Clinical UM Guideline

 

Subject: BRAF Mutation Analysis
Guideline #: CG-GENE-03 Publish Date:    08/29/2018
Status: Revised Last Review Date:    07/26/2018

Description

This document addresses genetic testing for BRAF mutation analysis.

BRAF (also known as serine/threonine-protein kinase B-Raf, v-raf murine sarcoma viral oncogene homolog B1) encodes a protein kinase which is implicated in intracellular signaling and cell growth and is a direct downstream effector of KRAS.  KRAS analysis has been studied as a tool to predict response to therapy for individuals with metastatic colorectal or anal cancer, as well as other conditions, including, but not necessarily limited to those with non-small cell lung, esophageal, pancreatic, gastric and endometrial cancer.  BRAF gene mutations are seen most commonly in melanoma, but have also been detected in acute leukemias, lymphoma, lung, thyroid, and colorectal cancer.  Mutations of the BRAF gene occur in less than 10–15% of colorectal cancers and in approximately 50% of cutaneous melanomas.  Mutations of the BRAF gene have been associated with shorter progression-free survival (PFS) and overall survival (OS).  

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Clinical Indications

Medically Necessary:

BRAF V600 mutation analysis is considered medically necessary in individuals with unresectable or metastatic melanoma to identify those who would benefit from treatment with an FDA-approved BRAF inhibitor.

BRAF V600E mutation analysis is considered medically necessary in individuals with non-small cell lung cancer (NSCLC) to identify those who would benefit from treatment with vemurafenib (Zelboraf®).

BRAF V600E mutation analysis is considered medically necessary in individuals with relapsed hairy-cell leukemia to identify those who would benefit from treatment with vemurafenib (Zelboraf®).

BRAF V600E mutation analysis is considered medically necessary in individuals with metastatic colorectal cancer to identify those who would benefit from epidermal growth factor receptor (EGFR)-directed therapy.

BRAF V600E mutation analysis is considered medically necessary in individuals with locally advanced, unresectable or metastatic anaplastic thyroid cancer to identify those who would benefit from treatment with dabrafenib (Tafinlar®) in combination with trametinib (Mekinist®).

Not Medically Necessary:

BRAF mutation analysis is considered not medically necessary for all applications not indicated above as medically necessary.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

BRAF V600 mutation testing

CPT

 

81210

BRAF (B-Raf proto-oncogene, serine/threonine kinase) (eg, colon cancer, melanoma), gene analysis, V600 variant(s)

88363

Examination and selection of retrieved archival (ie, previously diagnosed) tissue(s) for molecular analysis (eg, KRAS mutational analysis) [when specified in relation to BRAF testing]

 

 

ICD-10 Diagnosis

 

C18.0-C18.9

Malignant neoplasm of colon

C19-C20

Malignant neoplasm of rectosigmoid junction, rectum

C21.0-C21.8

Malignant neoplasm of anus and anal canal

C34.00-C34.92

Malignant neoplasm of bronchus and lung

C43.0-C43.9

Malignant melanoma of skin

C73

Malignant neoplasm of thyroid gland

C78.5

Secondary malignant neoplasm of large intestine and rectum

C79.2

Secondary malignant neoplasm of skin

C91.40-C91.42

Hairy cell leukemia

Z85.038

Personal history of other malignant neoplasm of large intestine

Z85.048

Personal history of other malignant neoplasm of rectum, rectosigmoid junction, and anus

Z85.118

Personal history of other malignant neoplasm of bronchus and lung

Z85.820

Personal history of malignant melanoma of skin

Z85.850

Personal history of malignant neoplasm of thyroid

Other BRAF testing

CPT

 

81406

Molecular pathology procedure, Level 7 (eg, analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons, cytogenomic array analysis for neoplasia) [when specified as the following]:

  • BRAF (B-Raf proto-oncogene, serine/threonine kinase) (eg, Noonan syndrome), full gene sequence

 

 

ICD-10 Diagnosis

 

 

Note: other BRAF testing is considered Not Medically Necessary for the following diagnoses:

C00.0-C80.1

Malignant neoplasms

C81.00-C96.9

Malignant neoplasms of lymphoid, hematopoietic and related tissue

Q87.1

Congenital malformations syndromes predominantly associated with short stature [when specified as Noonan syndrome]

Discussion/General Information

Metastatic or Unresectable Melanoma
Metastatic melanoma is an aggressive disease.  The median survival for individuals with stage IV melanoma is 6-10 months, and less than 5% of individuals survive beyond 5 years (Khan 2010).  It has been estimated that approximately 50% of cutaneous melanomas carry the mutated BRAF gene which keeps the protein constantly activated and driving cell growth (Davies, 2002).  Most of these mutations occur at amino acid position 600, the most common of which results in the V600E amino acid substitution (Arkenau, 2011).  The discovery that many melanomas harbor BRAF mutations has prompted a search for agents that can inhibit BRAF activity.

Flaherty and colleagues (2010) conducted a phase 1, dose-escalation trial investigating the use of the experimental drug PLX4032 (a mutated BRAF protein inhibitor) in individuals with metastatic melanoma.  The primary goals of the study were: (1) to define the safety and pharmacokinetic characteristics of treatment with continuous, twice-daily administration of PLX4032; (2) to determine the maximum dose that could be administered until adverse effects prevented further dose increases (that is, the recommended phase 2 dose); and (3) to determine the objective response rate, the duration of response, and the rate of progression among participants who had melanoma tumors with the V600E BRAF mutation and who were given the recommended phase 2 dose of PLX4032.  Fifty-five subjects participated in the dose-escalation phase of the study.  Treatment of melanomas harboring the BRAF V600E mutation resulted in complete or partial tumor regression in the majority of the subjects with the duration of the response ranging from 2 to more than 18 months.  In an extension phase of the trial, the participants were limited to individuals with BRAF mutations and PLZ4032 was limited to the maximum dose which could be tolerated without side effects.  Eighty-one percent (26 of 32) of the subjects in the extension phase of the study experienced tumor regression.  Tumor regression was not observed in participants with tumors not harboring the BRAF mutation.  Side effects related to PLX4032 appeared to be proportional to the dose administered and consisted primarily of cutaneous side effects, fatigue, and arthralgia.  The study findings suggest that therapy consisting of mutant BRAF inhibition is a specific and valid strategy exclusively for the treatment of BRAF mutant tumors.  The authors acknowledged that while the early response to PLX4032 seems to occur reliably, responsive tumors can develop resistance to treatment.  The authors also acknowledged that it is not yet known whether treatment with PLX4032 will result in improved OS.

