Cetuximab and panitumumab are monoclonal antibodies which inhibit the activity of human-epidermal growth factor receptor (EGFR) and are U.S. Food and Drug Administration (FDA) approved for the treatment of metastatic (stage IV) colorectal cancer. However, not all colorectal tumors exhibit the same response to EGFR monoclonal antibody therapy.  KRAS sequence variant analysis is being investigated as a tool to predict how well individuals with metastatic colorectal or anal cancer will respond to anti EGFR drug therapy (including but not necessarily limited to Cetuximab [Erbitux^®]).

The analysis of KRAS status is also being investigated as a clinical tool to predict response to therapy for individuals with other conditions, including, but not necessarily limited to those with non small cell lung cancer, esophageal, pancreatic, gastric and endometrial cancer.  This document addresses DNA testing used to determine the status of the KRAS gene in tumors.

For additional information, please refer to the following related documents:

• DRUG.00035 Panitumumab (Vectibix™)
• DRUG.00036 Cetuximab (Erbitux®)
• GENE.00006 Epithelial Growth Factor Receptor (EGFR) Testing for Non-Small Cell Lung Cancer (NSCLC)
• GENE.00013 Diagnostic Genetic Testing of a Potentially Affected Individual (Adult or Child)
• GENE.00019 BRAF Mutation Analysis

Medically Necessary:

Analysis of KRAS status is considered medically necessary as a technique to predict treatment response to the anti-EGFR monoclonal antibody cetuximab (Erbitux^®), or panitumumab (Vectibix^™) in individuals with stage IV colon, rectal, colorectal or anal adenocarcinoma prior to initiation of cetuximab or panitumumab.

Investigational and Not Medically Necessary: 

The analysis of KRAS status is considered investigational and not medically necessary for all applications not indicated above as medically necessary including but not limited to routine testing at initial diagnosis.

KRAS gene mutation status is being investigated as a possible biomarker of individuals with metastatic (Stage IV) colorectal cancer (CRC) who may not respond well to anti-EGFR monoclonal antibody drugs.  Because there are few treatment options for individuals with metastatic colorectal cancer, the most likely clinical application of KRAS status analysis would be to identify those individuals who would not respond to anti-EGFR monoclonal antibody therapy, thereby saving them the time, expense and unnecessary toxicity of ineffective therapies.  Both cetuximab (Erbitux^®) and panitumumab (Vectibix^™) are approved by the U.S. Food and Drug Administration (FDA) as anti-EGFR agents for the treatment of metastatic colorectal cancer in individuals with refractory disease.

Three studies presented at the 2008 American Society of Clinical Oncology (ASCO) annual meeting demonstrated that individuals with metastatic CRC whose tumors are carriers of the wild type version of the KRAS gene are much more likely than individuals with the mutant form of the gene to benefit from first-line treatment with the monoclonal antibody cetuximab (Erbitux^®).

Cervantes and colleagues (2008) assessed the efficacy of cetuximab alone and in combination with chemotherapy in the first-line setting.  The researchers analyzed the KRAS status in 48 individuals with EGFR-expressing metastatic CRC who received weekly versus bi-weekly administration of cetuximab.  Initially, cetuximab was administered as a first-line single therapeutic agent for 6 weeks, then individuals were assessed for a response to therapy, and lastly, FOLFIRI (leucovorin [folinic acid], 5-FU [flurorouracil] and irinotecan) chemotherapy was added to all participants.  KRAS status was determined using archived tumor material.  Histopathologic evaluation revealed that 48 of the 52 samples contained tumor tissue.  All 48 individuals were evaluated for efficacy.  KRAS mutations were detected in 19 samples (40%).  At the conclusion of the monotherapy phase, the response rate was 27.6% for the KRAS wild type group and 0% for the KRAS mutant group (p=0.015).  During the combination phase, this response rate rose to 55.2% vs. 31.6%, respectively (p=0.144).  Progression free survival for cetuximab in combination with FOLFIRI was significantly improved (hazard ratio: 0.47, p=0.0475) for KRAS wild type group compared to KRAS mutant type group.  The authors concluded that KRAS mutation status can be used to determine the efficacy of cetuximab in the first-line setting for individuals with metastatic CRC either alone or when subsequently used in combination with FOLFIRI.

