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MP 2.04.53

KRAS, NRAS and BRAF Mutation Analysis in Metastatic Colorectal Cancer


Medical Policy

 

 

Section
Medicine

Original Policy Date
10/2008

Last Review Status/Date
Reviewed with literature review/12:2014

Issue
12:2014

 

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Disclaimer
Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.


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 ofKRAS. BRAF mutations occur in less than 10% to 15% of colorectal cancers and appear to be a marker of poor prognosis. KRAS and BRAF mutations are considered to be mutually exclusive.

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.

Regulatory Status

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


 

Policy

KRAS mutation analysis may be considered medically necessary for patients with metastatic colorectal cancer to predict nonresponse prior to planned therapy with anti-EGFR monoclonal antibodies cetuximab or panitumumab.

NRAS mutation analysis is considered investigational to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of metastatic colorectal cancer.

BRAF mutation analysis is considered investigational to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of metastatic colorectal cancer.


 

Policy Guidelines

Effective in 2012, there are specific CPT codes for KRAS or BRAF mutation analysis.

81210: BRAF (v-raf murine sarcoma viral oncogene homolog B1) (eg, colon cancer), gene analysis, V600E variant
81275: KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene) (eg, carcinoma) gene analysis, variants in codons 12 and 13

Additionally, code 81403 would be reported for KRAS testing for variant(s) in exon 3 (eg, codon 61).

Code 81404 includes the following NRAS testing:

NRAS (neuroblastoma RAS viral oncogene homolog)(eg, colorectal carcinoma), exon 1 and exon 2 sequences.

Prior to 2012, multiple codes describing genetic analysis would likely be used to report this testing (eg, codes from 83890-83912).

Between October 2009 and April 2012, there was a HCPCS “S” code specific to KRAS testing:

S3713: KRAS mutation analysis testing.

In 2011, a new CPT code was added for using archival tissue for molecular analysis:

88363: Examination and selection of retrieved archival (ie, previously diagnosed) tissue(s) for molecular analysis (eg, KRAS mutational analysis).


Benefit Application
BlueCard/National Account Issues

 

State or federal mandates (e.g., FEP) may dictate that all devices approved by the U.S. Food and Drug Administration (FDA) may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.


Rationale

 

This policy was created in 2008 and updated regularly with reviews of the MEDLINE and EMBASE databases. The most recent literature review was performed for the period October 16, 2013 through September 30, 2014.

KRAS

This policy is based, in part, on a 2008 TEC Assessment.(1) Additional evidence is available from randomized controlled trials (RCTs) and single-arm studies, organized and outlined below.

Randomized Controlled Trials

RCTs have performed nonconcurrent subgroup analyses of the efficacy of epidermal growth factor receptor (EGFR) inhibitors in patients with wild-type (WT) versus mutated KRAS in metastatic colorectal cancer (CRC). 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 progressionfree survival (PFS) observed only in WT KRAS patients.

Amado et al(2) performed a subgroup analysis of KRAS tumor mutations in a patient population that had previously been randomly assigned to panitumumab versus best supportive care as third-line therapy for chemotherapy-refractory metastatic CRC. The original study was designed as a multicenter, RCT but was not blinded because of expected skin toxicity related to panitumumab administration.(3) 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 7 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, England) that identifies 7 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 DNA was insufficient or poor quality for analysis. 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 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 to 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.KRASStatus and Efficacy of Panitumumab as Monotherapy in the Treatment of Chemotherapy-Refractory Metastatic Colorectal Cancer

Total N=427

KRAS WT

KRAS MT

WT : MT

243 (57%):184 (43%)



P (n=124)



BSC (n=119)



P (n=84)



BSC (n=100)

mPFS

12.3 wk

7.3 wk

7.4 wk

7.3 wk

 

(HR=0.45; 95% CI, 0.34 to 0.59)

(HR=0.99; 95% CI, 0.73 to 1.36)

Response rate, %

17

 

0

 

BSC: best supportive care; CI: confidence interval; CRC: metastatic colorectal cancer; MT: mutated; P: panitumumab; WT: wild type.

Given the crossover design of the study and the fact that most of the 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 end points are limited. However, of the 168 BSC patients who crossed over to panitumumab after disease progression (119 with WT KRAS, 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; hazard ratio [HR], 0.32; 95% confidence interval [CI], 0.22 to 0.45).

