Putative contribution of CD56 positive cells in cetuximab treatment efficacy in first-line metastatic colorectal cancer patients.
BACKGROUND
Activity of cetuximab, a chimeric monoclonal antibody targeting the epidermal growth factor receptor, is largely attributed to its direct antiproliferative and proapoptotic effects. Antibody-dependent cell-mediated cytotoxicity (ADCC) could be another possible mechanism of cetuximab antitumor effects and its specific contribution on the clinical activity of cetuximab is unknown.


METHODS
We assessed immune cells infiltrate (CD56, CD68, CD3, CD4, CD8, Foxp3) in the primary tumor of metastatic colorectal cancer (mCRC) patients treated with a first-line cetuximab-based chemotherapy in the framework of prospective trials (treatment group) and in a matched group of mCRC patients who received the same chemotherapy regimen without cetuximab (control group). The relationship between intra-tumoral immune effector cells, the K-ras status and the efficacy of the treatment were investigated. We also evaluated in vitro, the ADCC activity in healthy donors and chemonaive mCRC patients and the specific contribution of CD56+ cells.


RESULTS
ADCC activity against DLD1 CRC cell line is maintained in cancer patients and significantly declined after CD56+ cells depletion. In multivariate analysis, K-ras wild-type (HR: 4.7 (95% CI 1.8-12.3), p = 0.001) and tumor infiltrating CD56+ cells (HR: 2.6, (95%CI:1.14-6.0), p = 0.019) were independent favourable prognostic factors for PFS and response only in the cetuximab treatment group. By contrast CD56+ cells failed to predict PFS and response in the control group.


CONCLUSIONS
CD56+ cells, mainly NK cells, may be the major effector of ADCC related-cetuximab activity. Assessment of CD56+ cells infiltrate in primary colorectal adenocarcinoma may provide additional information to K-ras status in predicting response and PFS in mCRC patients treated with first-line cetuximab-based chemotherapy.
Maréchal
Raphaël
R
Department of Gastroenterology, GI Cancer Unit, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium. rmarecha@ulb.ac.be
De Schutter
Jef
J
Nagy
Nathalie
N
Demetter
Pieter
P
Lemmers
Arnaud
A
Devière
Jacques
J
Salmon
Isabelle
I
Tejpar
Sabine
S
Van Laethem
Jean-Luc
JL
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D019002:CD56 Antigen / Q000378:metabolism*; D000068818:Cetuximab; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D019002:CD56 Antigen; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab