BlueCross and BlueShield of Montana Medical Policy/Codes
KRAS and BRAF Mutation Analysis in Metastatic Colorectal Cancer
Chapter: Medicine: Tests
Current Effective Date: August 27, 2013
Original Effective Date: February 26, 2009
Publish Date: August 27, 2013
Revised Dates: March 1, 2010, March 21, 2012; June 28, 2013
Description

Cetuximab (Erbitux®, ImClone Systems) and panitumumab (Vectibix®, Amgen) are monoclonal antibodies that bind to the epidermal growth factor receptor (EGFR), preventing intrinsic ligand binding and activation of downstream signaling pathways vital for cancer cell proliferation, invasion, metastasis, and stimulation of neovascularization.

The RAS-RAF-MAP kinase pathway is activated in the EGFR cascade.  RAS proteins are G-proteins that cycle between active (RAS-GTP) and inactive (RAS-GDP) forms, in response to stimulation from a cell surface receptor such as EGFR, and act as a binary switch between the cell surface EGFR and downstream signaling pathways.  The KRAS gene can harbor oncogenic mutations that result in a constitutively activated protein, independent of EGFR ligand binding, rendering antibodies to the upstream EGFR ineffective.  KRAS mutations are found in approximately 30–50% of colorectal cancer tumors and are common in other tumor types.  BRAF encodes a protein kinase and is involved in intracellular signaling and cell growth and is a principal downstream effector of KRAS.  BRAF mutations occur in less than 10–15% of colorectal cancers and appear to be a marker of poor prognosis.

Cetuximab and panitumumab are approved in the treatment of metastatic colorectal cancer in the refractory disease setting, and ongoing studies are investigating the use of these EGFR inhibitors as monotherapy and as part of combination therapy in first, second, and subsequent lines of therapy.  It has been shown that patients with a KRAS mutant tumor do not respond to cetuximab or panitumumab.  However, there are still patients with KRAS wild-type tumors that do not respond to these agents, suggesting that other factors, such as alterations in other EGFR effectors could drive resistance to anti-EGFR therapy, and therefore, BRAF mutations are now increasingly being investigated in metastatic colorectal cancer.  KRAS and BRAF mutations are considered to be mutually exclusive.

KRAS and BRAF mutation analyses using polymerase chain reaction (PCR) methodology are commercially available as laboratory-developed tests.  Such tests are regulated under the Clinical Laboratory Improvement Amendments (CLIA).  Premarket approval from the U.S. Food and Drug Administration (FDA) is not required when the assay is performed in a laboratory that is licensed by CLIA for high-complexity testing.

This policy summarizes the evidence for using tumor cell KRAS and BRAF mutational status as a predictor of nonresponse to EGFR-targeted therapy with monoclonal antibodies cetuximab and panitumumab in patients with metastatic colorectal cancer.

Policy

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions.  Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Medically Necessary

BCBSMT may consider KRAS mutation analysis medically necessary to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab (Erbitux®) and panitumumab (Vectibix®) in the treatment of metastatic colorectal cancer.

Investigational 

BCBSMT considers BRAF mutation analysis experimental, investigational and unproven to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab (Erbitux®) and panitumumab (Vectibix®) in the treatment of metastatic colorectal cancer.

Federal Mandate

Federal mandate prohibits denial of any drug, device or biological product fully approved by the FDA as investigational for the Federal Employee Program (FEP). In these instances coverage of these FDA-approved technologies are reviewed on the basis of medical necessity alone.

Policy Guidelines

Effective 1/1/2012, there are specific CPT codes for KRAS and BRAF tests, and the molecular “stacking codes” should no longer be used.

Rationale

KRAS

This policy is based, in part, on a 2008 TEC Assessment.

Randomized, controlled trials (RCTs) have performed nonconcurrent subgroup analyses of the efficacy of EGFR inhibitors in patients with wild-type versus mutated KRAS in metastatic colorectal cancer.  The data from these trials have consistently shown a lack of clinical response to cetuximab and panitumumab in patients with mutated KRAS, with tumor response and prolongation of progression-free survival (PFS) observed only in wild-type KRAS patients.