Van Cutsem and colleagues (2008) conducted efficacy analyses to evaluate the effect of KRAS status in individuals receiving first-line treatment with FOLFIRI with or without cetuximab under controlled study conditions.  Building upon the results of the CRYSTAL trial in which 1,198 individuals with metastatic CRC were randomized to receive either cetuximab in combination with FOLFIRI, 5-FU and irinotecan or FOLFIRI alone, a subgroup analysis assessing the response rate and progression free survival based on the KRAS status was carried out.  Of the 1,198 original study participants, 540 individuals had KRAS-evaluable achievable tumor material.  KRAS mutations were found in 192 (35.6%) of the individuals.  Participants with wild type KRAS status who received cetuximab in combination with FOLFIRI exhibited a statistically significant improvement in progression free survival, as compared with those with the KRAS mutation.  There was no significant difference in the mutant type KRAS individuals on FOLFIRI alone when compared to the group that received cetuximab in combination with FOLFIRI.  The researchers concluded that this study demonstrates the predictive value of KRAS status for the treatment of cetuximab in combination with FOLFIRI as a first-line treatment of metastatic CRC.  Individuals with the KRAS mutant type did not demonstrate a benefit from treatment with cetuximab.

The OPUS study was a randomized controlled trial that compared FOLFOX (leucovorin [folinic acid], 5-FU [flurorouracil] and oxaliplatin) alone to FOLFOX in combination with cetuximab for first-line treatment of colorectal cancer.  The OPUS trial had previously shown an improved response rate when cetuximab was used in combination with FOLFOX, but no improvement was noted in progression-free survival.  Bokemeyer and colleagues (2008) repeated the efficacy analyses of the OPUS trial to evaluate KRAS status and the influence of first-line treatment of individuals with metastatic CRC with FOLFOX with or without cetuximab.  KRAS mutations were detected in 99 of 233 (42%) of the evaluable samples.  The data suggest that the population with wild-type KRAS status benefited more (improved response rate and progression free survival) from the addition of cetuximab to standard treatment, as compared with those with the KRAS mutation.

A published study (Karapetis et al, 2008) analyzed KRAS status in tumor samples obtained from 394 of 572 individuals with colorectal cancer who had been randomly assigned to receive either cetuximab plus best supportive care, or best supportive care alone.  Cetuximab effectiveness was significantly associated with KRAS status; in those with the wild-type version, adding cetuximab to best supportive care alone improved median overall survival (9.5 vs. 4.8 months), hazard ratio for death (0.55), and median progression-free survival (3.7 vs. 1.9 months).  Among individuals with mutant KRAS, there was no benefit offered by adding cetuximab to best supportive care.  In all individuals receiving best supportive care alone without cetuximab, KRAS status was not significantly associated with improved overall survival (hazard ratio for death 1.01).  An accompanying editorial (Messersmith et al, 2008) stated it is reasonable to recommend that all individuals with advanced colorectal cancer being considered for anti-EGFR therapy should undergo KRAS testing, and if the mutant gene is detected, anti-EGFR therapy should not be administered.

De Roock and colleagues (2008) conducted a retrospective analysis of 113 individuals with irinotecan-refractory metastatic colorectal carcinoma with available tumor tissue, from four Belgian clinical trials.  One hundred two (102) individuals had completed tumor measurements throughout the clinical trials.  The clinical trials utilized cetuximab as monotherapy and in combination therapy.  KRAS mutations were detected in 46 of 113 (40.7%) tumors and BRAF V600E mutation was noted in 6 of 107 (5.6%) assessable participants.  The combined BRAF and KRAS mutations were not identified in any individual.  Five individuals were not assessable prior to the first evaluation.  Overall response (OR), including both complete (CR) and partial response (PR), was observed only in the individuals with KRAS wild-type (27 of 66 [41%]) compared to individuals with KRAS mutants (0 of 42 [0%]).  KRAS mutations were identified in 42 of 81 (51.9%) nonresponders, and in 27 OR individuals.  There was no statistically significant difference in the median progression-free survival (PFS) in the entire study.  However, in the cohort receiving cetuximab in combination therapy, there was a significant median PFS between wild-type KRAS (34 weeks) compared to mutant KRAS (12 weeks; P=0.016).  In the entire study population, there was also a significant difference in median OS for KRAS wild-type 43 weeks compared to KRAS mutants 27.3 weeks (P=0.020).  The authors concluded KRAS wild-type is a strong predictor of a significant increase in PFS and OS.  However, the KRAS status of a tumor may still fall short as a biomarker, as not all individuals with wild-type respond or have improved survival and some individuals with mutant KRAS experience long-term disease control.  The data suggest that the metastatic colorectal population with wild-type KRAS mutation status benefited more from cetuximab as compared with those with the activating KRAS mutation.  Therefore, analysis of KRAS may be appropriate to facilitate treatment plans.