Hauschild and colleagues (2012) carried out a Phase III, randomized, controlled clinical trial investigating the efficacy of dabrafenib in individuals with BRAF (V600E)-mutated metastatic melanoma.  Participants in the study were 18 years of age or older with previously untreated, stage IV or unresectable stage III BRAF (V600E) mutation-positive melanoma.  The participants were randomly assigned at a 3:1 ratio to receive dabrafenib (150 mg twice daily, orally) or dacarbazine (1000 mg/m(2) intravenously every 3 weeks).  The primary endpoint was PFS.  Median PFS was 5.1 months for dabrafenib and 2.7 months for dacarbazine.  At data cutoff, 107 (57%) of the participants in the dabrafenib group and 14 (22%) in the dacarbazine group remained on randomized treatment.  Treatment-related adverse events (grade 2 or higher) occurred in 100 (53%) of the 187 subjects who received dabrafenib and in 26 (44%) of the 59 subjects who received dacarbazine.  The most common adverse events with dabrafenib were skin-related toxic effects, fever, fatigue, arthralgia, and headache.  The most common adverse events with dacarbazine were nausea, vomiting, neutropenia, fatigue, and asthenia.  The authors concluded that dabrafenib significantly improved PFS compared with dacarbazine.

The Food and Drug Administration (FDA) has approved dabrafenib (Tafinlar) capsules for the “treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation as detected by an FDA-approved test.”  This product is not recommended for use in individuals with wild-type BRAF melanoma.  Tafinlar is marketed by GlaxoSmithKline.

In a multicenter Phase II clinical trial, Sosman and colleagues (2012) investigated the efficacy of vemurafenib in individuals with previously treated BRAF V600-mutant advanced melanoma.  The primary and secondary end-points were overall response rate as ascertained by the independent review committee and OS, respectively.  A total of 132 individuals had a median follow-up of 12.9 months (range, 0.6 to 20.1).  The confirmed overall response rate was 53% with 6% of the study participants demonstrating a complete response and 47% demonstrating a partial response.  The median duration of response was 6.7 months and the median PFS was 6.8 months.  Primary progression was observed in only 14% of the participants.  Some participants had a response after receiving vemurafenib for more than 6 months.  The median OS was 15.9 months (95% confidence interval [CI], 11.6 to 18.3).  The most common adverse events were grade 1 or 2 arthralgia, rash, photosensitivity, fatigue, and alopecia.  Cutaneous squamous-cell carcinomas (the majority, keratoacanthoma type) were diagnosed in 26% of the participants.  The authors concluded that vemurafenib induces clinical responses in more than half of the participants with previously treated BRAF V600-mutant metastatic melanoma. 

Chapman and colleagues (2011) conducted a Phase III trial which compared the use of vemurafenib and dacarbazine in 675 individuals with previously untreated metastatic melanoma (Stage IIIC or Stage IV) harboring the BRAF V600E mutation.  Participants in the study were randomly assigned to receive either vemurafenib or dacarbazine.  Primary endpoints were rates of OS and PFS.  Secondary end points included the response duration, response rate and safety.  At 6 months, OS in the vemurafenib group was 84% and 64% in the dacarbazine group.  In the interim analysis vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either disease progression or death, as compared with dacarbazine (P<0.001 for both comparisons).  After a review of the interim analysis by an independent data and safety monitoring board, it was recommended that the participants in the study receiving dacarbazine be moved to the vemurafenib arm of the study.  The researchers concluded that individuals with advanced melanoma who harbored the BRAF V600E mutation may benefit from specific inhibitor therapy.

In another phase III trial, Robert and colleagues (2015) evaluated dabrafenib combined with trametinib compared to vemurafenib alone in individuals with untreated metastatic melanoma and a BRAF V600E or V600K mutation.  A total of 704 participants with metastatic melanoma were randomized to receive either a combination of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily), or vemurafenib (960 mg twice daily) alone, as first-line therapy.  The primary endpoint was OS and the secondary endpoints were PFS, safety and over-all response rate.  Crossover between the cohorts was not permitted.  Evaluation of BRAF V600E and V600K mutations were conducted at a central laboratory that utilized the THxID-BRAF assay.  The criteria included but was not limited to an ECOG performance status of 0 or 1 and measurable disease.  Individuals who had undergone prior treatment for brain metastases with stable disease for 3 or more months were allowed to participate.  

At the preplanned interim overall survival analysis, the overall survival rate at 12 months was 72% (95% CI, 67 to 77) in the dabrafenib combined with trametinib group and 65% (95% CI, 59 to 70) in the vemurafenib alone group (hazard ratio [HR] for death in the combination-therapy group, 0.69; 95% CI, 0.53 to 0.89; P=0.005).  The predetermined interim stopping boundary was crossed, and the study was halted for efficacy in July 2014.  Median progression-free survival was 11.4 months in the dabrafenib combined with trametinib group and 7.3 months in the vemurafenib alone group (HR, 0.56; 95% CI, 0.46 to 0.69; P<0.001).  The objective response rate was 64% in the dabrafenib combined with trametinib group and 51% in the vemurafenib alone group (P<0.001).  The rates of adverse events were similar between the two groups although the spectrum of adverse events was different.  Cutaneous squamous-cell carcinoma and keratoacanthoma occurred in 1% of the subjects in the dabrafenib combined with trametinib group as opposed to 18% of those in the vemurafenib alone group.  Treatment was discontinued in 3% of the participants in the dabrafenib combined with trametinib group for reduced cardiac ejection and fever, and was discontinued in 2% of the participants in the vemurafenib alone group due to joint pain.  The authors concluded that dabrafenib combined with trametinib, as compared with vemurafenib alone, significantly improved overall survival in previously untreated individuals with metastatic melanoma with BRAF V600E or V600K mutations, without increased overall toxicity.

The FDA approved vemurafenib tablets (Zelboraf®) for the “treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation as detected by an FDA-approved test.”  ZELBORAF is not recommended for use in individuals with wild-type BRAF melanoma.  Zelboraf® is marketed by Genentech (San Francisco, CA). 

Shahabi and colleagues (2012) investigated whether the clinical activity of ipilimumab would be affected by the BRAF-V600E mutation status of the tumors.  The BRAF-V600E mutation status for 80 of the 82 participants was determined in tumor biopsies by PCR-based assays.  Forty of the 80 tumors (50%) had the BRAF-V600E mutation and 40 (50%) of the tumors were BRAF V600 wild-type.  Data on disease control were available for 69 subjects with evaluated BRAF-V600E mutation status.  Rates of objective responses and stable disease in subjects with BRAF-V600E mutation positive tumors (30%) were comparable to those in subjects with the wild-type gene (~33%).  Eleven participants displayed Durable Disease Control (DDC) of which 55% had BRAF-V600E mutation positive tumors and 45% did not.  In the 48 participants showing no DDC, the mutation frequency was 50%.  In this study, no association between BRAF-V600E mutation status of melanoma tumors and DDC after treatment with ipilimumab was detected.

Flaherty and colleagues (2012) reported the results of a phase III open-label trial (NCT01245062) which randomly assigned 322 subjects with metastatic melanoma with a V600E or V600K BRAF mutation to receive either trametinib, an oral selective MEK inhibitor, or chemotherapy in a 2:1 ratio.  Participants received trametinib (2 mg orally) once daily or intravenous dacarbazine (1000 mg per square meter of body-surface area) or paclitaxel (175 mg per square meter) every 3 weeks.  Participants in the chemotherapy group who had disease progression were permitted to cross over to receive trametinib.  PFS was the primary end point and OS was a secondary end point.  Median PFS was 4.8 months in the trametinib group and 1.5 months in the chemotherapy group.  At 6 months, the rate of OS was 81% in the trametinib group and 67% in the chemotherapy group despite crossover.  The most common toxic effects in the trametinib group were rash, diarrhea, and peripheral edema.  Asymptomatic and reversible reduction in the cardiac ejection fraction and ocular toxic effects occurred infrequently.  No secondary skin neoplasms were observed.  The authors concluded that trametinib, as compared with chemotherapy, improved rates of progression-free and OS among participants who had metastatic melanoma with a BRAF V600E or V600K mutation.

In May, 2013, the FDA approved trametinib (Mekinist tablet, GlaxoSmithKline, LLC), for the treatment of individuals with unresectable or metastatic melanoma with BRAF V600E or V600K mutation as detected by an FDA-approved test.  Trametinib is not indicated for treatment of individuals who have received prior BRAF inhibitor therapy.

Concurrent with the approval of Mekinist, the FDA approved the THxID BRAF assay (bioMerieux, Inc.) for detection of BRAF V600E and V600K mutations.  According the FDA Summary of Safety and Effectiveness Data (SEED):

The THxID™ BRAF kit is an In Vitro Diagnostic device intended for the qualitative detection of the BRAF V600E and V600K mutations in DNA samples extracted from formalin-fixed paraffin-embedded (FFPE) human melanoma tissue.  The THxID BRAF kit is a real-time PCR test on the ABI 7500 Fast Dx system and is intended to be used as an aid in selecting melanoma patients whose tumors carry the BRAF V600E mutation for treatment with dabrafenib (Tafinlar) and as an aid in selecting melanoma patients whose tumors carry the BRAF V600E or V600K mutation for treatment with trametinib (Mekinist) (U.S. FDA SEED, ThxID). 

A collaboration of multi-disciplinary experts from the European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO) and the European Organization of Research and Treatment of Cancer (EORTC) was formed to make recommendations on cutaneous melanoma diagnosis and treatment.  Based on systematic literature reviews and the experts' experience, the authors summarized the need for BRAF gene mutation analysis as follows: 

Molecular analysis of distant or regional metastasis or, if impossible, of the primary tumour is required for patients with distant metastasis or non-resectable regional metastasis, who are candidates for systemic medical treatment.  Currently, the main test performed involves the BRAF V600 mutational status, in order to identify patients eligible for treatment with BRAF inhibitors and MEK inhibitors (Garbe, 2012).

The National Comprehensive Cancer Networks (NCCN) Clinical Practice Guidelines in Oncology on Melanoma (V1.2017) recommends that in:

Patients presenting with stage IV distant metastatic disease, all panel members agree it is appropriate to confirm the suspicion of metastatic disease with either FNA or core, incisional, or excisional biopsy of the metastases.  Genetic analyses (eg, BRAF or KIT mutation status) are appropriate for patients being considered for treatment with targeted therapy, or if mutational status is relevant to eligibility for participation in a clinical trial.  To ensure that adequate metastatic material is available for mutational analysis, biopsy (core, excisional, or incisional) is preferred if initial therapy is to be systemic and archival tissue is not available.  However, the panel also recognized that brain metastases are typically treated without histologic confirmation.

In summary, preliminary research has demonstrated complete or partial tumor regression when vemurafenib was administered to study participants who harbored the BRAF V600E mutation.  Due to the aggressive nature of and the poor prognosis associated with metastatic melanoma, genetic testing for BRAF V600E mutations may be appropriate in individuals with unresectable or metastatic melanoma who are being considered for treatment with Zelboraf (vemurafenib), Mekinist (trametinib) or Tafinlar (dabrafenib).

Colorectal Cancer and Targeted Therapy with an Anti-Epidermal Growth Factor Receptor (EGFR)
One approach in managing the care of individuals with advanced and metastatic (Stage IV) colorectal cancer (CRC) has been to address the delivery of anti-EGFR agents whose primary purpose is to interfere with the biological activity of the EGFR.  However, only a portion of individuals with CRC have a tumor type which will exhibit a favorable biological and clinical response to anti-EGFR antibody therapy.  Researchers are investigating whether BRAF mutation status can affect response to anti-EGFR monoclonal antibody drugs, especially in individuals with wild-type KRAS.  For more information on KRAS, refer to CG-GENE-02 Analysis of KRAS Status.

In a small, retrospective, multicenter study conducted by Di Nicolantonio and colleagues (2008), an analysis of 113 individuals who received cetuximab or panitumumab demonstrated the following: (a) None of the individuals with KRAS wild-type and BRAF mutations responded to therapy, (b) None of the individuals who responded had BRAF mutations; and (c) The individuals with the BRAF mutations demonstrated significantly shorter progression-free and OS when compared with individuals with the BRAF wild-type alleles.

