PIK3CA, BRAF, and PTEN status and benefit from cetuximab in the treatment of advanced colorectal cancer--results from NCIC CTG/AGITG CO.17.
OBJECTIVE
Cetuximab improves survival in patients with K-ras wild-type advanced colorectal cancer. We examined the predictive and prognostic significance of additional biomarkers in this setting, in particular BRAF, PIK3CA, and PTEN.


METHODS
Available colorectal tumor samples were analyzed from the CO.17 study. BRAF mutations were identified in tumor-derived DNA by direct sequencing and PIK3CA mutations were identified using a high-resolution melting screen with confirmation by sequencing. PTEN expression by immunohistochemistry (IHC) was performed on tissue microarrays. For each biomarker, prognostic and predictive effects were examined using a Cox model with tests for treatment-biomarker interaction.


RESULTS
A total of 572 patients with pretreated colorectal cancer were randomly assigned to receive cetuximab or best supportive care (BSC). Of 401 patients assessed for BRAF status, 13 (3.2%) had mutations. Of 407 patients assessed for PIK3CA status, 61 (15%) had mutations. Of 205 patients assessed for PTEN, 148 (72%) were negative for IHC expression. None of BRAF, PIK3CA, or PTEN was prognostic for overall or progression-free survival in the BSC arm. None was predictive of benefit from cetuximab, either in the whole study population or the K-ras wild-type subset. In the K-ras wild-type subgroup, the overall survival adjusted HR according to BRAF mutation status was 1.39 (interaction P = 0.69), PIK3CA mutation status HR = 0.79 (interaction P = 0.63), and PTEN expression HR = 0.75 (interaction P = 0.61).


CONCLUSIONS
In chemotherapy-refractory colorectal cancer, neither PIK3CA mutation status nor PTEN expression were prognostic, nor were they predictive of benefit from cetuximab. Evaluation of predictive significance of BRAF mutations requires a larger sample size.
Authors' Affiliation: Flinders University, Flinders Centre for Innovation in Cancer; Department of Medical Oncology, Flinders Medical Centre, Flinders Drive, Bedford Park, South Australia, Australia.
Christos S
CS
Karapetis
Derek
D
Jonker
Manijeh
M
Daneshmand
Jennifer E
JE
Hanson
Christopher J
CJ
O'Callaghan
Celia
C
Marginean
John R
JR
Zalcberg
John
J
Simes
Malcolm J
MJ
Moore
Niall C
NC
Tebbutt
Timothy J
TJ
Price
Jeremy D
JD
Shapiro
Nick
N
Pavlakis
Peter
P
Gibbs
Guy A
GA
Van Hazel
Ursula
U
Lee
Rashida
R
Haq
Shakeel
S
Virk
Dongsheng
D
Tu
Ian A J
IA
Lorimer
D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D000068818:Cetuximab; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D051059:PTEN Phosphohydrolase / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D046888:Tissue Array Analysis; D016896:Treatment Outcome
D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D000068818:Cetuximab