After completion of the CRYSTAL trial, in which 1198 patients with metastatic CRC were randomly assigned to receive either cetuximab (C) in combination with folinic acid [leucovorin], 5-florouracil (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.(4) 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 1198 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. 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 computed tomography scan every 8 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.KRASStatus and Efficacy in the First-Line Therapy of Metastatic Colorectal Cancer Treated With FOLFIRI with or without Cetuximab (the CRYSTAL Trial)

ITT a

KRAS WT

(n=348b) (64.4%)

KRAS MT

(n=192b) (35.6%)

 

C + F

F

C + F

F

C + F

F

N

599

599

172

176

105

87

Response rate (95% CI), %

46.9

(42.9 to 51.0)

38.7

(34.8 to 42.8)

59.3

(51.6 to 66.7)

43.2

(35.8 to 50.9)

36.2

(27.0 to 46.2)

40.2

(29.9 to 51.3)

p value

0.0025

0.46

mPFS, mo b

8.9

8.0

9.9

8.7

7.6

8.1

 

(HR=0.68, p=0.017)

(HR=1.07; p=0.47)

C: cetuximab; F: FOLFIRI; WT: wild type; MT: mutated; mPFS: median progression-free survival; HR: hazard ratio.
a ITT (intention-to-treat) in the original CRYSTAL trial assessing C+F versus F alone as first-line therapy for metastatic colorectal cancer.
b 540 patients had available archival pathology material for the KRAS mutation subset analysis.
c Confidence intervals for mPFS were not provided in the presentation slides.

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. (5) 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 reevaluated the efficacy in the 2 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.KRASStatus and Efficacy in the First-Line Therapy of Metastatic Colorectal Cancer Treated With FOLFOX with or without Cetuximab (OPUS Study)

 

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 (95% CI), %

60.7

(47.3 to 72.9)

37.0

(26.0 to 49.1)

32.7

(20.3 to 47.1)

48.9

(34.1 to 63.9)

p value

p=0.011

p=0.106

Odds ratio (95% CI)

2.54 (1.24 to 5.23)

0.51 (0.22 to 1.15)

mPFS, mo a

7.7

7.2

5.5

8.6

p value

p=0.016

p=0.0192

Hazard ratio

0.57

1.83

C: cetuximab; CI: confidence interval; Fx: FOLFOX; WT: wild type; MT: mutated; mPFS: median progression-free survival.
a Confidence intervals for mPFS were not provided in the presentation slides.

 

In the CAIRO2 study, Tol et al analyzed tumor samples from 528 of 755 previously untreated patients with metastatic CRC who were randomly assigned to receive capecitabine, oxaliplatin and bevacizumab (CB regimen, n=378), or the same regimen plus C (CBC regimen, n=377).(6) 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 overall survival (OS) (17.2 vs 24.9 months, respectively, p=0.03). For patients
with WT tumors, no significant PFS differences were reported between the 2 groups. Overall, patients treated with C who had tumors with a mutated KRAS gene had significantly decreased PFS compared with C-treated patients with WT KRAS tumors or patients with mutated KRAS tumors in the CB group.

Karapetis et al analyzed tumor samples from 394 of 572 patients (69%) with CRC who were randomly assigned to receive C plus BSC (n=287) versus BSC alone (n=285) for KRAS mutations and assessed whether mutation status was associated with survival.(7) The patients had advanced CRC, had failed chemotherapy and had no other standard anticancer therapy available. Of the tumors that were evaluated (198 from the C group, 196 from the BSC group), 41% and 42% had a KRAS mutation, respectively. In OS (median, 9.5 months vs 4.8 months, respectively; HR for death, 0.55; 95% confidence interval [CI], 0.41 to 0.74; p<0.001) and PFS (median, 3.7 months vs 1.9 months, respectively; HR for progression to death, 0.40; 95% CI, 0.30 to 0.54; p<0.001). For patients with MT KRAS tumors, no significant differences
were reported between those treated with C versus BSC alone with respect to OS (HR=0.98, p=0.89) or PFS (HR=0.99, p=0.96).

