Department of GI Medical Oncology ALPHABET SOUP: MAKING SENSE OF KRAS, BRAF, RAS AND OTHER BIOMARKERS IN METASTATIC COLORECTAL CANCER Cathy Eng, M.D., F.A.C.P. Associate Professor Associate Medical Director, Colorectal Center Director of Network Clinical Research, GI Med Oncology Co-Chairman, SWOG Rectal Subcommittee April 23, 2014
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Alphabet Soup - Biomarker testing for colon and rectal cancer patients - KRAS, RAS
Dr. Cathy Eng's presentation regarding biomarkers. Explaining why colon and rectal cancer patients should undergo testing for KRAS, NRAS and other tumor tests.
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Transcript
Department of GI Medical Oncology
ALPHABET SOUP: MAKING SENSE OF KRAS, BRAF, RAS AND OTHER BIOMARKERS
IN METASTATIC COLORECTAL CANCER
Cathy Eng, M.D., F.A.C.P.Associate Professor
Associate Medical Director, Colorectal CenterDirector of Network Clinical Research, GI Med Oncology
Cancers of the Colon and RectumInternational Statistics
Jemal et al: Cancer Epidemiol Biomarkers Prev; 19(8) August 2010; Siegel et al: CA Cancer J Clin 2014
Incidence
Mortality
1.2 Million
609,000
Worldwide
per annum
USA (2014)
Incidence
Mortality
136,830
50,310
Colorectal cancer is the 3rd most common cancer inmen and the 2nd in women.
Advances in the Treatment of Metastatic Colorectal Cancer
1980 1985 1990 1995 2000 2005
Therapeutic concepts
Palliative CTNeoadjuvant CT
CapecitabineOxaliplatin
Cetuximab
Bevacizumab
Irinotecan5-FU
Panitumumab Targeted therapies
{
5-FU = 5-fluorouracil; CT = chemotherapy.
{Cytotoxic chemotherapies
Ras
OS: 20M
OS: 32 months
AfliberceptRegorafenib
IFL
IFL + b
evaciz
umab
FOLFOX/Cap
eOx
FOLFOX/Cape
Ox + be
v
FOLFIRI
FOLFIRI +
beva
cizum
abmIFL
mIFL + be
vaciz
umab
0
5
10
15
20
25
30
15.6
20.3 19.9 21.323.1
28
17.619.2
First-Line Bevacizumab in mCRC: Overall Survival
*P<0.001; †P = 0.0769.1. Hurwitz H et al. N Engl J Med. 2004;350:2335-2342; 2. Saltz LB et al. J Clin Oncol. 2008;26:2013-2019; 3. Fuchs C et al. J Clin Oncol. 2007;25:4779-4786; 4. Fuchs C et al. J Clin Oncol. 2008;26:689-690;
Khambata-Ford, S. et al. J Clin Oncol; 25:3230-3237 2007
Cetuximab and K-ras modulate signaling through the epidermal growth factor receptor (EGFR) pathway
BRAF MT Serine-threonine kinase belong to the RAF
family Mutation also leads to constitutive activation V600E accounts for 90% of mutations Found in < 10 % of all CRC patients Associated with hypermethylation of CpG island. Mutually exclusive with KRAS MT Prognostic but NOT predictive
All studies insufficiently powered to provide sufficient data to determine use of anti-EGFR therapy based on BRAF status.
NRAS Resembles Kras Oncogene < 5% of all mCRC Mutations in codons 12, 13, 61, 117 and
146 Usually codon 61
Mutually exclusive with KRAS
Front-line chemotherapy with anti-EGFR therapy
Update on PRIME Study Phase III
Douillard JY, et al. J Clin Oncol. 2010;28:4697-4705.
Patients• Previously untreated mCRC
• Fluorouracil-based adjuvant chemotherapy allowed if PD occurred ≥6 mo after completion; no oxaliplatin
• Tumor tissue from primary tumor or metastasis available for biomarker analysis
About 17% of patients with mCRC harbor mutations beyond KRAS exon 2 mutations
Excluding patients with RAS mutations identifies patients more likely to benefit from anti-EGFR therapy.
Practical interpretation: until an all-RAS test becomes available, EGFR monoclonal antibodies have the potential to be detrimental in patients who may harbor an unrecognized RAS mutation when administered with oxaliplatin-based chemotherapy regimens