In a study of using panitumumab versus best supportive care in a large series of such individuals, Amado and colleagues (2008) found that response rates to the drug were significantly better in those with wild-type KRAS status as compared with those with the mutant variety (response rates 17% vs. 0%, and longer overall survival).  The authors concluded that KRAS status should be considered when selecting such individuals for panitumumab monotherapy.

In 2009, ASCO (Allegra, 2009) issued a provisional consensus clinical opinion based on systematic reviews of literature primarily from phase II and III clinical trials involving individuals with metastatic colorectal cancer.  "All patients with metastatic colorectal carcinoma who are candidates for anti-EGFR antibody therapy should have their tumor tested for KRAS mutations in a CLIA-accredited laboratory.  If KRAS mutation in codon 12 or 13 is detected, then patients with metastatic colorectal carcinoma should not receive anti-EGFR antibody therapy as part of their treatment."

The College of American Pathologists (CAP) document titled "Perspectives on Emerging Technology (POET) Report" states the following:

"KRAS mutations can be detected in approximately 30-40% of all patients with CRC.  Although no level I evidence has been published, multiple studies with strong level II evidence have convincingly shown that patients with KRAS mutations in codons 12 or 13 do not benefit from anti-EGFR therapy with cetuximab or panitumumab.  In contrast, about 40% of patients with metastatic colorectal cancer unresponsive to other therapies, and who lack a KRAS mutation, show a partial response with these agents.  These findings suggest that only patients without KRAS mutations should be eligible to receive these therapies." (CAP 2009)

The updated NCCN (2011) guidelines on Colon Cancer and the guidelines on Rectal Cancer include recommendations for KRAS gene testing for all stage IV colon and rectal disease.  Use of cetuximab or panitumumab is indicated for individuals with tumors that express the wild-type KRAS gene. The NCCN also recommends that individuals with anal adenocarcinoma be managed according to their Rectal Cancer guidelines.

In summary, clinical studies and guidelines suggest that those individuals with metastatic colorectal tumors demonstrating wild-type KRAS status are more likely to benefit from cetuximab or panitumumab than those individuals whose tumors demonstrate a KRAS mutation.  Therefore, analysis of KRAS may be appropriate to facilitate treatment plans for individuals with metastatic colorectal tumors, both in terms of enhancing efficacy and preventing unnecessary adverse effects.

KRAS gene mutation status is also being investigated as a tool to better manage individuals with other types of cancer including, but not necessarily limited to non-small-cell lung cancer (NSCLC), esophageal, pancreatic, gastric and endometrial cancer.  However, research demonstrating the efficacy of KRAS status in influencing clinical outcomes has not proceeded as rapidly for these indications as it has for metastatic colorectal cancer.

While there are some studies suggesting that KRAS status testing may be useful in select individuals with NSCLC, no general consensus has been reached regarding its role in improving clinical management or individual outcomes.  Several randomized controlled trials suggest that additional research is needed in order to determine how KRAS status can be used to determine which tumors are likely to respond to select pharmacologic agents and the impact of KRAS status on the survival outcomes of individuals with NSCLC. (Douillard, 2010; Eberhard, 2005; Khambata-Ford, 2010; Schneider, 2008.)  Mao and colleagues (2010) carried out a meta-analysis that included 22 studies.  The final analysis consisted of a total of 1,470 individuals with NSCLC of whom 231 (16%) had KRAS mutations.  The objective response rates for individual with a KRAS mutation was 3% (6/210), as opposed to the response rate in individuals with the wild-type KRAS which was 26% (287/1125).  Subgroup analyses were carried out on the basis of ethnicity and study treatment; however, the results were not materially altered.  The researchers concluded that KRAS mutations may represent negative predictive biomarkers for tumor response in individuals with NSCLC treated with EGFR-tyrosine kinase inhibitors (TKIs).  However, due to the mutually exclusive relationship between KRAS and EGFR mutation and no difference in survival between KRAS mutant/EGFR wild-type and KRAS wild-type/EGFR wild-type NSCLC, the clinical usefulness of KRAS mutation as a selection marker for EGFR-TKIs sensitivity in NSCLC is limited."

The National Comprehensive Cancer Network (NCCN) guidelines on Non-Small Cell Lung Cancer recommend that individuals with NSCLC whose tumors harbor KRAS mutations should be considered for therapy other than erlotinib, but do not recommend that KRAS status testing be performed on all individuals with NSCLC or provide criteria for when this testing would be appropriate.