Douillard et al reported the results of a multicenter, phase 3 trial in which patients with no prior chemotherapy for metastatic CRC, ECOG Performance Status of 0 to 2, and available tissue for biomarker testing were randomly assigned 1:1 to receive panitumumab-FOLFOX4 versus FOLFOX4.(8) The primary end point was PFS; OS was a secondary end point. Results were prospectively analyzed on an ITT basis by tumor KRAS status. KRAS results were available for 93% of the 1183 patients randomly
assigned. In the WT KRAS group, panitumumab-FOLFOX4 significantly improved PFS compared with FOLFOX4 alone (median PFS, 9.6 vs 8.0 months, respectively; HR=0.80; 95% CI, 0.66 to 0.97; p=0.02). A nonsignificant increase in OS was also observed for panitumumab-FOLFOX4 versus FOLFOX4 (median OS=23.9 vs 19.7 months, respectively; HR=0.83; 95% CI, 0.67 to 1.02; p=0.072). In the mutant KRAS group, PFS was significantly reduced in the panitumumab-FOLFOX4 arm versus the FOLFOX4 arm (HR=1.29; 95% CI, 1.04 to 1.62; p=0.02), and median OS was 15.5 months versus 19.3 months, respectively (HR=1.24; 95% CI, 0.98 to 1.57; p=0.068). Adverse event rates were generally comparable across arms with the exception of toxicities known to be associated with anti-EGFR therapy. The study demonstrated that panitumumab-FOLFOX4 was well-tolerated and significantly improved PFS in patients with WT KRAS tumors.

The CRYSTAL trial(4) demonstrated that the addition of cetuximab to a combined first-line chemotherapy regimen of irinotecan, infusional fluorouracil and leucovorin (FOLFIRI) statistically significantly reduced the risk of disease progression and increased the chance of response in patients with metastatic CRC that was KRAS WT, compared with chemotherapy alone. An updated analysis of the CRYSTAL trial reported increased follow-up time and an increased number of patients evaluable for tumor KRAS status and considered the clinical significance of the tumor mutation status of BRAF in the expanded population of patients with KRAS WT tumors.(9) Subsequent to the initial published analysis, which had a cutoff for OS of December 2007, and an associated overall median duration of follow-up of 29.7 months, additional tumor analysis allowed for the typing of an additional 523 tumors for KRAS mutation status, representing an increase in the ascertainment rate from 45% of ITT population patients in the original analysis to 89% (540 to 1063) in the current analysis, with mutations detected in 37% of tumors. The updated analysis of OS was carried out with a new cutoff date of May 2009, giving an overall median duration of follow-up of 46 months. The addition of cetuximab to FOLFIRI in patients with KRAS WT disease resulted in significant improvements in OS (median, 23.5 vs. 20.0 months; HR=0.796; p=0.009), PFS (median, 9.9 vs 8.4 months; HR=0.696; p=0.001), and response (rate 57.3% vs 39.7%; odds ratio [OR], 2.069; p<0.001) compared with FOLFIRI alone. Significant interactions between KRAS status and treatment effect were
noted for all key efficacy end points. KRAS mutation status was confirmed as a powerful predictive biomarker for the efficacy of cetuximab plus FOLFIRI. BRAF V600E mutations were detected in 60 (6%) of 999 tumor samples evaluable for both BRAF and KRAS. In all but 1 case, BRAF mutations were identified in tumors that were WT for KRAS. The impact of BRAF tumor mutation status in relation to the efficacy of cetuximab plus FOLFIRI was examined in the population of patients with KRAS WT disease (n=625). No evidence was reported for an independent treatment interaction by tumor BRAF mutation status. The authors concluded that BRAF mutation status was not predictive of treatment effects of cetuximab plus FOLFIRI but that BRAF tumor mutation was a strong indicator of poor prognosis for all efficacy end points compared with those whose tumors were WT.

Peeters et al reported the results of a phase 3 study in which 1186 patients with metastatic CRC were randomized to receive panitumumab with FOLFIRI versus FORFIRI alone as second-line treatment.(10) The study end points were PFS and OS, which were independently tested and prospectively analyzed by KRAS status. KRAS status was available for 91% of patients: 597 (55%) with WT KRAS tumors and 486 (45%) with MT KRAS tumors. In the WT KRAS subpopulation, when panitumumab was added to chemotherapy, a significant improvement in PFS was observed (HR=0.73; 95% CI, 0.59 to 0.90; p=0.004); median PFS was 5.9 months for panitumumab-FOLFIRI versus 3.9 months for FOLFIRI. A nonsignificant trend toward increased OS was observed; median OS was 14.5 months versus 12.5 months, respectively (HR=0.85, 95% CI, 0.70 to 1.04; p=0.12); response rate was improved to 35% versus 10% with the addition of panitumumab. In patients with MT KRAS, no difference was reported in efficacy. Adverse events were comparable across arms. The authors concluded that panitumumab plus FOLFIRI significantly improved PFS and is well-tolerated as second-line treatment in patients with WT KRAS metastatic CRC (mCRC).