Amado et al. performed a subgroup analysis of KRAS tumor mutations in a patient population that had been previously randomly assigned to panitumumab versus best supportive care as third-line therapy for chemotherapy-refractory metastatic colorectal cancer.  The original study was designed as a multicenter, RCT but was not blinded because of expected skin toxicity related to panitumumab administration.  Patients were randomly assigned 1:1 to receive panitumumab or best supportive care.  Random assignment was stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1 vs. 2) and geographic region.  Crossover from best supportive care to the panitumumab arm was allowed in patients who experienced disease progression.  Of the 232 patients originally assigned to best supportive care alone, 176 crossed over to the panitumumab arm, at a median time to crossover of seven weeks (range: 6.6–7.3). 

Of the 463 patients in the original study, 427 (92%) were included in the KRAS subgroup mutation analysis.  A central laboratory performed the KRAS mutational analysis in a blinded fashion, using formalin-fixed, paraffin-embedded (FFPE) tumor sections and a validated KRAS mutation kit (DxS Ltd, Manchester, U.K.) that identifies seven somatic mutations located in codons 12 and 13 using real-time polymerase chain reaction (PCR).  KRAS mutation status could not be determined in 36 patients because tumor samples were not available or there was insufficient or poor quality DNA.  Forty-three percent of the KRAS-evaluable patients had KRAS-mutated tumors, with similar distribution of KRAS mutation types between treatment arms.

Patient demographics and baseline characteristics were balanced between the wild-type (WT) and mutated groups (MT) for panitumumab versus best supportive care including patient age, sex, and ECOG performance status.  The interaction between mutational status and PFS was examined, controlling for randomization factors.  PFS and tumor response rate was assessed radiographically every 4-8 weeks until disease progression using Response Evaluation Criteria in Solid Tumors (RECIST) criteria by blinded, central review.  In the KRAS-assessable population, 20% of patients had a treatment-related grade 3 or 4 adverse event.  As shown in Table 1, the relative effect of panitumumab on PFS was significantly greater among patients with WT KRAS, compared with patients with MT KRAS in whom no benefit from panitumumab was observed. No responders to panitumumab were identified in the MT group, indicating a 100% positive predictive value for nonresponse in the mutant group.

Table 1. KRAS Status and Efficacy of Panitumumab as Monotherapy in the Treatment of Chemotherapy-Refractory Metastatic Colorectal Cancer (Amado, et al.)

Total n=427

KRAS WT

KRAS MT

WT : MT

243 (57%):184 (43%)

P                         BSC

n=124                 n=119

P                            BSC

n=84                      n=100 

mPFS

12.3 weeks 7.3 weeks

(HR 0.45; 95% CI: 0.34–0.59)

7.4 weeks 7.3 weeks

(HR 0.99; 95% CI: 0.73–1.36)

Response rate

17%

0%

WT: wild type; MT: mutated; P: panitumumab; BSC: best supportive care; mPFS: median progression-free survival; HR: hazard ratio; CI: confidence interval

Given the crossover design of the study and the fact that the majority of best supportive care (BSC) patients crossed over to the panitumumab arm early in the trial, conclusions of the effect of KRAS mutational status on PFS and tumor response rate endpoints are limited.  However, of the 168 BSC patients that crossed over to panitumumab after disease progression (119 with WT and 77 with MT KRAS), PFS was significantly longer among patients with WT KRAS (mPFS 16.4 weeks for WT vs. 7.9 weeks for MT; HR 0.32; 95% CI: 0.22–0.45).

After completion of the CRYSTAL trial, in which 1,198 patients with metastatic colorectal cancer were randomly assigned to receive either cetuximab (C) in combination with folinic acid [leucovorin], 5-FU, and irinotecan (FOLFIRI) or FOLFIRI alone for first-line treatment, a subgroup analysis of response rate and PFS according to KRAS mutational status was performed. The original trial design consisted of a central stratified permuted block randomization procedure with geographic regions and ECOG performance status as randomization strata.  Two interim assessments of safety data were conducted by an independent data safety monitoring board (DSMB).

