In February 2010, the Medical Advisory Secretariat (MAS) began work on 
evidence-based reviews of the literature surrounding three pharmacogenomic 
tests. This project came about when Cancer Care Ontario (CCO) asked MAS to 
provide evidence-based analyses on the effectiveness and cost-effectiveness of 
three oncology pharmacogenomic tests currently in use in Ontario.Evidence-based 
analyses have been prepared for each of these technologies. These have been 
completed in conjunction with internal and external stakeholders, including a 
Provincial Expert Panel on Pharmacogenomics (PEPP). Within the PEPP, subgroup 
committees were developed for each disease area. For each technology, an 
economic analysis was also completed by the Toronto Health Economics and 
Technology Assessment Collaborative (THETA) and is summarized within the 
reports.THE FOLLOWING REPORTS CAN BE PUBLICLY ACCESSED AT THE MAS WEBSITE AT: 
www.health.gov.on.ca/mas or at 
www.health.gov.on.ca/english/providers/program/mas/mas_about.htmlGENE EXPRESSION 
PROFILING FOR GUIDING ADJUVANT CHEMOTHERAPY DECISIONS IN WOMEN WITH EARLY BREAST 
CANCER: An Evidence-Based and Economic AnalysisEpidermal Growth Factor Receptor 
Mutation (EGFR) Testing for Prediction of Response to EGFR-Targeting Tyrosine 
Kinase Inhibitor (TKI) Drugs in Patients with Advanced Non-Small-Cell Lung 
Cancer: an Evidence-Based and Economic AnalysisK-RAS testing in Treatment 
Decisions for Advanced Colorectal Cancer: an Evidence-Based and Economic 
Analysis.
OBJECTIVE: The objective of this systematic review is to determine the 
predictive value of KRAS testing in the treatment of metastatic colorectal 
cancer (mCRC) with two anti-EGFR agents, cetuximab and panitumumab. Economic 
analyses are also being conducted to evaluate the cost-effectiveness of KRAS 
testing.
CLINICAL NEED: CONDITION AND TARGET POPULATION Metastatic colorectal cancer 
(mCRC) is usually defined as stage IV disease according to the American Joint 
Committee on Cancer tumour node metastasis (TNM) system or stage D in the Duke's 
classification system. Patients with advanced colorectal cancer (mCRC) either 
present with metastatic disease or develop it through disease progression. KRAS 
(Kristen-RAS, a member of the rat sarcoma virus (ras) gene family of oncogenes) 
is frequently mutated in epithelial cancers such as colorectal cancer, with 
mutations occurring in mutational hotspots (codons 12 and 13) of the KRAS 
protein. Involved in EGFR-mediated signalling of cellular processes such as cell 
proliferation, resistance to apoptosis, enhanced cell motility and 
neoangiogenesis, a mutation in the KRAS gene is believed to be involved in 
cancer pathogenesis. Such a mutation is also hypothesized to be involved in 
resistance to targeted anti-EGFR (epidermal growth factor receptor with tyrosine 
kinase activity) treatments such as cetuximab and panitumumab, hence, the 
important in evaluating the evidence on the predictive value of KRAS testing in 
this context. KRAS MUTATION TESTING IN ADVANCED COLORECTAL CANCER: Both 
cetuximab and panitumumab are indicated by Health Canada in the treatment of 
patients with metastatic colorectal cancer whose tumours are WT for the KRAS 
gene. Cetuximab may be offered as monotherapy in patients intolerant to 
irinotecan-based chemotherapy or in patients who have failed both irinotecan and 
oxaliplatin-based regimens and who received a fluoropyrimidine. It can also be 
administered in combination with irinotecan in patients refractory to other 
irinotecan-based chemotherapy regimens. Panitumumab is only indicated as a 
single agent after failure of fluoropyrimidine-, oxaliplatin-, and 
irinotecan-containing chemotherapy regimens. In Ontario, patients with advanced 
colorectal cancer who are refractory to chemotherapy may be offered the targeted 
anti-EGFR treatments cetuximab or panitumumab. Eligibility for these treatments 
is based on the KRAS status of their tumour, derived from tissue collected from 
surgical or biopsy specimens. It is believed that KRAS status is not affected by 
treatments, therefore, for patients for whom surgical tissue is available for 
KRAS testing, additional biopsies prior to treatment with these targeted agents 
is not necessary. For patients that have not undergone surgery or for whom 
surgical tissue is not available, a biopsy of either the primary or metastatic 
site is required to determine their KRAS status. This is possible as status at 
the metastatic and primary tumour sites is considered to be similar.