In a multicenter, retrospective study, Laurent-Puig and colleagues (2009) analyzed tissue samples from a group of 173 individuals with metastatic CRC who had been treated at six different hospitals.  All of the participants had received cetuximab-based therapies as second-line or subsequent treatments, with the exception of 1 individual who received cetuximab alone as a first-line therapy.  The KRAS and BRAF status, EGFR amplification and PTEN expression were examined.  While individuals with KRAS wild-type tumors (n=16), or BRAF mutations (n=5) were weakly associated with a lack of response (P=0.063.), they were strongly associated with shorter PFS (p<0.001) and shorter OS (p<0.001).  In the multivariate analysis, BRAF mutation and PTEN expression status were associated with OS.  The authors concluded that in addition to KRAS mutation status, BRAF mutation status, PTEN expression and EGFR amplification may be biomarkers for predicting outcomes in individuals with metastatic CRC who are receiving anti-EGFR therapy.  The authors acknowledged that subsequent studies in clinical trial cohorts are needed to confirm the clinical utility of these markers.

Richman and colleagues (2009) sought to determine whether KRAS and/or BRAF mutation is a predictive biomarker for other advanced CRC therapies.  The Medical Research Council Fluorouracil, Oxaliplatin and Irinotecan: Use and Sequencing (MRC FOCUS) trial compared treatment sequences including first line fluorouracil (FU), FU/irinotecan or FU/oxaliplatin in individuals with advanced CRC.  After obtaining tumor specimens from 711 participants, DNA was extracted and KRAS codons 12, 13, and 61 and BRAF codon 600 were assessed.  The mutation status was first assessed as a prognostic factor and then as a predictive biomarker for the benefit of adding irinotecan or oxaliplatin to FU.  The association of BRAF-mutation with loss of MLH1 was also assessed.  Of the 711 participants, 308 (43.3%) had KRAS-mutations and 56 (7.9%) of the 711 had BRAF-mutations.  Mutation of KRAS, BRAF, or both was present in 360 (50.6%) of the 711 participants.  Mutation in either KRAS or BRAF was a poor prognostic factor for OS, but had little impact on PFS.  Mutation status did not influence the impact of irinotecan or oxaliplatin on PFS or OS.  The findings of this study suggest that while KRAS and BRAF mutations are associated with shorter OS, they do not necessarily predict reduced benefit from the chemotherapeutic agents oxaliplatin and irinotecan.

Bokemeyer and colleagues (2010) conducted a pooled analysis of the CRYSTAL and OPUS study populations to evaluate OS, PFS and best overall response using updated data.  The analysis was performed on individual participant data from both studies for all efficacy endpoints according to KRAS/BRAF mutation status.  The analysis confirmed that the addition of cetuximab to first-line chemotherapy treatment in subjects with KRAS wild-type tumors achieves a statistically significant improvement in overall response rate, PFS, and OS compared with chemotherapy alone.  The best outcome was demonstrated in individuals with both KRAS wild-type and BRAF wild-type tumors.  However, there were too few participants with BRAF mutations to determine whether BRAF mutation status alone was a predictor of response to therapy. 

In 2011, Bokemeyer and colleagues extended the biomarker analysis of the OPUS study through the use of additional DNA samples extracted from stained tissue sections.  KRAS and BRAF tumor mutation status was determined for new (and for BRAF, existing) samples using a PCR technique.  Clinical outcome was reassessed according to mutation status.  The authors concluded that the addition of cetuximab to FOLFOX-4 significantly improved PFS and response in subjects with KRAS wild-type tumors and confirmed KRAS mutation status as an effective predictive biomarker.  The small number of tumors with BRAF mutations precluded the drawing of definitive conclusions concerning the predictive or prognostic utility of this biomarker.

Van Cutsem and colleagues (2011) performed an updated survival analysis, including additional subjects analyzed for tumor mutation status. Study participants were randomly assigned to receive FOLFIRI with or without cetuximab.  Clinical outcomes were assessed according to tumor KRAS and BRAF mutation status.  While KRAS mutation status was confirmed as a powerful predictive biomarker for the efficacy of cetuximab plus FOLFIRI, BRAF V600E mutation was an indicator of poor prognosis.

Lin and colleagues (2011) conducted a systematic review of pharmacogenetic testing for predicting clinical benefit to anti-EGFR therapy in metastatic CRC.  The authors identified a total of seven studies that explored CRC tumor response in the presence of BRAF V600E mutations, three of which assessed survival.  Of these studies, the authors concluded that the best evidence came from the retrospective analysis by De Roock and colleagues (discussed below).

Bokemeyer and colleagues (2012) pooled the individual subject data from the CRYSTAL and OPUS clinical trials and analyzed the OS, PFS and best overall response rate in subjects evaluable for KRAS and BRAF mutation status.  The researchers concluded that the analysis of pooled data from the CRYSTAL and OPUS studies confirms the consistency of the benefit obtained across all efficacy end-points from adding cetuximab to first-line chemotherapy in individuals with KRAS wild-type metastatic CRC.  BRAF mutation does not appear to be a predictive biomarker in this setting, but is a marker of poor prognosis.

Ogino and colleagues (2012) examined the effect of BRAF mutation on survival and treatment efficacy in 506 individuals with stage III colon cancer.  The researchers assessed BRAF V600E mutation status and microsatellite instability (MSI) in a randomized adjuvant chemotherapy trial [5-fluorouracil and leucovorin (FU/LV) vs. irinotecan (CPT11), FU and LV (IFL).  Cox proportional hazards model was used to assess the prognostic role of BRAF mutation, adjusting for adjuvant chemotherapy arm, clinical features and MSI status.  Compared with 431 BRAF wild-type participants, 75 BRAF-mutated subjects experienced significantly worse OS.  By assessing combined status of BRAF and MSI, BRAF-mutated microsatellite stable (MSS) tumor was an unfavorable subtype, whereas BRAF wild-type MSI-high tumor was a favorable subtype, and BRAF-mutated MSI-high tumor and BRAF wild-type MSS tumor were intermediate subtypes.  Among subjects with BRAF-mutated tumors, a nonsignificant trend toward improved OS was observed for IFL versus FU/LV arm.  Among participants with BRAF wild-type cancer, IFL conferred no suggestion of benefit beyond FU/LV alone.  The researchers concluded that BRAF mutation is associated with inferior survival in stage III colon cancer and acknowledged that additional studies are needed to assess whether there is any predictive role of BRAF mutation for irinotecan-based therapy.