Maughan et al reported the results of a phase 3, multicenter trial (MRC COIN trial) which randomized patients with advanced CRC who had not received previous chemotherapy to oxaliplatin and fluoropyrimidine chemotherapy (arm A) or the same combination plus cetuximab.(11) The comparison between arms A and B (for which the primary outcome was OS) was in patients with KRAS WT tumors. Baseline characteristics were well-balanced between the trial groups. Analysis was by ITT and treatment allocation was not masked. Further analysis with respect to other mutations, including BRAF, was done; 1630 patients were randomly assigned to treatment groups (815 to standard therapy, 815 to the addition of cetuximab). Tumor samples from 1316 (81%) of patients were used for somatic mutation analyses; 43% had KRAS mutations. In patients with KRAS WT tumors, OS did not differ between treatment groups (median survival, 17.9 months in the control group vs 17.0 months in the cetuximab group (HR=1.04; 95% CI, 0.87 to 1.23; p=0.67). BRAF mutations were detected in 8% of patients; BRAF did not show any evidence of a benefit from the addition of cetuximab. Contrary to other trials that have assessed KRAS mutation status and the benefit of the addition of cetuximab to the regimen of WT KRAS patients, this trial did not show a benefit of the addition of cetuximab to oxaliplatin-based chemotherapy.

Systematic Reviews

Qiu et al conducted a meta-analysis of 22 studies on the predictive and prognostic value of KRAS mutations in metastatic CRC patients treated with cetuximab.(12) The overall KRAS mutation rate was 38% (829/2188 patients). The results of the meta-analysis were consistent with previous reports on the use of cetuximab and KRAS mutation status, that patients with tumors that harbor mutant-type KRAS are more likely to have a worse response, PFS and OS when treated with cetuximab when compared with those with WT KRAS.

Dahabreh et al conducted a systematic review of RCTs that assessed the use of KRAS mutation testing as a predictive biomarker for treatment of advanced CRC with cetuximab and panitumumab.(13) The authors concluded that, compared with patients with WT KRAS, KRAS mutations are consistently associated with reduced OS and PFS and increased treatment failure rates among patients with advanced CRC who are treated with anti- EGFR antibodies.

A pooled analysis of the CRYSTAL and OPUS RCT data was performed to further investigate the findings of these trials in patients with KRAS WT tumors, using extended survival data and following an enhancement in the ascertainment rate of KRAS and BRAF tumor mutation status.(14) Pooled individual patient data from each study were analyzed for OS, PFS and best objective response rate (ORR) in patients evaluable for KRAS and BRAF mutation status. Treatment arms were compared according to
mutation status using log-rank and Cochran-Mantel-Haenszel tests. In 845 patients with KRAS WT tumors, adding cetuximab to chemotherapy led to a significant improvement in OS (HR= 0.81; p=0.006), PFS (HR=0.66; p<0.001), and ORR (OR=2.16; p<0.001). BRAF mutations were detected in 70 of 800 (8.8%) evaluable tumors. No significant differences were found in outcome between the treatment groups in these patients. However, prognosis was worse in each treatment arm for patients with BRAF tumor and OPUS studies confirms the consistency of the benefit obtained across all efficacy end points from adding cetuximab to first-line chemotherapy in patients with KRAS WT mCRC. It further suggests that BRAF mutation does not appear to be a predictive biomarker in this setting, but is a marker of poor prognosis.

Single-Arm Studies (Cetuximab or Panitumumab)

In addition to the 3 randomized trials outlined here, a number of single-arm studies retrospectively evaluated KRAS mutational status and treatment response in patients with metastatic CRC.(15-19) Overall they showed similar nonresponse to anti-EGFR monoclonal antibodies in patients with MT KRAS tumors. Two of these single-arm studies also reported a difference in PFS and OS.(16,19)

NRAS

No RCT evidence is available to evaluate an effect of NRAS mutation status alone on anti-EGFR therapies in CRC. Evidence is available on RAS mutations (KRAS and NRAS) in tumor samples from patients enrolled in the PRIME RCT (Panitumumab Randomized Trial in Combination with Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy).(20) In a prospective-retrospective analysis, a total of 108 of 641(17%) tumor specimens that did not harbor KRAS mutations in exon 2 had mutations in other RAS exons, including NRAS (exons 2 or 4) and KRAS (exons 3 and 4). Among the WT KRAS exon in 2 patients (n=656), OS was significantly better with panitumumab added to FOLFOX4 (n=325, median 23.8 months) versus FOLFOX4 alone (n=331, median 19.4 months, p=0.03). Among patients with no KRAS exon 2 mutation but with one type of RAS mutation, median OS with panitumumab-FOLFOX4 was shorter (n=51, 17.1 months) than with FOLFOX4 alone (n=57, 17.8 months) (p=0.01). These data suggest mutation in a RAS gene exon other than KRAS exon 2 negatively affects anti-EGFR therapy. However, the investigators do not discriminate specific types of RAS mutations, so it is not possible to relate NRAS to these results. Furthermore, the numbers of patients involved are very small, further limiting conclusions.

Tumor specimens (n=288 of 320) from a second RCT3 were analyzed using massively parallel multigene sequencing (next-generation sequencing) to investigate whether EGFR pathway mutations predicted response to monotherapy with panitumumab compared with BSC.(21) This analysis showed that NRAS was mutated in 14 of 282 (5%) samples with available data. Among patients with WT KRAS (codons 12, 13, 61) and WT NRAS (n=138), treatment with panitumumab was associated with improved PFS (HR=0.39; 95% CI, 0.27 to 0.56; p<0.001) compared with BSC. Among those with WT KRAS but mutated NRAS (n=11), treatment with panitumumab was no longer associated with longer PFS (HR=1.94; 95% CI, 0.44 to 8.44; p=0.379). A treatment interaction analysis was suggestive but not significantly indicative of an interaction between the presence of mutated NRAS and poorer outcome (p=0.076). The authors suggest their data are consistent with a hypothesis that NRAS mutations may limit the efficacy of anti-EGFR therapy. However, because the prevalence of NRAS mutations is low, their true predictive or prognostic value is unclear.

A retrospective consortium analysis reported results of centrally performed high-throughput mass spectrometric mutation profiling of CRC specimens gathered from 11 centers in 7 European countries.(22) Patients had been treated with panitumumab alone, cetuximab alone, or cetuximab plus chemotherapy. Among 747 of 773 samples with data, KRAS was mutated in 299 (40%), including codons 12, 13, 61, and 146. By contrast, NRAS mutations were identified in 17 of 644 (2.6%) samples with data, primarily in codon 61. KRAS and NRAS mutations were mutually exclusive. Among WT KRAS samples from patients treated with cetuximab plus chemotherapy, NRAS mutation was associated with an ORR of 7.7% (1/13) compared with WT NRAS (ORR=38%, p=0.013). However, there were no significant differences between NRAS mutants and WT in median PFS (14 vs 26 weeks, p=0.055) or OS (38 vs 50 weeks, p=0.051). Similar to the results previously reported, the results for this analysis show a very low prevalence of NRAS mutations and are inconclusive as to whether NRAS mutation is predictive of non-response to anti-EGFR therapy or is a prognostic indicator of poor outcomes of CRC.

The rarity of NRAS mutations reported in the studies previously outlined in this Policy is also shown in a study that used PCR and pyrosequencing (Qiagen, Valencia, CA) to assess tumor samples from individuals who developed CRC and were identified within the databases of 2 prospective cohort studies: the Nurses ‘Health Study and the Health Professionals Follow-Up Study.(23) Among 225 CRC specimens, NRAS mutations were identified in 5 (2.2%). Because of the low frequency of NRAS mutations, they were not associated with any clinical or pathologic features or with patient survival.

A recent meta-analysis evaluated the predictive value of NRAS mutations on clinical outcomes of anti-EGFR therapy in CRC.(24) The meta-analysis included data from 3 studies included in this policy.(20-22) The investigators suggest that the pooled analyses showed a trend toward poor odds ratio (OR) based on 17 events, but significant effects on PFS (HR=2.30; 95% CI, 1.30 to 4.07) and OS (HR=1.85; 95% CI, 1.23 to 2.78) among patients with WT KRAS. These results are limited by the small pool of mutations, permitting no conclusions as to whether NRAS mutations have an effect on anti-EGFR therapy.

BRAF

A meta-analysis of BRAF mutation and resistance to anti-EGFR monoclonal antibodies in patients with metastatic CRC was performed.(25) The primary end point of eligible studies was ORR, defined as the sum of complete and partial tumor response. A total of 11 studies(26-35) reported sample sizes ranging from 31 to 259 patients. All studies were conducted retrospectively (1 study was a nonconcurrent analysis of response in a population previously randomized35 ). Anti-EGFR therapy was given as first-line treatment in 1 study and as second-line or greater in the other 10. In 2 studies, the anti-EGFR monoclonal antibody was given as monotherapy, and in 9 studies, patients received various chemotherapies. Seven studies were performed in unselected patients (ie, 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 CRC. 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% (0/40), whereas the ORR of patients with WT BRAF was 36.3% (122/336). Only 3 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 CRC, 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 CRC patients with assessors blinded to the clinical data.