RESEARCH QUESTION: To determine if there is predictive value of KRAS testing in 
guiding treatment decisions with anti-EGFR targeted therapies in advanced 
colorectal cancer patients refractory to chemotherapy.
LITERATURE SEARCH: The Medical Advisory Secretariat followed its standard 
procedures and on May 18, 2010, searched the following electronic databases: 
Ovid MEDLINE, EMBASE, Ovid MEDLINE In-Process & Other Non-Indexed Citations, 
Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic 
Reviews and The International Network of Agencies for Health Technology 
Assessment database. The subject headings and keywords searched included 
colorectal cancer, cetuximab, panitumumab, and KRAS testing. The search was 
further restricted to English-language articles published between January 1, 
2009 and May 18, 2010 resulting in 1335 articles for review. Excluded were case 
reports, comments, editorials, nonsystematic reviews, and letters. Studies 
published from January 1, 2005 to December 31, 2008 were identified in a health 
technology assessment conducted by the Agency for Healthcare Research and 
Quality (AHRQ), published in 2010. In total, 14 observational studies were 
identified for inclusion in this EBA: 4 for cetuximab monotherapy, 7 for the 
cetuximab-irinotecan combination therapy, and 3 to be included in the review for 
panitumumab monotherapy
INCLUSION CRITERIA: English-language articles, and English or French-language 
HTAs published from January 2005 to May 2010, inclusive.Randomized controlled 
trials (RCTs) or observational studies, including single arm treatment studies 
that include KRAS testing.Studies with data on main outcomes of interest, 
overall and progression-free survival.Studies of third line treatment with 
cetuximab or panitumumab in patients with advanced colorectal cancer refractory 
to chemotherapy.For the cetuximab-irinotecan evaluation, studies in which at 
least 70% of patients in the study received this combination therapy.
EXCLUSION CRITERIA: Studies whose entire sample was included in subsequent 
publications which have been included in this EBA.Studies in pediatric 
populations.Case reports, comments, editorials, or letters.
OUTCOMES OF INTEREST: Overall survival (OS), medianProgression-free-survival 
(PFS), median.Response rates.Adverse event rates.Quality of life (QOL). SUMMARY 
OF FINDINGS OF SYSTEMATIC REVIEW: CETUXIMAB OR PANITUMUMAB MONOTHERAPY: Based on 
moderate GRADE observational evidence, there is improvement in PFS and OS 
favouring patients without the KRAS mutation (KRAS wildtype, or KRAS WT) 
compared to those with the mutation. CETUXIMAB-IRINOTECAN COMBINATION THERAPY: 
There is low GRADE evidence that testing for KRAS may optimize survival benefits 
in patients without the KRAS mutation (KRAS wildtype, or KRAS WT) compared to 
those with the mutation. However, cetuximab-irinotecan combination treatments 
based on KRAS status discount any effect of cetuximab in possibly reversing 
resistance to irinotecan in patients with the mutation, as observed effects were 
lower than for patients without the mutation. Clinical experts have raised 
concerns about the biological plausibility of this observation and this 
conclusion would, therefore, be regarded as hypothesis generating.
ECONOMIC ANALYSIS: Cost-effectiveness and budget impact analyses were conducted 
incorporating estimates of effectiveness from this systematic review. Evaluation 
of relative cost-effectiveness, based on a decision-analytic cost-utility 
analysis, assessed testing for KRAS genetic mutations versus no testing in the 
context of treatment with cetuximab monotherapy, panitumumab monotherapy, 
cetuximab in combination with irinotecan, and best supportive care. Of 
importance to note is that the cost-effectiveness analysis focused on the impact 
of testing for KRAS mutations compared to no testing in the context of different 
treatment options, and does not assess the cost-effectiveness of the drug 
treatments alone.
CONCLUSIONS: KRAS status is predictive of outcomes in cetuximab and panitumumab 
monotherapy, and in cetuximab-irinotecan combination therapy. While KRAS testing 
is cost-effective for all strategies considered, it is not equally 
cost-effective for all treatment options.