Published studies evaluating the role of KRAS in individuals with esophageal cancer are also limited.  Working on the premise that KRAS status is a predictor of resistance to cetuximab therapy in colorectal cancer, researchers conducted a retrospective analysis of tumor samples from individuals with metastatic esophageal squamous cell carcinoma (ESCC) who were treated within the OESOTUX trial, to evaluate the KRAS status (Lorenzen, 2009).  Chemo-naïve participants were randomized to receive either cetuximab plus cisplatin/5FU (CET-CF) or cisplatin/5FU (CF) alone.  Tumor samples were collected from previous diagnostic or surgical procedures and were examined for the presence of somatic mutations in the KRAS gene.  Sixty-two (62) individuals with metastatic ESCC were included; of which 32 participants were allocated to the CET-CF and 30 of the participants to the CF arm.  The individuals who were treated with CET-CF compared to individuals treated with CF alone tended to have a higher confirmed overall response rate (PR+CR) (19% versus 13%), a better disease control rate (CR+PR+SD) (75% versus 57%) as well as a longer median progression free survival (5.9 [3.8-8.0] versus 3.6 [1.0-6.2] months) and a longer median overall survival (9.5 [8.4-10.6] and 5.5 [1.9-9.1] months).  Tumor samples from 37 of the 62 individuals were analyzed for KRAS status.  Researchers were unable to obtain tumor samples or deemed the samples inadequate for testing in 25 of the participants.  No mutations of the KRAS gene could be detected in any of the 37 tumor samples that were evaluated.  The authors concluded that KRAS "gene mutations in codon 12 and 13 are rare to absent events in ESCC. However, due to the small samples size, further studies are needed to confirm the findings of this subset analysis. Other activating mutations in the EGFR downstream signaling pathway cannot be excluded."

At the time of this review, there were no published peer-reviewed randomized controlled trials investigating the possible role of KRAS status in individuals with pancreatic cancer.  However, the results of at least one phase I clinical trial exploring the role of KRAS in individuals with pancreatic cancer have been published.  In the study by Olson and colleagues (2009), researchers evaluated plasma KRAS as a potential marker of response to gefitinib and concurrent chemoradiation in 12 individuals with advanced pancreatic cancer.  The researchers concluded changes in serum KRAS may provide critical information as to the efficacy of gefitinib and assist in tailoring treatment for cancers of the pancreas.

Peer-reviewed published literature regarding the relationship between KRAS status and gastric cancer is also limited.  Hunt and colleagues (2001) explored if KRAS mutations were predictive for the development of gastric carcinoma.  After three years, the data suggested that individuals whose baseline stomach biopsies revealed KRAS mutations were 3.74 times as likely to progress to a higher premalignant stage than those who lacked baseline mutations.  However, at 6 years, baseline KRAS mutations failed to predict histological progression.

The available peer-reviewed studies investigating the value of KRAS status and endometrial cancer are also limited. Several small studies have suggested a relationship between KRAS mutations and the development of endometrial cancer (Caduff, 1995; Duggan, 1994; and Fujimoto, 1993), but stopped short of identifying the exact role of KRAS mutations in the clinical setting.  Estellar and colleagues (1997) analyzed KRAS point mutation and gene amplification in 55 endometrial carcinomas using polymerase to examine the prevalence and clinicopathological significance of KRAS oncogene activation in endometrial carcinoma and atypical hyperplasia.  Point mutations at codon 12 of KRAS oncogene were identified in eight of the 55 (14.5%) tumor specimens.  The researchers did not detect any KRAS gene amplification in any of the endometrial carcinomas studied.  No correlation was established between KRAS gene mutation and age at onset, histological subtype, grade of differentiation or clinical stage.  The researchers concluded that KRAS mutation is a relatively common event in endometrial carcinomas, but did not provide any clear prognostic value. 

The peer-reviewed literature regarding the role of KRAS status in individuals with ovarian cancer has been predominately limited to small, non-randomized, uncontrolled studies.  While these studies have demonstrated that there may be an association between KRAS mutations and the development of ovarian cancer, more research is needed to determine its exact role in the development of ovarian tumors (Cuatrecasas, 1997; Hogdall, 2003; Semczuk, 2004; and Varraas, 1999).