Several meta-analyses have explored whether the absence or presence of BRAF mutations is associated with a response to EGFR-directed therapies.  De Roock and colleagues (2010) reported the results of a meta- analysis which explored the effect of four mutations (KRAS, BRAF, NRAS and PIK3CA) on the efficacy of cetuximab plus chemotherapy in individuals with chemotherapy-refractory metastatic CRC.  A total of 773 primary tumor samples had sufficient quality DNA to be included in the mutation frequency analyses.  Tumor samples were obtained from fresh frozen or FFPE tissue.  The mutation status was compared to retrospectively collected clinical outcomes including objective response, PFS and OS.  BRAF mutations were identified in 36 of 761 tumors (4.7%).  In individuals with KRAS wild-type, carriers of BRAF mutations had a significantly lower response rate (2 of 24 subjects or 8.3%) than BRAF wild-type (124 of 326 subjects or 38.0%).  PFS for BRAF-mutated versus BRAF wild-type 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). 

In another meta-analysis, Mao and colleagues (2011) investigated the role of EGFR-directed therapies in individuals with BRAF-mutant CRCs and determined that the response rate to EGFR-directed therapies in BRAF-mutant versus BRAF wild-type subjects was 0.14 (95% CI, 0.04–0.53), suggesting that individuals with BRAF-mutant CRCs do not respond to EGFR-directed therapy. 

In the meta-analysis conducted by Pietrantonio (2015), researchers evaluated nine Phase III trials and one Phase II trial for a total of 463 subjects with BRAF-mutant CRC.  The researchers found that the addition of EGFR-directed therapies in BRAF-mutant individuals did not significantly improve progression-free survival (HR, 0.88; 95% CI, 0.67–1.14; p=0.33), overall survival (HR, 0.91; 95% CI, 0.62–1.34; p=0.63) or overall response rate (relative risk, 1.31; 95% CI, 0.83–2.08; p=0.25) compared with control regimens.  The authors concluded that the presence of RAS or BRAF mutations in CRC predicts lack of response to EGFR-directed therapies and recommended that comprehensive evaluation for the presence or absence of BRAF and RAS alterations should be performed at the time of diagnosis of metastatic disease to determine whether subjects will benefit from EGFR-directed therapies.

Rowland and colleagues (2015) conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) published prior to July 2014 that evaluated the effect of BRAF mutation on the treatment benefit from anti-EGFR therapy for metastatic CRC.  A total of seven RCTs met the inclusion criteria for assessing OS, whereas eight RCTs fulfilled the inclusion criteria for assessing PFS.  For RAS wild-type/BRAF-mutated tumors, the hazard ratio for OS benefit with anti-EGFR monoclonal antibodies was 0.97 (95% CI; 0.67–1.41), whereas the hazard ratio was 0.81 (95% CI; 0.70–0.95) for RAS wild-type/BRAF wild-type tumors.  However, the test of interaction (P=0.43) was determined to not be statistically significant.  With regard to PFS benefit using anti-EGFR monoclonal antibodies, the hazard ratio for RAS wild-type/BRAF-mutated tumors was 0.86 (95% CI; 0.61–1.21) compared to the hazard ratio for RAS wild-type/BRAF wild-type tumors which was 0.62 (95% CI; 0.50–0.77).  The test of interaction was P=0.07).  The authors concluded that the meta-analysis did not produce sufficient evidence to definitively state that RAS wild-type/BRAF-mutated individuals experience a different treatment benefit from anti-EGFR monoclonal antibodies for metastatic CRC compared with RAS wild-type/BRAF wild-type individuals.  The authors also determined that there are insufficient data to justify the exclusion of anti-EGFR monoclonal antibody therapy for individuals with RAS wild-type/BRAF mutated metastatic CRC.

The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found that there was insufficient evidence to recommend for or against BRAF V600E testing for individuals with metastatic CRC who are being considered for treatment with the anti-EGFR agents cetuximab or panitumumab, because the level of certainty for BRAF V600E testing to guide anti-EGFR therapy was deemed low (EGAPP, 2013).

The NCCN guidelines on Colon Cancer (V2, 2017) recommend that all individuals with metastatic CRC have tumor tissue (either primary tumor or metastasis) genotyped for RAS (KRAS and NRAS) and BRAF mutations. The NCCN guidelines also state the following:

Overall, the panel believes that evidence increasingly suggests that BRAF V600E mutation makes response to panitumumab or cetuximab as single agents or in combination with cytotoxic chemotherapy, highly unlikely.  The panel recommends BRAF genotyping of tumor tissue (either primary tumor or metastasis) at diagnosis of stage IV disease.  Testing for the BRAF mutation can be performed on formalin-fixed paraffin-embedded tissues and is usually performed by PCR amplification and direct DNA sequence analysis.  Allele-specific PCR is another acceptable method for detecting this mutation.

In summary, published literature suggests that the presence of BRAF mutations in CRC predicts lack of response to EGFR-directed therapies.  Therefore, genetic testing for BRAF V600E mutations may be appropriate in individuals with metastatic CRC.

Lynch Syndrome (Hereditary Nonpolyposis Colorectal cancer [HNPCC])
BRAF mutation analysis is also being investigated as a tool to identify individuals with Lynch Syndrome.  Lynch syndrome is most commonly caused by mutations in the two MMR genes MLH1 and MSH2; less commonly by mutations in MSH6 and PMS2.  Nearly 100% of individuals with Lynch syndrome do not carry the BRAF mutation, whereas 68% of those without Lynch syndrome carry the BRAF mutation.  Researchers have hypothesized that performing BRAF testing on tumors with absent MLH1 staining might identify a population that is almost entirely composed of sporadic CRC that would not benefit from MLH1 sequencing.  This could potentially result in important cost savings, as BRAF testing is relatively inexpensive in comparison to direct sequencing of MLH1 (Palomaki, 2009).

The EGAPP Working Group (2009) found sufficient evidence to recommend offering genetic testing for Lynch syndrome.  Based on evidence in the AHRQ evidence report (Bonis, 2007), the EGAPP Working Group decided not to use the family history as an initial screening test (for example, Amsterdam II or Bethesda criteria) because of the difficulty and costs of obtaining reliable family history and the overall poor sensitivity and specificity of this approach as a first step in identifying risk for Lynch syndrome in this clinical scenario.  Alternative preliminary screening methods suggested included either microsatellite instability (MSI) of tumor tissue that can identify the loss of a germline mismatch repair (MMR) gene function, or immunohistochemical (IHC) testing that identifies the absence of MMR gene protein in tumor tissue.  The sensitivity of BRAF mutation testing was estimated to be 69% and the specificity 100% among newly diagnosed CRC cases with absent IHC staining for MLH1 (Palomaki, 2009).  Based on the EGAPP Working Group recommendations, preliminary (screening) tests (microsatellite instability testing or IHC testing [with or without BRAF mutation testing] of the tumor tissue) are appropriate for all individuals with a new diagnosis of CRC.  The screening methods are suggested as a means to identify individuals at sufficient risk for Lynch syndrome to be candidates for subsequent MMR diagnostic testing.  The EGAPP Working Group did not find sufficient evidence to recommend a specific genetic testing strategy. 