Of the original 1,198 patients, 540 had KRAS-evaluable, archival material.  KRAS testing was performed from genomic DNA isolated from archived FFPE tissue, using quantitative PCR to detect the KRAS mutation status of codons 12 and 13.  It is not stated whether the KRAS mutation analysis was performed blinded; however, the data available are from a video/slide presentation only.  KRAS mutations were present in 192 patients (35.6%).  No differences were found in patient demographics or baseline characteristics between the MT and WT populations, including age, sex, ECOG performance status, involved disease sites, and liver-limited disease.  PFS and tumor response rate were assessed by a blinded, independent review committee by CT scan every eight weeks.  A multivariate analysis performed for PFS according to patient characteristics showed a trend for PFS favoring the C plus FOLFIRI combination.  The patients with WT KRAS who received C with FOLFIRI showed a statistically significant improvement in median PFS and tumor response rate, whereas the KRAS mutant population did not, as summarized in Table 2.

Table 2.  KRAS Status and Efficacy in the First-Line Therapy of Metastatic Colorectal Cancer treated with FOLFIRI with or without Cetuximab (the CRYSTAL Trial; 4) 

ITT

KRAS WT

n=348** (64.4%)

KRAS MT

n=192** (35.6%)

N

C + F

599

F

599

C  + F

172

F

176

C + F

105

F

87

Response rate (%)

46.9

(95% CI:

42.9-51.0)

38.7

(95% CI:

34.8-42.8)

59.3

(95% CI:

51.6-66.7%)

43.2

(95% CI:

35.8-50.9%)

36.2

(95% CI:

27.0-46.2%)

40.2

(95% CI: 29.9-51.3%)

P value

 

0.0025

0.46

mPFS (months)***

8.9

8.0

9.9 8.7

(HR 0.68; p=0.017)

7.6 8.1

(HR 1.07; p=0.47)

*ITT(intent to treat) in the original CRYSTAL trial assessing C+F versus F alone as first-line therapy for metastatic colorectal cancer.

**540 patients had available archival pathology material for the KRAS mutation subset analysis.

***Confidence intervals for mPFS were not provided in the presentation slides.

C: cetuximab; F: FOLFIRI; WT: wild type; MT: mutated; mPFS: median progression-free survival; HR: hazard ratio

In a third trial, the randomized, Phase II OPUS trial, the intention-to-treat (ITT) population consisted of 337 patients randomly assigned to C and folinic acid [leucovorin], 5-FU, oxaliplatin (FOLFOX) versus FOLFOX alone in the first-line treatment of metastatic colorectal cancer.  A 10% higher response rate (assessed by independent reviewers) was observed in the population treated with C, but no difference in PFS was seen between the two groups.  The researchers then re-evaluated the efficacy in the two treatment arms with consideration of KRAS mutational status of the patients’ tumors.  Of the original ITT population, 233 subjects had evaluable material for KRAS testing, and 99 (42%) were KRAS mutant.  There was no difference in demographics or baseline characteristics between the WT and MT groups, including patient age, sex, ECOG performance status, involved disease sites, and liver-limited disease.  The study showed that the addition of C to FOLFOX resulted in a significant improvement in response rate and PFS only in the WT KRAS group.  The study findings are summarized in Table 3.

Table 3.  KRAS Status and Efficacy in the First-Line Therapy of Metastatic Colorectal Cancer Treated with FOLFOX with or without Cetuximab (OPUS Study, 5)  

KRAS WT

n=134 (58%)

KRAS MT

n=99 (42%)

 

C + Fx

Fx

C + Fx

Fx

n (KRAS evaluable)

61

73

52

47

Response rate (%)

60.7%

(95% CI:

47.3-72.9%)

37.0%

(95% CI:

26.0-49.1%)

32.7%

(95% CI:

20.3-47.1)

48.9%

(95% CI:

34.1-63.9%)

p value

p=0.011

p=0.106

Odds ratio

2.54 (95% CI: 1.24-5.23)

0.51 (95% CI: 0.22-1.15)

mPFS (months)*

7.7

7.2

5.5

8.6

p value

p=0.016

p=0.0192

Hazard ratio

0.57

1.83

*Confidence intervals for mPFS were not provided in the presentation slides.

C: cetuximab; Fx: FOLFOX; WT: wild type; MT: mutated; mPFS: median progression-free survival

Single-Arm Studies (Cetuximab or Panitumumab)

In addition to the three randomized trials outlined here, several single-arm studies that retrospectively evaluated KRAS mutational status and treatment response, showed similar nonresponse to anti-EGFR monoclonal antibodies in patients with MT KRAS tumors in metastatic colorectal cancer.  These studies are summarized in Table 4.

