Potential applications for circulating tumor cells expressing the insulin-like growth factor-I receptor.
OBJECTIVE
To detect insulin-like growth factor-IR (IGF-IR) on circulating tumor cells (CTC) as a biomarker in the clinical development of a monoclonal human antibody, CP-751,871, targeting IGF-IR.


METHODS
An automated sample preparation and analysis system for enumerating CTCs (CellTracks) was adapted for detecting IGF-IR-positive CTCs with a diagnostic antibody targeting a different IGF-IR epitope to CP-751,871. This assay was used in three phase I trials of CP-751,871 as a single agent or with chemotherapy and was validated using cell lines and blood samples from healthy volunteers and patients with metastatic carcinoma.


RESULTS
There was no interference between the analytic and therapeutic antibodies. Eighty patients were enrolled on phase I studies of CP-751,871, with 47 (59%) patients having CTCs detected during the study. Before treatment, 26 patients (33%) had CTCs, with 23 having detectable IGF-IR-positive CTCs. CP-751,871 alone, and CP-751,871 with cytotoxic chemotherapy, decreased CTCs and IGF-IR-positive CTCs; these increased toward the end of the 21-day cycle in some patients, falling again with retreatment. CTCs were commonest in advanced hormone refractory prostate cancer (11 of 20). Detectable IGF-IR expression on CTCs before treatment with CP-751,871 and docetaxel was associated with a higher frequency of prostate-specific antigen decline by >50% (6 of 10 versus 2 of 8 patients). A relationship was observed between sustained decreases in CTC counts and prostate-specific antigen declines by >50%.


CONCLUSIONS
IGF-IR expression is detectable by immunofluorescence on CTCs. These data support the further evaluation of CTCs in pharmacodynamic studies and patient selection, particularly in advanced prostate cancer.
de Bono
Johann S
JS
Royal Marsden NHS Foundation Trust, London, United Kingdom. johann.de-bono@icr.ac.uk
Attard
Gerhardt
G
Adjei
Alex
A
Pollak
Michael N
MN
Fong
Peter C
PC
Haluska
Paul
P
Roberts
Luisa
L
Melvin
Carrie
C
Repollet
Madeline
M
Chianese
David
D
Connely
Mark
M
Terstappen
Leon W M M
LW
Gualberto
Antonio
A
D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D005455:Fluorescent Antibody Technique; D006801:Humans; D007158:Immunologic Techniques; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009360:Neoplastic Cells, Circulating / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D017526:Receptor, IGF Type 1