The NCCN guidelines on Colon Cancer (Genetic/Familial High-Risk Assessment: Colorectal [V2.2017]) indicate that:

Ten percent to 15% of sporadic colon cancers exhibit abnormal IHC and are MSI-H most often due to abnormal methylation of the MLH1 gene promoter, rather than due to LS (an inherited mutation of one of the MMR genes or EPCAM).  Mutant BRAF V600E is found in the majority of sporadic MSI CRCs and is rarely found in LS-related CRCs. Thus, the presence of an abnormal MLH1 IHC test increases the possibility of LS but does not make a definitive diagnosis.

Non-Small-Cell Lung Cancer (NSCLC)
The BRAF gene mutation has been identified in NSCLC and is estimated to occur in approximately 1% to 3% of adenocarcinomas.  Unlike melanoma, as much as 50% of the mutations in NSCLC are non-V600E mutations.  BRAF mutations occur more frequently in smokers.

Clinical trials are being developed to evaluate the effectiveness of drugs targeted for BRAF V600E mutations.  Interim results of a study (BRF113928) exploring the use of dabrafenib in BRAF V600E mutation–positive stage IV non–small-cell lung cancer (NSCLC) were presented at the annual meeting of the American Society of Clinical Oncology (ASCO, 2013).  The study was a single arm, phase II, open label trial with an interim analysis planned after 20 participants.  The results presented included 20 subjects evaluated for efficacy and 25 for safety.  All participants were positive for the V600E mutation and had progressed after at least one prior line of therapy.  The investigators reported no complete responses among the 20 participants; 8 subjects (40%) experienced a partial response, 4 subjects (20%) with stable disease, 6 subjects (30%) with progressive disease, and 2 individuals (10%) were not evaluable.  The overall response rate was 40%, and the disease control rate (complete and partial responses along with stable disease) was 60%.  At the time of data cutoff, 13 participants had discontinued treatment (10 because of disease progression, 2 because of an adverse event, and 1 by patient decision).  Ninety-six percent (96%) of the participants reported at least one adverse event with dabrafenib, with fatigue as the most common.  The median duration of treatment was 84 days (Planchard, 2013).

Gautschi and colleagues (2012) reported the results of a single case study of an 80 year old male with NSCLC who, due to his very poor prognosis, was offered vemurafenib off-label use.  Although the individual was treated with vemurafenib for only a little more than 2 weeks when he expired due to complications of chronic cardiac failure, the cytology examination demonstrated near complete absence of cancer cells in pleural fluid, and histology revealed massive tumor regression with fibrosis and few residual cancer cell islets.

Hyman and colleagues (2015) reported the findings of a histology-independent, flexible, early phase 2 “basket” study of vemurafenib in individuals with BRAF V600 mutation–positive nonmelanoma cancers.  The study design included 6 cohorts of individuals with prespecified cancers (NSCLC, CRC, ovarian cancer, cholangiocarcinoma, breast cancer, and multiple myeloma).  A 7th, “all others” cohort was comprised of individuals with any other BRAF V600 mutation-positive cancer.  The study protocol permitted additional tumor-specific cohorts to be analyzed if a sufficient number of participants enrolled in the “all-others” cohort.  Individuals with hairy-cell leukemia and papillary thyroid cancer were excluded from inclusion in the study.  A total of 122 subjects with BRAF V600 mutation–positive cancer were treated.  The response rate served as the primary study endpoint while progression-free and overall survival were the secondary endpoints.  In the cohort of participants with NSCLC, approximately 90% of whom had received prior platinum-based chemotherapy, the response rate was 42% (95% CI, 20 to 67) and the median progression-free survival time was 7.3 months.  The authors indicate that this rate compared favorably with the 7% response rate reported for standard second-line docetaxel in molecularly unselected subjects.  None of the participants experienced disease progression during treatment.  

The NCCN guidelines on Non-Small Cell Lung Cancer (V8 2017) state:

The international panel and NCCN recommend that all patients with adenocarcinoma be tested for EGFR mutations; the NCCN Panel also recommends that these patients be tested for anaplastic lymphoma kinase (ALK) gene rearrangements, ROS1 rearrangements, BRAF mutations, and programmed death (PD-1) receptor expression levels, which are considered to be the standard set of biomarkers.

Hairy-Cell Leukemia (HCL)
HCL, a type of non-Hodgkin’s lymphoma, is a chronic B-cell lymphoproliferative disorder.  A rare disorder, HCL is diagnosed in approximately 700 people in the United States each year and represents approximately 2% of all leukemias.  Because HCL is an indolent disease, some individuals may never need treatment.  Pancytopenia and splenomegaly are the most common reasons to initiate treatment.  Standard treatment options for HCL may include chemotherapy, biologic therapy, allogeneic stem cell transplantation and splenectomy. 

The BRAF V600E mutation has been identified in individuals with HCL.  Several studies have demonstrated the presence of BRAF V600E mutation in all of the cases tested for HCL, while the BRAF V600E was not exhibited in other cases of lymphoma or B-cell leukemia (Andrulis, 2012; Arcaini, 2012; Boyd, 2011; Tiacci, 2011).  There have also been studies which reported the absence of BRAF V600E mutation in HCL variant cases, and in a small number of classic HCL cases.  In the classic HCL cases, approximately half of the BRAF wild-type cases demonstrated VH4-34 rearrangement of the immunoglobulin heavy chain variable (IGHV) gene (Shao, 2013; Xi, 2011).  An accurate diagnosis is essential in order to differentiate classic forms from HCL variants, such as the HCL-variant and VH4-34 molecular variant, which tend to be more resistant to available treatments.