Table 4.  Single-Arm Studies Showing Objective Response Rate (n [%]) to Anti-EGFR Monoclonal Antibodies in Chemotherapy Refractory Metastatic Colorectal Cancer

Study

Treatment

Total patients

(WT:MT)

WT

n (%)

MT

N (%)

Lievre et al. 2008

C +/- CT

89 (65:24)

34 (44)

0 (0)

De Roock et al. 2008

C +/- CT

113 (57:46)

27 (41)

0 (0)

Khambata-Ford et al. 2007

C

80 (50:30)

5 (10)

0 (0)

Di Fiore et al. 2007

C + CT

59 (43:16)

13 (28)

0 (0)

Benvenuti et al 2007

P or C or C+CT

48 (32:16)

10 (31)

1 (6)

C: cetuximab; CT: chemotherapy; P: panitumumab; WT: wild type; MT: mutated

Two of these single-arm studies also reported a difference in progression-free survival (PFS) and overall survival (OS), as summarized in Table 5.

Table 5.  Single-Arm Studies of Treatment of Metastatic Colorectal Cancer with Anti-EGFR Monoclonal Antibodies and KRAS Mutational Status  

Study/Year

Description

Results

 

 

 

 

 

Outcome

WT

MT

p value

De Roock et al. 2008

113 patients with irinotecan (I) -refractory mCRC treated with cetuximab (C) with or without I

 

 

WT:MT:

67 (59.3%):46 (40.7%)

Overall response (n=108), C+I and C

 

27/66 (41%)

0/42 (0%)

p=0.000001 (C+I) p=0.126 (C alone)

 

mPFS (C+I)

 

34 weeks (95% CI: 28.5–40.0)

12 weeks (95% CI: 5.4–18.7)

p=0.016

 

mPFS (C)

12 weeks (95% CI: 4.2–20.0)

12 weeks (95% CI: 7.0–17.0)

p=0.351

 

 

mOS (C+I)

 

44.7 weeks (95% CI: 28.4–61.0)

27.3 weeks (95% CI: 9.5–45.0)

p=0.003

 

mOS (C)

27 weeks (95% CI: 8.9–45.1)

25.3 weeks (95% CI: 0.0-70.0)

p=0.330

Lievre et al. 2008

89 patients treated with C monotherapy after treatment failure with I

Response rate

 

 

40%

 

 

0%

 

 

p<0.001

 

WT:MT:

65 (73%):24 (27%)

mPFS

31.4 weeks (95% CI: 19.4–36)

10.1 weeks (95% CI: 8–16)

p=0.0001

 

 

mOS

14.3 months (95% CI: 9.4–20)

10.1 months (95% CI: 5.1–13)

p=0.026

C: cetuximab; I: irinotecan; mCRC: metastatic colorectal cancer; WT: wild type; MT=mutated; mPFS: median progression-free survival; mOS: median overall survival

Two additional RCTs have performed nonconcurrent subgroup analyses of the efficacy of EGFR inhibitors in patients with WT versus MT KRAS in metastatic colorectal cancer.

In the CAIRO2 study, Tol and colleagues analyzed tumor samples from 528 of 755 previously untreated patients with metastatic colorectal cancer who were randomly assigned to receive capecitabine, oxaliplatin and bevacizumab (CB regimen n=378) or the same regimen plus C (CBC regimen n=377).  A KRAS mutation was found in 40% of tumors (108 from patients in the CB group and 98 from the CBC group).  Patients with KRAS mutations treated with C had significantly shorter PFS than the KRAS WT patients who received C (8.1 vs. 10.5 months, respectively, p=0.04).  In addition, patients who had MT KRAS tumors who received C had significantly shorter PFS than patients with MT KRAS tumors who did not receive C (8.1 vs. 12.5 months, respectively, p=0.003) and OS (17.2 versus 24.9 months, respectively, p=0.03).  For patients with WT tumors, there were no significant PFS differences between the two groups.  Overall, patients treated with C who had tumors with a mutated KRAS gene had significantly decreased PFS as compared with C-treated patients with WT KRAS tumors or patients with mutated KRAS tumors in the CB group. 

