and death for patients with all stages of CRC, recurrence in patients with Dukes’ D tumors was less than might be expected. The RASCAL II study concluded that there was a significant prognostic value in failure-free survival alone in patients with Dukes’ C cancer harboring a KRAS G12V mutation.

Few studies have evaluated the relationship between patients with stage IV disease at the time of diagnosis and KRAS mutations [2023]. Patients with metastatic CRC with limited metastases undergo curative primary resection with or without metastasectomy, anti-EGFR antibody therapy, and heterogeneous chemotherapy regimens, making it difficult to evaluate the precise prognostic value of KRAS status in this setting. To overcome this limitation, in this study, we included only patients who underwent curative resection of the primary and metastatic sites who received perioperative chemotherapy. To our knowledge, this study is the first to report TTR in such patients. In this homogenous cohort of Korean patients with metastatic CRC, we observed that KRAS mutation was not associated with TTR or OS, which is congruent with previous studies [2022]. Phipps et al., reported that KRAS mutations did not differ by stage at diagnosis, and that the prognostic value of KRAS mutations only became evident in patients with stage I-III disease [22]. Furthermore, Nash et al., reported that the prevalence of KRAS mutations did not vary with stage, but that KRAS mutations were strong independent predictors of survival for patients with stage I-III CRC [21].

We also investigated the association KRAS mutations with recurrence pattern in our cohort. KRAS mutations were significantly more common in lung metastases compared with liver and bladder/ovary metastases. These finding were concordant with those of Tie et al., who observed a significantly higher prevalence of KRAS mutations in patients with lung metastases compared with those with liver metastases [24]. In addition, in their study, KRAS mutations were associated with an increased risk of lung relapse in patients with stage II/III CRC who were enrolled on the VICTOR clinical trial [21]. However, in the present study, we did not observe recurrence-specific associations with KRAS mutation status. The differential impact of KRAS mutations on recurrence-specific sites according to disease stage requires evaluation in further studies.

Limitations of the present study included the relatively short follow-up, where the median OS was not reached in the KRAS mutation group. Nevertheless, sufficient TTR events occured enabling analysis of recurrence. In addition, the BRAF mutation status was not determined for 19 (33 %) patients, but BRAF mutations were only detected in a small proportion of patient and were not significantly different between KRAS wild type and KRAS mutated patients. In addition, the small sample size did not allow us to evaluate the impact of different KRAS mutation subtypes.

In conclusion, KRAS mutation was not associated with TTR or OS in curatively resected, metastatic CRC. Further validation of these finding is needed in metastatic CRC patients treated with curative resection in prospective controlled trials.

Conclusions

The present study, to our knowledge, is the first report on the effect of KRAS mutations on prognosis in surgically treated CRC patients with synchronous metastases. The most of previous studies evaluating the prognostic impact of KRAS in CRC have been conducted in patients with non-metastatic CRC, and the influence of KRAS mutations on outcome is conflicting. In our study, KRAS mutation was not associated with TTR or OS in metastatic CRC patients who undergo curative surgery and perioperative chemotherapy. KRAS mutation status was also not linked to recurrence pattern. Prospective studies will be necessary to evaluate the prognostic effect of KRAS mutation in metastatic CRC patients.

Consent

This research is strictly retrospective and involving the collection of existing data and records. The study protocol was reviewed and approved consent exemptions by the SMC institutional review board.

Notes

Abbreviations

BRAF: 

v-Raf murine sarcoma viral oncogene homolog B

CIs: 

Confidence intervals

CRC: 

Colorectal cancer

EGFR: 

Epidermal growth factor receptor

KRAS: 

V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog

OS: 

Overall survival

TTR: 

Time to recurrence

Declarations

Acknowledgements

This work was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI14C2750, and HI14C3418).

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
(2)
Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
(3)
Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
(4)
Thoracic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
(5)
Division of Hematology-Oncology, Department of Medicine, Veterans Health Service Medical Center, Seoul, Korea