Emerging therapies to provide better treatment options for affected individuals with HCL are under study.  The BRAF inhibitor vemurafenib has been proposed as a treatment of individuals with relapsed HCL in several studies (Dietrich, 2012; Follows, 2013; Peyrade, 2013).  The NCCN guideline on Hairy Cell Leukemia (V1.2018) concludes that:

Although further studies are needed, the BRAF V600E mutation may potentially serve as a reliable molecular marker that distinguishes HCL from other B-cell lymphoproliferative disorders.  Moreover, the presence of this mutation may have implications for the use of new targeted therapies for HCL. 

Based on this NCCN recommendation and other specialty consensus input, BRAF V600E mutation analysis is considered appropriate in individuals with HCL.

Anaplastic Thyroid Cancer
Anaplastic thyroid cancer is a very aggressive and rare thyroid malignancy with an overall survival measured in months.  Despite multimodality treatment including surgery, antineoplastic chemotherapy and radiotherapy, outcomes remain dismal.  According to the American Cancer Society, the 5-year relative survival rate for anaplastic (undifferentiated) carcinomas, all of which are considered stage IV, is approximately 7%.  The National Cancer Institute (NCI) estimates there will be approximately 54,000 new cases of thyroid cancer and an estimated 2,060 deaths from the disease in the United States in 2018.  Due to the poor prognosis, the fact that when diagnosed the cancer is often in an advanced stage, and limited treatment options, there is an need for better treatment strategies for this aggressive form of thyroid cancer (NCI Cancer Stat Facts, 2018).  

BRAF V600E mutations occur in between 20% to 50% of individuals with anaplastic thyroid cancer.  In May 2018, the FDA approved dabrafenib and trametinib in combination for the treatment of subjects with locally advanced or metastatic anaplastic thyroid cancer with BRAF V600E mutation and with no satisfactory locoregional treatment options.  In addition to granting the application priority review, the FDA also granted orphan drug designation and breakthrough designation for the trametinib and dabrafenib combination as a treatment for individuals with anaplastic thyroid cancer and the BRAF V600 mutation (U.S. FDA Mekinist, 2018; U.S. FDA Tafinlar, 2018).

The FDA approval was based on a nine-cohort, non-randomized trial (NCT02034110) enrolling individuals with rare cancers with the BRAF V600E mutation, including locally advanced, unresectable, or metastatic anaplastic thyroid cancer with no locoregional treatment options.  The trial measured the percentage of participants with a complete or partial reduction in tumor size (overall response rate).  Of 23 evaluable subjects, 57% experienced a partial response and 4% experienced a complete response.  In nine (64%) of the 14 subjects with responses, there were no significant tumor growth for at least six months.  Of the 23 subjects with anaplastic thyroid cancer who were evaluable for response, the overall response rate was 61% (95% CI: 39%, 80.  Common adverse events included but were not limited to fatigue (38%), pyrexia (37%) and nausea (35%) (Subbiah, 2018). 

The FDA prescribing information warns that dabrafenib is not indicated for treatment of individuals with wild-type BRAF anaplastic thyroid cancer and noted that the development of new primary malignancies and hemorrhage are possible major side effects.  The FDA prescribing information for trametinib cautions that major side effects may include hemorrhage and when trametinib is used in combination with dabrafenib, new primary malignancies may develop (U.S. FDA Mekinist, 2018; U.S. FDA Tafinlar, 2018).

The NCCN guidelines on thyroid cancer assign a level 2A recommendation for the use of trametinib in combination with dabrafenib for the treatment of individuals with metastatic differentiated thyroid disease.  The NCCN has concluded the following:

Overall, traditional cytotoxic systemic chemotherapy, such as doxorubicin, has minimal efficacy in patients with metastatic differentiated thyroid disease.  Novel treatments for patients with metastatic differentiated thyroid carcinoma have been evaluated.  Agents include … BRAF V600E mutation inhibitors, such as vemurafenib and dabrafenib. (NCCN Thyroid Cancer, 2018).

Definitions

BRAF: A protein which influences the regulation of the MAP kinase / ERKs signaling pathway, which affects cell division, differentiation, and secretion. BRAF is also known as serine/threonine-protein kinase B-Raf, v-raf murine sarcoma viral oncogene homolog B1.

Colon cancer: A type of cancer originating in the tissues of the colon (the longest part of the large intestine); most colon cancers are adenocarcinomas that begin in cells that make and release mucus and other fluids.

Colorectal cancer: A type of cancer originating in the colon (the longest part of the large intestine) or the rectum (the last several inches of the large intestine before the anus).

DNA (also known as deoxyribonucleic acid): The basic material responsible for coding genetic information in a cell.

Epidermal Growth Factor Receptor: A cell receptor that is associated with regulation of cell growth.

Genetic testing: A type of test that is used to determine the presence or absence of a specific gene or set of genes to help diagnose a disease, screen for specific health conditions, and for other purposes.

Hereditary nonpolyposis colorectal cancer (Lynch Syndrome): An inherited CRC syndrome that accounts for 5% to 8% of all CRCs.

KRAS status: Mutated: An altered DNA sequence within the KRAS gene, codons 12 or 13. Tumors with this KRAS type are much less likely to benefit from anti-EGFR therapy with cetuximab or with panitumumab. 

KRAS status: Wild-type: The normal or typical form of the KRAS gene, as distinguished from any mutant forms. Tumors with this KRAS type are much more likely to benefit from anti-EGFR therapy with cetuximab or with panitumumab.

Lynch Syndrome: A hereditary predisposition to CRC and certain other malignancies (for example, endometrial and gastric cancer) due to a DNA mismatch repair gene mutation.

MAPK/ERK pathway: a chain of proteins within the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. The pathway includes many proteins, including MAPK (also known as ERK).

Mekinist (trametinib): A multi-kinase inhibitor approved for use in individuals whose tumors express the BRAF V600E or V600K gene mutations as detected by an FDA-approved test.

Melanoma: A type of cancer that begins in the melanocytes. Melanoma is also referred to as malignant melanoma and cutaneous melanoma.

Metastatic: The spread of cancer from one part of the body to another; a metastatic tumor contains cells that are like those in the original (primary) tumor and have spread; also referred to as stage IV cancer.

MMR: DNA mismatch repair.

Mutation: A permanent, transmissible change in genetic material.

Oncogene: A gene having the potential to cause a normal cell to become cancerous.

Tafinlar (dabrafenib): A BRAF inhibitor approved for use in individuals with melanoma whose tumors express the BRAF V600E gene mutation as detected by an FDA-approved test.