Karapetis and colleagues analyzed tumor samples from 394 of 572 patients (69%) with colorectal cancer who were randomly assigned to receive C plus best supportive care (n=287) versus best supportive care alone (n=285) for KRAS mutations and assessed whether mutation status was associated with survival.  The patients had advanced colorectal cancer, had failed chemotherapy and had no other standard anticancer therapy available.  Of the tumors that were evaluated (198 from the C group and 196 from the BSC group), 41% and 42% had a KRAS mutation, respectively.  In patients with WT KRAS tumors, treatment with C as compared to best supportive care alone improved OS (median, 9.5 months versus 4.8 months, respectively; hazard ratio [HR] for death 0.55; 95% CI: 0.41-0.74; p<0.001) and PFS (median, 3.7 months versus 1.9 months, respectively; HR for progression to death, 0.40; 95% CI: 0.30-0.54; p<0.001).  For patients with MT KRAS tumors, there were no significant differences between those treated with C versus best supportive care alone with respect to OS (HR, 0.98; p=0.89) or PFS (HR, 0.99; p=0.96). 

BRAF

A meta-analysis of BRAF mutation and resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer was performed.  The primary endpoint of eligible studies was objective response rate (ORR), defined as the sum of complete and partial tumor response (CR and PR).  There were a total of 11 studies (14-23), with sample sizes ranging from 31 to 259 patients.  All studies were conducted retrospectively (one study was a nonconcurrent analysis of response in a population previously randomized [23]) Anti-EGFR therapy was given as first-line treatment in one study and as second-line or greater in the other ten.  In two studies, the anti-EGFR monoclonal antibody was given as monotherapy, and in nine studies, patients received various chemotherapies.  Seven studies were performed in unselected patients (i.e., KRAS mutational status was unknown) totaling 546 patients, for whom 520 were assessable for tumor response.  In the unselected population, a BRAF mutation was detected in 8.8% of patients, and the ORR for patients with mutant BRAF was 29.2% (14/48) and for WT BRAF was 33.5% (158/472; p=0.048).  Four studies were performed in patients with WT KRAS metastatic colorectal cancer.  BRAF mutational status was performed on 376 KRAS WT tumors.  BRAF mutation was detected in 10.6% (n=40) of primary tumors.  Among the 376 analyzed, all patients were assessable for tumor response.  ORR of patients with mutant BRAF was 0% (0 of 40), whereas the ORR of patients with WT BRAF was 36.3% (122 of 336).  Only three studies presented data on PFS and OS; and therefore, a pooled analysis was not performed.  The authors conclude that although the meta-analysis provided evidence that BRAF mutation is associated with lack of response to anti-EGFR monoclonal antibodies in WT KRAS metastatic colorectal cancer, the number of studies and number of patients included in the meta analysis were relatively small and that large studies are needed to confirm the results of the meta-analysis using homogenous metastatic colorectal cancer patients with assessors blinded to the clinical data.

Phillips and colleagues analyzed the data from four studies which reported tumor response and survival in patients with mCRC treated with anti-EGFR monoclonal antibodies as related to BRAF mutational status.  Di Nicolantonio and colleagues looked retrospectively at 113 patients with mCRC who had received cetuximab or panitumumab.  None of the BRAF-mutated tumors responded to treatment (0 of 11), whereas 32.4% (22 of 68) of the BRAF WT did.  Loupakis and colleagues retrospectively assessed 87 patients receiving I and C.  Of the 87 patients in the study, BRAF was mutated in 13 cases, and none of them responded to chemotherapy, compared to 32% (24 of 74) with WT BRAF who did.  In the CAIRO2 study, a retrospective analysis of BRAF mutations was performed in 516 available tumors from patients previously randomized to CB regimen or the same regimen plus cetuximab(CBC regimen).  A BRAF mutation was found in 8.7% (n=45) of the tumors.  Patients with a BRAF mutation had a shorter median PFS and OS compared to WT BRAF tumors in both treatment arms.  The authors concluded that a BRAF mutation is a negative prognostic marker in patients with mCRC and that this effect, in contrast to KRAS mutations, is not restricted to the outcome of cetuximab treatment.  In the CRYSTAL trial, Van Cutsem and colleagues randomized 1,198 patients with untreated mCRC to FOLFIRI with or without cetuximab.  A recent analysis of BRAF mutations in this patient population and the influence on outcome was presented at the 2010 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium.  The authors showed that of the KRAS WT/BRAF-mutated patients, the OS for FOLFIRI plus cetuximab and FOLFIRI alone was 14.1 and 10.3 months, respectively (p=0.744).  Although this was not statistically significant, it showed a trend toward improved OS, PFS, and response, suggesting that KRAS wild-type/BRAF-mutant patients may benefit from anti-EGFR therapy.  This unpublished analysis is the first to show a possible benefit of anti-EGFR therapy in patients with BRAF-mutant tumors.

De Roock and colleagues reported the effects of four mutations, including BRAF, on the efficacy of cetuximab and chemotherapy in chemotherapy-refractory metastatic colorectal cancer in 773 primary tumor samples.  Tumor samples were from fresh frozen or FFPE tissue and the mutation status was compared to retrospectively collected clinical outcomes including objective response, PFS, and OS.  BRAF mutations were found in 36 of 761 tumors (4.7%).  In patients with WT KRAS, carriers of BRAF mutations had a significantly lower response rate (8.3% or 2 of 24 patients) than BRAF WT (38.0% or 124 of 326 patients; OR: 0.15; 95% CI: 0.02-0.51; p=0.0012).  PFS for BRAF-mutated versus WT was a median of 8 weeks versus 26 weeks, respectively (HR 3.74; 95% CI: 2.44-5.75; p<0.0001) and OS median 26 weeks versus 54 weeks, respectively (HR 3.03; 1.98-4.63; p<0.0001).

The National Comprehensive Cancer Network (NCCN) guidelines (January 2011) on the treatment of colon cancer recommend that tumor KRAS gene status testing be performed for all patients with metastatic colon cancer, on archived specimens of primary tumor or a metastasis, at the time of diagnosis of metastatic disease.  The guidelines indicate that cetuximab and panitumumab are only indicated for patients with tumors that express the WT KRAS gene (category 2A recommendation).  The guidelines state that there is the option of BRAF genotyping of tumor tissue at the diagnosis of KRAS WT stage IV disease but that data regarding BRAF as a predictor of response (or lack of) to anti-EGFR therapy remain inconclusive.

Summary

In summary, clinical trial data show that patients with KRAS-mutated metastatic colorectal cancer do not benefit from cetuximab or panitumumab, either as monotherapy or in combination with other treatment regimens.  These data support the use of KRAS mutation analysis of tumor DNA before considering use of cetuximab or panitumumab in a treatment regimen.  Identifying patients whose tumors express mutated KRAS will avoid exposing patients to ineffective drugs and unnecessary drug toxicities and expedites the use of alternative therapies.  Thus, KRAS mutation analysis may be considered medically necessary to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of metastatic colorectal cancer.

The data for patients with metastatic colorectal cancer and a BRAF mutation have shown consistently that a BRAF mutation is a poor prognostic marker, as it is associated with shorter PFS and OS regardless of treatment.  However, the data for a BRAF mutation predicting response to anti-EGFR therapy are limited by small numbers of patients and conflicting results among studies, with recent data (currently unpublished) from the CRYSTAL trial suggesting that patients with KRAS WT/BRAF mutant tumors may respond to anti-EGFR therapy.  Nonconcurrent subgroup analyses of BRAF mutations in patients previously randomized in the large trials in which KRAS mutations predicted nonresponsiveness to anti-EGFR therapy are necessary to confirm the current data available for BRAF mutations.

Coding

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy.  They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers.  Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