Mao et al conducted a meta-analysis of BRAF mutation V600E and resistance to anti-EGFR monoclonal antibodies in patients with metastatic CRC.(25) Eleven studies were included, with sample sizes ranging from 31 to 259; all of the studies were retrospective analyses. Seven of the studies included unselected patients, and 4 included only patients with WT KRAS. The primary end point was ORR. In the 7 studies with unselected patients, BRAF mutational status was performed successfully on 546 mCRC. BRAF mutation was detected in 8.8% of primary tumors. The ORR of mCRC patients with mCRC with mutant BRAF was 29.2% versus 33.5% in patients with WT BRAF. In the 4 studies that included patients with WT KRAS, BRAF mutational status was performed successfully on 376 KRAS WT mCRC. BRAF mutations were detected in 10.6% of primary tumors. The ORR of patients with mutant BRAF was 0.0%, whereas the ORR of patients with WT BRAF was 36.3%. The authors concluded that the results of their metaanalysis provided evidence that BRAF mutation is associated with lack of response in WT KRAS mCRC treated with anti-EGFR monoclonal antibodies.

Phillips et al analyzed the data from 4 studies that reported tumor response and survival in patients with mCRC treated with anti-EGFR monoclonal antibodies as related to BRAF mutational status.(36) Di Nicolantonio et al looked retrospectively at 113 patients with mCRC who had received cetuximab or panitumumab.(27) None of the BRAF-mutated tumors responded to treatment (0/11), whereas 32.4% (22/68) of the BRAF WT did. Loupakis et al retrospectively assessed 87 patients receiving irinotecan and cetuximab.(30) Of the 87 patients in the study, BRAF was mutated in 13 cases, and none of them responded to chemotherapy, compared with 32% (24/74) 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).(35) 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 with 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 with KRAS mutations, is not restricted to the outcome of cetuximab treatment. In the CRYSTAL trial, Van Cutsem et al
randomized 1198 patients with untreated mCRC to FOLFIRI with or without cetuximab.(4) 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.(37) 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 WT/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 et al reported the effects of 4 mutations, including BRAF, on the efficacy of cetuximab and chemotherapy in chemotherapy-refractory metastatic CRC in 773 primary tumor samples.(22) Tumor samples were from fresh frozen or FFPE tissue, and the mutation status was compared with 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 124/326 patients; OR=0.15; 95% CI, 0.02 to 0.51; p=0.001). PFS for BRAF-mutated versus WT was a median of 8 weeks versus 26 weeks, respectively (HR=3.74; 95% CI, 2.44 to 5.75; p<0.001) and OS median 26 weeks versus 54 weeks, respectively (HR=3.03; 95% CI, 1.98 to 4.63; p<0.001).

An updated analysis of the CRYSTAL trial reported increased follow-up time and an increased number of patients evaluable for tumor KRAS status and considered the clinical significance of the tumor mutation status of BRAF in the expanded population of patients with KRAS WT tumors.(9) The impact of BRAF tumor mutation status in relation to the efficacy of cetuximab plus FOLFIRI was examined in the population of patients with KRAS WT disease (n=625). No evidence was reported for an independent treatment interaction by tumor BRAF mutation status. The authors concluded that BRAF mutation status was not predictive of treatment effects of cetuximab plus FOLFIRI but that BRAF tumor mutation was a strong indicator of poor prognosis for all efficacy end points compared with those whose tumors were WT.

At the latest review of this policy (December 2013), no new clinical trials were identified on the use of BRAF mutation analysis to guide use of anti-EGFR therapy in patients with metastatic CRC.

Ongoing and Unpublished Clinical Trials

National Cancer Institute PDQ® Clinical Trials Registry

A search of the National Cancer Institute PDQ® clinical trials registry on November 3, 2014, did not identify any phase 3 clinical trials in which BRAF, NRAS, or KRAS mutation testing was used to guide management of CRC patients.

Summary of Evidence

Clinical trial data show that patients with KRAS-mutated metastatic colorectal cancer (CRC) 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-epidermal growth factor receptor (EGFR) monoclonal antibodies in the treatment of metastatic CRC.

Another member of the RAS family of protooncogenes, NRAS, can harbor mutations in codons 12, 13 and 61 that constitutively activate the EGFR-mediated signaling pathway as do specific mutations in KRAS. Thus, the NRAS oncogene also may have an impact on outcomes of anti-EGFR treatments for CRC. Compared with KRAS, NRAS mutations are extremely rare. Although NRAS mutations account for approximately 15% of all RAS mutations, they are found in perhaps 2% to 7% of all CRC. As a
consequence of the low prevalence of NRAS mutations in CRC, it is difficult to assess their effect on cancer behavior or therapy. Current clinical evidence is sparse and inconclusive as to whether NRAS mutations are prognostic markers for poor outcomes similar to BRAF (discussed next) or may be like KRAS mutations, acting as predictive markers for poor response to anti-EGFR therapy. Given these uncertainties, NRAS mutation analysis is considered investigational to predict nonresponse to anti-EGFR
monoclonal antibodies in the treatment of metastatic CRC.

The data for patients with metastatic CRC and a BRAF mutation have shown consistently that a BRAF mutation is a poor prognostic marker, as it is associated with shorter progression-free survival and overall survival, regardless of treatment. Most of the data for a BRAF mutation predicting response to anti-EGFR therapy are limited by small numbers of patients and conflicting results among studies. No evidence is available from a randomized trial designed specifically to assess the clinical utility of BRAF mutation analysis in guiding management of patients with metastatic CRC. The large, randomized CRYSTAL trial, with nonconcurrent subgroup analyses of BRAF mutations in patients previously randomized, reported the impact of BRAF tumor mutation status in relation to the efficacy of cetuximab plus FOLFIRI in the population of patients with KRAS wild-type (WT) disease. No evidence was reported for an independent treatment interaction by tumor BRAF mutation status, and the trial showed that BRAF mutation status was not predictive of treatment effects of cetuximab plus folinic acid [leucovorin], 5-fluorouracil, and irinotecan. BRAF tumor mutation was a strong indicator of poor prognosis for all efficacy end points compared with those whose tumors were BRAF WT. Thus, BRAF mutation analysis is considered investigational to
predict nonresponse to anti-EGFR monoclonal antibodies in the treatment of metastatic CRC.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network

The National Comprehensive Cancer Network (NCCN) guidelines on the treatment of colon cancer recommend that tumor KRAS and NRAS gene status testing be performed for all patients with metastatic colon cancer (http://www.nccn.org/professionals/physician_gls/pdf/colon.pdf, v2.2015). Testing should be performed 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 appropriate only for patients with a tumor that expresses the WT KRAS and NRAS gene. The guidelines further state that if the tumor harbors the WT KRAS and NRAS gene, the clinician should consider testing for BRAF mutation status.

NCCN guidelines also state that patients with a BRAF V600E mutation appear to have a poorer prognosis. However, evidence is insufficient to guide the use of anti-EGFR therapy in the first-line setting with active chemotherapy based on BRAF V600E mutation status. Limited evidence suggests lack of antitumor activity from anti-EGFR monoclonal antibodies in the presence of a BRAF V600E mutation when used after a patient has progressed on first-line therapy.

An evidence review published in 2013 by the American College of Medical Genetics and Genomics, Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group, states that evidence is insufficient to support the clinical validity or utility of testing CRC specimens for NRAS mutations to guide patient management.(38) In the same review, EGAPP found no guidelines on NRAS testing from any other U.S. group. The EGAPP recommendations align with the Policy statements in this Policy document.

U.S. Preventive Services Task Force Recommendations
Not applicable.

Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.

 

References:

 