References

  1. Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 2011;61:212–36.View ArticlePubMedGoogle Scholar
  2. 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. N Engl J Med. 2008;359:1757–65.View ArticlePubMedGoogle Scholar
  3. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–42.View ArticlePubMedGoogle Scholar
  4. Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, et al. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988;319:525–32.View ArticlePubMedGoogle Scholar
  5. Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360:1408–17.View ArticlePubMedGoogle Scholar
  6. Nosho K, Irahara N, Shima K, Kure S, Kirkner GJ, Schernhammer ES, et al. Comprehensive biostatistical analysis of CpG island methylator phenotype in colorectal cancer using a large population-based sample. PLoS One. 2008;3:e3698.View ArticlePubMedPubMed CentralGoogle Scholar
  7. Bos JL, Fearon ER, Hamilton SR, Verlaan-de Vries M, van Boom JH, van der Eb AJ, et al. Prevalence of ras gene mutations in human colorectal cancers. Nature. 1987;327:293–7.View ArticlePubMedGoogle Scholar
  8. Di Fiore F, Blanchard F, Charbonnier F, Le Pessot F, Lamy A, Galais MP, et al. Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by Cetuximab plus chemotherapy. Br J Cancer. 2007;96:1166–9.View ArticlePubMedPubMed CentralGoogle Scholar
  9. Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, Zanon C, Moroni M, Veronese S, et al. Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res. 2007;67:2643–8.View ArticlePubMedGoogle Scholar
  10. Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004;116:855–67.View ArticlePubMedGoogle Scholar
  11. 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. J Clin Oncol. 2009;27:663–71.View ArticlePubMedGoogle Scholar
  12. Roth AD, Tejpar S, Delorenzi M, Yan P, Fiocca R, Klingbiel D, et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60–00 trial. J Clin Oncol. 2010;28:466–74.View ArticlePubMedGoogle Scholar
  13. Imamura Y, Morikawa T, Liao X, Lochhead P, Kuchiba A, Yamauchi M, et al. Specific mutations in KRAS codons 12 and 13, and patient prognosis in 1075 BRAF wild-type colorectal cancers. Clin Cancer Res. 2012;18:4753–63.View ArticlePubMedPubMed CentralGoogle Scholar
  14. Blons H, Emile JF, Le Malicot K, Julie C, Zaanan A, Tabernero J, et al. Prognostic value of KRAS mutations in stage III colon cancer: post hoc analysis of the PETACC8 phase III trial dataset. Ann Oncol. 2014;25:2378–85.View ArticlePubMedGoogle Scholar
  15. Lee DW, Kim KJ, Han SW, Lee HJ, Rhee YY, Bae JM, et al. KRAS Mutation is Associated with Worse Prognosis in Stage III or High-risk Stage II Colon Cancer Patients Treated with Adjuvant FOLFOX. Ann Surg Oncol. 2015;22:187–94.View ArticlePubMedGoogle Scholar
  16. Ogino S, Meyerhardt JA, Irahara N, Niedzwiecki D, Hollis D, Saltz LB, et al. KRAS mutation in stage III colon cancer and clinical outcome following intergroup trial CALGB 89803. Clin Cancer Res. 2009;15:7322–9.View ArticlePubMedPubMed CentralGoogle Scholar
  17. Hutchins G, Southward K, Handley K, Magill L, Beaumont C, Stahlschmidt J, et al. Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer. J Clin Oncol. 2011;29:1261–70.View ArticlePubMedGoogle Scholar
  18. Andreyev HJ, Norman AR, Cunningham D, Oates JR, Clarke PA. Kirsten ras mutations in patients with colorectal cancer: the multicenter “RASCAL” study. J Natl Cancer Inst. 1998;90:675–84.View ArticlePubMedGoogle Scholar
  19. Andreyev HJ, Norman AR, Cunningham D, Oates J, Dix BR, Iacopetta BJ, et al. Kirsten ras mutations in patients with colorectal cancer: the ‘RASCAL II’ study. Br J Cancer. 2001;85:692–6.View ArticlePubMedPubMed CentralGoogle Scholar
  20. Inoue Y, Saigusa S, Iwata T, Okugawa Y, Toiyama Y, Tanaka K, et al. The prognostic value of KRAS mutations in patients with colorectal cancer. Oncol Rep. 2012;28:1579–84.View ArticlePubMedGoogle Scholar
  21. Nash GM, Gimbel M, Cohen AM, Zeng ZS, Ndubuisi MI, Nathanson DR, et al. KRAS mutation and microsatellite instability: two genetic markers of early tumor development that influence the prognosis of colorectal cancer. Ann Surg Oncol. 2010;17:416–24.View ArticlePubMedGoogle Scholar
  22. Phipps AI, Buchanan DD, Makar KW, Win AK, Baron JA, Lindor NM, et al. KRAS-mutation status in relation to colorectal cancer survival: the joint impact of correlated tumour markers. Br J Cancer. 2013;108:1757–64.View ArticlePubMedPubMed CentralGoogle Scholar
  23. Perez-Ruiz E, Rueda A, Pereda T, Alcaide J, Bautista D, Rivas-Ruiz F, et al. Involvement of K-RAS mutations and amino acid substitutions in the survival of metastatic colorectal cancer patients. Tumour Biol. 2012;33:1829–35.View ArticlePubMedGoogle Scholar
  24. Tie J, Lipton L, Desai J, Gibbs P, Jorissen RN, Christie M, et al. KRAS mutation is associated with lung metastasis in patients with curatively resected colorectal cancer. Clin Cancer Res. 2011;17:1122–30.View ArticlePubMedGoogle Scholar

Copyright

© Kim et al. 2016

Advertisement