A monoclonal antibody is a protein developed in the laboratory that can locate and bind to specific substances in the body, including on the surface of cancer cells.  Cetuximab is a monoclonal antibody that binds specifically to the human epidermal growth factor receptor.  As a result, cetuximab may interrupt the signals necessary for certain cancer cells' growth and survival.  For additional information on cetuximab (Erbitux^®) or Vectibix^™_, refer to DRUG.00036 Cetuximab (Erbitux^®) or DRUG.00035 Panitumumab (Vectibix^™).

KRAS status analysis using polymerase chain reaction (PCR) analysis is available in regions of the United States as a laboratory-developed test.  Premarket approval from the U.S. Food and Drug Administration (FDA) is not required when the assay is performed in a CLIA certified laboratory.

Adenocarcinoma: A type of cancer originating in cells that line specific internal organs and that have gland-like (secretory) properties.

Anal cancer: A type of cancer originating in the tissues of the anus; the anus is the opening of the rectum (last part of the large intestine) to the outside of the body.

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).

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

Gene Amplification:A genetic variation characterized by the presence of multiple copies of the same genetic code on a chromosome.

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.

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.

Monoclonal antibody: A protein developed in the laboratory that can locate and bind to specific substances in the body, including on the surface of cancer cells.

Rectal cancer: A type of cancer originating in tissues of the rectum (the last several inches of the large intestine closest to the anus).

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.

When services may be Medically Necessary when criteria are met: 

When services are Investigational and Not Medically Necessary:
For KRAS analysis services for the diagnoses listed above when criteria are not met or for all other diagnoses not listed, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Future ICD-10 coding (effective 10/01/2013)
A draft of ICD-10 Coding related to this document, as it might look today, is available for reference and comments at: Appendix 1: Future ICD-10 coding

Peer Reviewed Publications: 

1. Al-Jehani RM, Jeyarajah AR, Hagen B, et al. Model for the molecular genetic diagnosis of endometrial cancer using K-ras mutation analysis. J Natl Cancer Inst. 1998; 90(7):540-542.
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. Bokemeyer C, Bondarenko I, Hartmann JT, et al. KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: The OPUS experience. J Clin Oncol 26: 2008 (May 20 suppl; abstr 4000).
4. Caduff RF, Johnston CM, Frank TS. Mutations of the Ki-ras oncogene in carcinoma of the endometrium. Am J Pathol 1995; 146(1):182–188.
5. Cervantes A, Macarulla T, Martinelli E, et al. Correlation of KRAS status (wild type [wt] vs. mutant [mt]) with efficacy to first-line cetuximab in a study of cetuximab single agent followed by cetuximab + FOLFIRI in patients (pts) with metastatic colorectal cancer (mCRC). J Clin Oncol 26: 2008 (May 20 suppl; abstr 4129).
6. Cuatrecasas M, Villanueva A, Matias-Guiu X, Prat J. K-ras mutations in mucinous ovarian tumors: a clinicopathologic and molecular study of 95 cases. Cancer. 1997; 79(8):1581-1586.
7. 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.
8. Douillard JY, Shepherd FA, Hirsh V, et al. Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial. J Clin Oncol. 2010; 28(5):744-752.
9. Duggan BD, Felix JC, Muderspach LI, et al. Early mutational activation of the c-Ki-ras oncogene in endometrial carcinoma. Cancer Res 1994; 54(6):1604–1607.
10. Eberhard DA, Johnson BE, Amler LC et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 2005; 23(25):5900-5909.
11. Esteller M, García A, Martínez-Palones JM, et al. The clinicopathological significance of K-RAS point mutation and gene amplification in endometrial cancer. Eur J Cancer. 1997; 33(10):1572-1577.
12. Fujimoto I, Shimizu Y, Hirai Y, et al. Studies on ras oncogene activation in endometrial carcinoma. Gynecol Oncol. 1993; 48(2):196-202.
13. Hogdall EV, Hogdall CK, Blaakaer J, et al. K-ras alterations in Danish ovarian tumour patients. From the Danish "Malova" Ovarian Cancer study. Gynecol Oncol. 2003; 89(1):31-36.
14. Hunt JD, Mera R, Strimas A, et al. KRAS mutations are not predictive for progression of preneoplastic gastric lesions. Cancer Epidemiol Biomarkers Prev. 2001;10(1):79-80.
15. 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.
16. Khambata-Ford S, Harbison CT, Hart LL, Awad M, et al. Analysis of potential predictive markers of cetuximab benefit in BMS099, a phase III study of cetuximab and first-line taxane/carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2010; 28(6):918-927.
17. Mao C, Qiu LX, Liao RY et al. KRAS mutations and resistance to EGFR-TKIs treatment in patients with non-small cell lung cancer: a meta-analysis of 22 studies. Lung Cancer 2010; 69(3):272-278.
18. Messersmith WA, Ahnen DJ. Targeting EGFR in colorectal cancer. N Engl J Med. 2008; 359(17):1834-1836.
19. Olsen C;Schefter T;Chen, et al. Results of a phase I trial of 12 patients with locally advanced pancreatic carcinoma combining gefitinib, paclitaxel, and 3-dimensional conformal radiation: report of toxicity and evaluation of circulating K-ras as a potential biomarker of response to therapy. Am J Clin Oncol. 2009; 32(2):115-121.
20. Schneider CP, Heigener D, Schott-von-Romer K et al. Epidermal growth factor receptor-related tumor markers and clinical outcomes with erlotinib in non-small cell lung cancer. J Thorac Oncol. 2008; 3(12):1446-1453.
21. Semczuk A, Postawski K, Przadka D et al. K-ras gene point mutations and p21ras immunostaining in human ovarian tumors. Eur J Gynaecol Oncol. 2004; 25(4):484-488.
22. Van Cutsem E, Lang I, D'haens G, et al. KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience. Clin Oncol 26: 2008 (May 20 suppl; abstr 2).
23. Varras MN, Sourvinos G, Diakomanolis E, et al. Detection and clinical correlations of ras gene mutations in human ovarian tumors. Oncology. 1999; 56(2):89-96.