  1. 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.
  2. 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):1626-1634.
  3. 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):1658-1664.
  4. 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):1408-1417.
  5. 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):663-671.
  6. Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009;360(6):563-572.
  7. 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):1757-1765.
  8. Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: The PRIME study. J Clin Oncol. 2010;28(31):4697-4705.
  9. Van Cutsem E, Köhne CH, Láng I, et al. Cetuximab plus irinotecan, fluorouracil and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011;29(15):2011-2019.
  10. Peeters M, Price TJ, Cervantes A, et al. Randomized phase 3 study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010;28(31):4706-4713.
  11. Maughan TS, Adams RA, Smith CG, et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomized phase 3 MRC COIN trial. Lancet. 2011;377(9783):2103-2114.
  12. Qui LX, Mao C, Zhang J, et al. Predictive and prognostic value of KRAS mutations in metastatic colorectal cancer patients treated with cetuximab: a meta-analysis of 22 studies. Eur J Cancer. 2010;46(15):2781-2787.
  13. Dahabreh IJ, Terasawa T, Castaldi PJ, et al. Systematic review: anti-epidermal growth factor receptor treatment effect modification by KRAS mutations in advanced colorectal cancer. Ann Intern Med. 2011;154(1):37-49.
  14. Bokemeyer C, Van Cutsem E, Rougier P, et al. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. Jul 2012;48(10):1466-1475. PMID 22446022
  15. 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):2643-2648.
  16. 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):508-515.
  17. 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):1166-1169.
  18. 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):3230-3237.
  19. 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):374-379.
  20. Douillard JY, Oliner KS, Siena S, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. Sep 12 2013;369(11):1023-1034. PMID 24024839
  21. Peeters M, Oliner KS, Parker A, et al. Massively parallel tumor multigene sequencing to evaluate response to panitumumab in a randomized phase III study of metastatic colorectal cancer. Clin Cancer Res. Apr 1 2013;19(7):1902-1912. PMID 23325582
  22. 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):753-762. PMID
  23. Irahara N, Baba Y, Nosho K, et al. NRAS mutations are rare in colorectal cancer. Diagn Mol Pathol. Sep 2010;19(3):157-163. PMID 20736745
  24. Therkildsen C, Bergmann TK, Henrichsen-Schnack T, et al. The predictive value of KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer: A systematic review and metaanalysis. Acta Oncol. Jul 2014;53(7):852-864. PMID 24666267
  25. 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. 2011;38(4):2219-2223.
  26. Cappuzzo F, Varella-Garcia M, Finocchiaro G, et al. Primary resistance to cetuximab therapy in EGFR FISHpositive colorectal cancer patients. Br J Cancer. 2008;99(1):83–89.
  27. 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):5705–5712.
  28. 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):184–190.
  29. 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):5924–5930.
  30. 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):715–721.
  31. 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):1087–1094.
  32. 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):279-286.
  33. 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.
  34. 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.
  35. Tol J, Nagtegaal ID, Punt CJ. BRAF mutation in metastatic colorectal cancer. N Engl J Med. 2009;361(1):98–99.
  36. Phillips B, Kalady M, Kim R. BRAF testing in advanced colorectal cancer: is it ready for prime time? . Clin AdvHematol Oncol 2010;8 6):437-444.
  37. Peeters M, Price TJ, Cervantes A, et. Final results from a randomized phase 3 study of FOLFIRI {+/-} panitumumab for second-line treatment of metastatic colorectal cancer. Ann Oncol. Jan 2014;25(1):107-116.PMID 24356622
  38. Evaluation of Genomic Applications in P, Prevention Working G. Recommendations from the EGAPP Working Group: can testing of tumor tissue for mutations in EGFR pathway downstream effector genes in patients with metastatic colorectal cancer improve health outcomes by guiding decisions regarding anti-EGFR therapy? Genet Med. Jul 2013;15(7):517-527. PMID 23429431

Codes

Number

Description

CPT   See Policy Guidelines section
ICD-9-CM Diagnosis 153.0-153.9 Malignant neoplasm of colon code range
  154.0-154.8 Malignant neoplasm of rectum code range
  197.5 Secondary malignant neoplasm of respiratory and digestive systems: large intestine and rectum
HCPCS S3713 KRAS mutation analysis testing
ICD-10-CM (effective 10/1/15) C18.0-C18.9 Malignant neoplasm of colon code range
  C19 Malignant neoplasm of rectosigmoid junction
  C20 Malignant neoplasm of rectum
  C78.5 Secondary malignant neoplasm of large intestine and rectum
ICD-10-PCS (effective 10/1/15)   Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests.

Index

BRAF Mutation Testing
KRAS Mutation Testing


Policy History

Date

Action

Reason

10/07/08

Add policy

New policy

01/08/09

Replace policy – correction only

Policy updated to reflect Section & subsection

11/11/10 Replace policy Policy updated with literature search. Title changed to indicate inclusion of BRAF testing to the policy; 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 4, 5, 11-27 added; reference 28 updated
12/08/11 Replace policy Policy updated with literature search. References 27-34 added. Policy statements unchanged
12/13/12 Replace Policy Policy updated with literature search. Reference 14 added. Policy statements unchanged.
12/12/13 Replace policy Policy updated with literature search through October 16, 2013; no references added. Policy statements unchanged except for minor wording change in statement on KRAS testing.
12/11/14 Replace policy Policy updated with literature review through September 30, 2014; references 20-24 and 38 were added. Title changed to indicate inclusion of NRAS testing to the policy; NRAS testing policy statement added as investigational to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab and panitumumab in the treatment of metastatic colorectal
cancer.