THxID BRAF test: An FDA-Approved diagnostic test used to help determine wither an individual’s melanoma cells have the V600E or V600K mutation in the BRAF gene. The ThxID BRAF test was approved by the FDA to be used as a companion diagnostic test to aid in the selection of individuals for treatment with dabrafenib (Tafinlar) and trametinib (Mekinist).

Zelboraf (vemurafenib): A kinase inhibitor indicated for the treatment of individuals with metastatic melanoma with BRAFV600E mutation as detected by BRAF V600E mutation analysis.

References

Peer Reviewed Publications:

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Government Agency, Medical Society, and Other Authoritative Publications:

  1. Bonis PA, Trikalinos TA, Chung M, et al. Hereditary Nonpolyposis Colorectal Cancer: Diagnostic Strategies and Their Implications. Evidence Report/Technology Assessment No. 150 (Prepared by Tufts-New England Medical Center Evidence-based Practice Center under Contract No. 290-02-0022). AHRQ Publication No. 07-E008. Rockville, MD: Agency for Healthcare Research and Quality. May 2007.
  2. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. 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. 2013; 15(7):517-527.
  3. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med. 2009; 11(1):35-41.
  4. Garbe C, Peris K, Hauschild A, et al. Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline--Update 2012. Eur J Cancer. 2012; 48(15):2375-2390.
  5. Giardiello FM, Allen JI, Axilbund JE, et al. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the U.S. Multi-Society Task Force on Colorectal Cancer. Gastrointest Endosc. 2014; 80(2):197-220.
  6. Hedge M, Ferber M, Mao R, et al. ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). Genet Med. 2014; 16(1):101-116.
  7. NCCN Clinical Practice Guidelines in Oncology™. © 2018 National Comprehensive Cancer Network, Inc. Available at: http://www.nccn.org/index.asp.
    • Colon Cancer (V2.2017). Revised March 13, 2017. Accessed on September 24, 2017.
    • Genetic/Familial High-Risk: Colorectal (V2.2017). Revised August 9, 2017. Accessed on September 23, 2017.
    • Hairy Cell Leukemia (V1.2018). Revised August 21, 2017. Accessed on September 23, 2017.
    • Melanoma (V1.2017). Revised November 10, 2016. Accessed on September 23, 2017.
    • Non-Small Cell Lung Cancer (V8.2017). Revised July 14, 2017. Accessed on September 23, 2017.
    • Rectal Cancer (V3.2017). Revised March 13, 2017. Accessed on September 23, 2017.
    • Soft Tissue Sarcoma (V2.2017). Revised February 08, 2017. Accessed on September 23, 2017.
    • Thyroid Carcinoma (v1.2018). Revised May 22, 2018. Accessed on June 20, 2018.
  8. Palomaki GE, McClain MR, Melillo S, et al. EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from Lynch syndrome. Genet Med. 2009; 11(1):42-65.
  9. Planchard D, Mazieres J, Riely GJ, et al. Interim results of phase II study BRF113928 of dabrafenib in BRAF V600E mutation–positive non-small cell lung cancer (NSCLC) patients. J Clin Oncol 31, 2013 (suppl; abstr 8009).
  10. U.S. Food and Drug Administration. Label and approval information: Mekinist (trametinib). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204114s009lbl.pdf. Accessed on June 20, 2018.
  11. U.S. Food and Drug Administration. Label and approval information: Tafinlar (dabrafenib). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/202806s010lbl.pdf. Accessed on June 20, 2018.
  12. U.S. Food and Drug Administration. Label and approval information: Zelboraf (vemurafenib) Tablet, 240mg. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/202429s012lbl.pdf. Accessed on September 25, 2017.
  13. U.S. Food and Drug Administration. List of cleared or approved companion diagnostic devices (in vitro and imaging tools). Updated 08/02/2017. Available at: https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm. Accessed on September 25, 2017.
  14. United States Food and Drug Administration (FDA). Premarket Approval Letter (PMA). cobas® 4800 BRAF V600 Mutation Test, PMA # P110020. Available at: http://www.accessdata.fda.gov/cdrh_docs/pdf11/P110020a.pdf. Accessed on September 25, 2017.
  15. U.S. Food and Drug Administration. Premarket Notification Database. THxID™ BRAF Kit for use on the ABI 7500 Fast Dx Real-Time PCR Instrument Summary of Safety and Effectiveness. Available at: http://www.accessdata.fda.gov/cdrh_docs/pdf12/P120014b.pdf. Accessed on September 25, 2017.
  16. U.S. Food and Drug Administration. Summary of Safety and Effectiveness Data (SEED). THxID™ BRAF Kit for use on the ABI 7500 Fast Dx Real-Time PCR Instrument. Available at: http://www.accessdata.fda.gov/cdrh_docs/pdf12/P120014b.pdf. Accessed on September 25, 2017.
Websites for Additional Information
  1.  American Cancer Society.
  2. Genetics Home Reference. BRAF. Reviewed June 2016. Available at: http://ghr.nlm.nih.gov/gene/BRAF. Accessed on September 25, 2017.
  3. National Cancer Institute (NCI): PDR Treatment Information for Patients.
  4. National Cancer Institute (NCI): Surveillance, epidemiology, and end results program. Cancer stat facts: thyroid cancer. Available at: https://seer.cancer.gov/statfacts/html/thyro.html. Accessed on June 20, 2018.
Index

Anaplastic thyroid cancer
BRAF Mutation Analysis
Cobas® 4800 BRAF V600 Mutation Test
Colorectal Cancer
Hairy-cell leukemia
Lynch Syndrome
Melanoma
Mekinist (trametinib)
Non-small cell lung cancer
Tafinlar (dabrafenib)
THxID BRAF assay
Zelboraf® (vemurafenib)

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

History

Status

Date

Action

Revised

07/26/2018

Medical Policy & Technology Assessment Committee (MPTAC) review.

Revised

07/18/2018

Hematology/Oncology Subcommittee review. Added position statement indicating that BRAF mutation analysis is considered medically individuals with unresectable or metastatic anaplastic thyroid cancer to identify those who would benefit from treatment with dabrafenib (Tafinlar) in combination with trametinib (Mekinist). Updated Discussion/General Information, References, Index and History sections. Updated Coding section; added ICD-10-CM C73 and Z85.850.

New

11/02/2017

MPTAC review. Initial document development.

New

11/01/2017

Hematology/Oncology Subcommittee review. Initial document development. Moved content of GENE.00019 to new clinical utilization management guideline document with the same title.