Government Agency, Medical Society, and Other Authoritative Publications: 

1. Allegra CJ, Jessup JM, Somerfield MR, et al. American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol. 2009.  Available at:  http://jco.ascopubs.org/cgi/reprint/JCO.2009.21.9170v1.  Accessed on March 30, 2011.
2. Cetuximab (systemic). In: DrugPoints^® System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Updated December 13, 2010. Available at: http://www.thomsonhc.com  Accessed on March 30, 2011.
3. College of American Pathologists (CAP). Perspectives on Emerging Technology Report (POET). KRAS Mutation Testing for Colorectal Cancer (CRC). September 2009 (Rev 3). Available at: http://www.cap.org/apps/docs/committees/technology/KRAS.pdf.  Accessed March 30, 2011.
4. Erbitux (cetuximab) [Product Information]. Branchburg, NJ. ImClone Systems Incorporated. March 2010. Available at: http://packageinserts.bms.com/pi/pi_erbitux.pdf.  Accessed on March 30, 2011.
5. Lorenzen S, Langer R, Röthling N, et al. Absence of mutations of the K-ras gene in squamous cell carcinoma of the esophagus: Analysis from the randomized oesotux phase II study (cetuximab and cisplatin/5-FU versus cisplatin/5-FU alone). ASCO. 2009; Suppl Abstract No.38.  Available at: http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=63&abstractID=10244  Accessed on March 30, 2011.
6. NCCN Clinical Practice Guidelines in Oncology™. © 2009. National Comprehensive Cancer Network, Inc. For additional information: http://www.nccn.org. Accessed on March 30, 2011.
   • Anal Carcinoma (V.2.2011). Revised February 02, 2011.
   • Colon Cancer (V.3.2011). Revised February 25, 2011.
   • Non-Small Cell Lung Cancer (V.3.2011) Revised January 7, 2011.
   • Rectal Cancer (V.4.2011). Revised February 25, 2011.
7. Panitumumab (systemic). In: DrugPoints^® System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Updated March 04, 2011. Available at: http://www.thomsonhc.com.  Accessed on March 30, 2011.
8. Vectibix (Panitumumab) [Product Information], Thousand Oaks, CA. Amgen. July 2009. Available at: http://pi.amgen.com/united_states/vectibix/vectibix_pi.pdf .  Accessed on March 30, 2011.

1. American Cancer Society. Overview: Colon and Rectum Cancer. Revised March 01, 2010. Available at: http://www.orgsites.com/ga/acs/.  Accessed on. March 30, 2011.
2. American Cancer Society. Monoclonal Antibodies. Reviewed October 27, 2009. Available at: http://www.orgsites.com/ga/acs/.  Accessed on March 30, 2011.
3. National Cancer Institute. Dictionary of Cancer Terms.  Monoclonal Antibodies. Available at: http://www.cancer.gov/. Accessed on March 30, 2011.

Cetuximab   
EGFR
Epidermal Growth Factor Receptor (EGFR)
Erbitux^®
Monoclonal Antibody
Panitumumab
Vectibix™

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.