ICD-9 Codes
153.0 - 153.9, 154.0 - 154.8, 197.5
ICD-10 Codes
C18.0-C18.9, C19, C20, C78.5 
Procedural Codes: 81210, 81275, 88363, [Deleted 4/2012: S3713]
References
  1. Moroni M, Veronese S, Benvenuti S et al.  Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study.  Lancet Oncol 2005; 6(5):279-86.
  2. Van Cutsem E, Peeters M, Siena S et al.  Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer.  J Clin Oncol 2007; 25(13):1658-64.
  3. Khambata-Ford S, Garrett CR, Meropol NJ et al. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab.  J Clin Oncol 2007; 25(22):3230-7.
  4. Di Fiore F, Blanchard F, Charbonnier F et al.  Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy.  Br J Cancer 2007; 96(8):1166-9.
  5. Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F 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(6):2643-8.
  6. Karapetis CS, Khambata-Ford S, Jonker DJ et al.  K-ras mutations and benefit from cetuximab in advanced colorectal cancer.  N Engl J Med 2008; 359(17):1757-65.
  7. Lievre A, Bachet JB, Boige V et al.  KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab.  J Clin Oncol 2008; 26(3):374-9.
  8. 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(3):508-15.
  9. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC).  KRAS mutations and epidermal growth factor receptor inhibitor therapy in metastatic colorectal cancer.  TEC Assessments 2008; Volume 23, Tab 6.
  10. Amado RG, Wolf M, Peeters M et al.  Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer.  J Clin Oncol 2008; 26(10):1626-34.
  11. Cappuzzo F, Varella-Garcia M, Finocchiaro G et al.  Primary resistance to cetuximab therapy in EGFR FISH-positive colorectal cancer patients.  Br J Cancer 2008; 99(1):83–9.
  12. Di Nicolantonio F, Martini M, Molinari F et al.  Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer.  J Clin Oncol 2008; 26(35):5705–12.
  13. Freeman DJ, Juan T, Reiner M et al.  Association of K-ras mutational status and clinical outcomes in patients with metastatic colorectal cancer receiving panitumumab alone.  Clin Colorectal Cancer 2008; 7(3):184–90.
  14. Laurent-Puig P, Cayre A, Manceau G et al.  Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer.  J Clin Oncol 2009; 27(35):5924–30.
  15. Loupakis F, Ruzzo A, Cremolini C et al.  KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer.  Br J Cancer 2009; 101(4):715–21.
  16. Molinari F, Martin V, Saletti P et al.  Differing deregulation of EGFR and downstream proteins in primary colorectal cancer and related metastatic sites may be clinically relevant.  Br J Cancer 2009; 100(7):1087–94.
  17. Perrone F, Lampis A, Orsenigo M et al.  PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients.  Ann Oncol 2009; 20(1):84–90.
  18. Sartore-Bianchi A, Di Nicolantonio F, Nichelatti M et al.  Multi-determinants analysis of molecular alterations for predicting clinical benefit to EGFR-targeted monoclonal antibodies in colorectal cancer.  PLoS One 2009; 4(10):e7287.
  19. Tol J, Nagtegaal ID, Punt CJ.  BRAF mutation in metastatic colorectal cancer.  N Engl J Med 2009; 361(1):98–9.
  20. Van Cutsem E, Kohne CH, Hitre E et al.  Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer.  N Engl J Med 2009; 360(14):1408-17.
  21. Bokemeyer C , Bondarenko I , Makhson A et al.  Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer.  J Clin Oncol 2009; 27(5):663-71.
  22. Tol J, Koopman M, Cats A et al.  Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer.  N Engl J Med 2009; 360(6):563-72.
  23. Mao C, Liao RY, Qiu LX et al.  BRAF V600E mutation and resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer: a meta-analysis.  Mol Biol Rep 2010 [Epub ahead of print]
  24. Phillips B, Kalady M, Kim R.  BRAF testing in advanced colorectal cancer: is it ready for prime time?  Clin Adv Hematol Oncol 2010; 8(6):437-44.
  25. Van Cutsem E, Lang I, Folprecht G et al.  Cetuximab plus FOLFIRI in the treatment of metastatic colorectal cancer (mCRC): the influence of KRAS and BRAF biomarkers on outcome: updated data from the CRYSTAL trial.  Paper presented at: American Society of Clinical Oncology 2010 Gastrointestinal Cancers Symposium (GCS); January 22-24, 2010; Orlando, FL.
  26. De Roock W, Claes B, Bernasconi D 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.  Lancet Oncol 2010; 11(8):753-62.
  27. National Comprehensive Cancer Network.  Clinical Practice Guidelines in Oncology. Colon cancer.  Version 1.2011.  Available online at: www.nccn.org Last accessed October 2010.
  28. KRAS and BRAF Mutation Analysis in Metastatic Colorectal Cancer.  Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2010 November) Surgery 2.04.53.
History
April 29, 2011 Title changed to indicate inclusion of BRAF testing; BRAF testing policy statement added as investigational to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of metastatic colorectal cancer; KRAS policy statement unchanged. References updated.  
March 2012 Policy updated with literature search. References 27-34 added. Policy statement changed from Not Medically Necessary to Investigational.   
August 2013 Policy formatting and language revised.  Policy statement unchanged.
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KRAS and BRAF Mutation Analysis in Metastatic Colorectal Cancer