Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer.
OBJECTIVE
The occurrence of KRAS mutation is predictive of nonresponse and shorter survival in patients treated by anti-epidermal growth factor receptor (anti-EGFR) antibody for metastatic colorectal cancer (mCRC), leading the European Medicine Agency to limit its use to patients with wild-type KRAS tumors. However, only half of these patients will benefit from treatment, suggesting the need to identify additional biomarkers for cetuximab-based treatment efficacy.


METHODS
We retrospectively collected tumors from 173 patients with mCRC. All but one patient received a cetuximab-based regimen as second-line or greater therapy. KRAS and BRAF status were assessed by allelic discrimination. EGFR amplification was assessed by chromogenic in situ hybridization and fluorescent in situ hybridization, and the expression of PTEN was assessed by immunochemistry.


RESULTS
In patients with KRAS wild-type tumors (n = 116), BRAF mutations (n = 5) were weakly associated with lack of response (P = .063) but were strongly associated with shorter progression-free survival (P < .001) and shorter overall survival (OS; P < .001). A high EGFR polysomy or an EGFR amplification was found in 17.7% of the patients and was associated with response (P = .015). PTEN null expression was found in 19.9% of the patients and was associated with shorter OS (P = .013). In multivariate analysis, BRAF mutation and PTEN expression status were associated with OS.


CONCLUSIONS
BRAF status, EGFR amplification, and cytoplasmic expression of PTEN were associated with outcome measures in KRAS wild-type patients treated with a cetuximab-based regimen. Subsequent studies in clinical trial cohorts will be required to confirm the clinical utility of these markers.
Laurent-Puig
Pierre
P
INSERM UMR-S775 Molecular Basis of Xenobiotics Response, Paris, France. pierre.laurent-puig@parisdescartes.fr
Cayre
Anne
A
Manceau
Gilles
G
Buc
Emmanuel
E
Bachet
Jean-Baptiste
JB
Lecomte
Thierry
T
Rougier
Philippe
P
Lievre
Astrid
A
Landi
Bruno
B
Boige
Valérie
V
Ducreux
Michel
M
Ychou
Marc
M
Bibeau
Fréderic
F
Bouché
Olivier
O
Reid
Julia
J
Stone
Steven
S
Penault-Llorca
Frédérique
F
D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000556:secondary; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D005602:France / Q000453:epidemiology; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000032:analysis*; D018579:Patient Selection; D057285:Precision Medicine; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012189:Retrospective Studies; D018570:Risk Assessment; D013997:Time Factors; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab