Factors influencing the sensitivity of tumor imaging with a receptor-binding radiopharmaceutical.
The overexpression of cell surface receptors on cancer cells is a potential target for the design of receptor-binding radiopharmaceuticals for tumor imaging. The sensitivity of these agents depends on the interaction in vivo of factors such as the level and heterogeneity of receptor expression, the proportion of targeted cells, the tumor/ nontarget (T/NT) ratio and attenuation by overlying normal tissue. The relative importance of a single factor or combination of factors is unknown. Our objective was to evaluate, under controlled experimental conditions, the effect of these factors on the sensitivity for imaging breast cancer with a new receptor-binding radiopharmaceutical: human epidermal growth factor (HEGF)51 labeled with 111In.


METHODS
MDA-MB-468, S1 or MCF-7 breast cancer cells expressing 1.3 x 10(6), 3.3 x 10(4) and 1.5 x 10(4) epidermal growth factor receptors (EGFR)/cell were targeted in vitro with 111In-HEGF51. Phantoms were constructed with an internal well to simulate a lesion and surrounded by an outer well to simulate normal tissue. The effect of the level of receptor expression was studied with phantoms containing targeted MDA-MB-468, S1 or MCF-7 cells. The effect of the proportion of cells targeted was evaluated using phantoms containing mixed targeted or nontargeted MDA-MB-468 cells. Receptor heterogeneity was studied using phantoms containing mixed MDA-MB-468 and S1 cells. The T/NT ratio was evaluated by varying the concentration of radioactivity in the outer well and tissue attenuation was simulated by overlaying the phantoms with water. Phantoms were imaged using a gamma camera fitted with a medium-energy collimator interfaced to a computer.


RESULTS
The sensitivity for detection of a lesion was directly proportional to the level of receptor expression or to the proportion of cells targeted and inversely proportional to the level of receptor heterogeneity. A T/NT ratio > or = 2:1 was required for detection. Under ideal conditions with a single factor varied, as few as 5 x 10(4) to 10(5) MDA-MB-468 cells with a high level of EGFR expression or 2.5 x 10(5) to 10(6) S1 or MCF-7 cells with a low level of EGFR expression were detected. When the receptor heterogeneity, the proportion of targeted cells and tissue attenuation were varied in combination with a T/NT ratio of 3:1, the sensitivity for detection approached that observed clinically with receptor-binding radiopharmaceuticals (10(7) cells).


CONCLUSIONS
Our results suggest that combinations of four factors may account for the relatively low sensitivity for tumor imaging observed clinically with receptor-binding radiopharmaceuticals and, in particular, strategies aimed at minimizing the effects of receptor heterogeneity; a low proportion of cells targeted and tissue attenuation would improve the detection of small lesions.
Reilly
R M
RM
Division of Nuclear Medicine, The Toronto Hospital, Ontario, Canada.
Gariépy
J
J
D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism; D004815:Epidermal Growth Factor; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D007205:Indium Radioisotopes; D019047:Phantoms, Imaging; D011877:Radionuclide Imaging; D011994:Recombinant Proteins; D012680:Sensitivity and Specificity; D014407:Tumor Cells, Cultured / Q000378:metabolism
D007205:Indium Radioisotopes; D011994:Recombinant Proteins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors