Abstract
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Objectives Tumor uptake of 64Cu-DOTA-trastuzumab varies widely among patients with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (Mortimer,et al., JNM 2014; 55:23-29). We sought to determine the degree to which this observation reflects variation of HER2 gene amplification, a strong correlate of tumor HER2 expression (Slamon, et al., Science 1989;244:707-712).
Methods Patient HER2 status at time of study was determined from biopsied tumor tissue and classified by standard criteria [HER2+: immunohistochemistry IHC 3+ or IHC 2+ and fluorescence in situ hybridization (FISH)-derived HER2-to-reference gene copy ratio > 2.0]. Patients with HER2+ (n=8) or HER2- (n=10) metastatic breast cancer who had not received anti-HER2 therapy for 蠅 2 mo were given trastuzumab i.v. (45 mg, to reduce liver uptake) prior to i.v. injection of 64Cu-DOTA-trastuzumab (364-551 MBq). PET-CT scans were obtained at 21-25 h (3-4 bed positions, 20 or 15 min each) over fields of view based on recent (≤ 17 d prior) 18F-FDG scans. Radiolabel uptake in lesions with maximum diameter on CT 蠅 15 mm (3-10 per patient) was measured as maximum voxel SUV (SUVmax). Residual tissue from tumor biopsies was assayed by FISH to determine average number of HER2 gene copies per tumor cell (<#HER2 copies/cell>).
Results Intra-patient average SUVmax (<SUVmax>, range 3-16 g/mL) was positively correlated (r = 0.86, P < 0.001) with measured <#HER2 copies/cell> (range 2-28). The HER2+ group had higher average <SUVmax> than the HER2- group [9.1 ± 3.8 vs 4.9 ± 1.1 g/mL (mean ± SD); P <0.01], but <#HER2 copies/cell> accounted for more of the variance in <SUVmax> than did HER2 class (74 vs 42%). Although the two groups were well separated with respect to <#HER2 copies/cell>, two HER2+ patients had lower <SUVmax> than three of the HER2- patients. Furthermore, some HER2+ patients with very similar <#HER2 copies/cell> had widely different <SUVmax>, indicating that tumor uptake is not determined solely by HER2 expression.
Conclusions Tumor uptake of 64Cu-DOTA-trastuzumab reflects binding to HER2 as early as 1 d post injection. Measurement of <#HER2 copies/cell> by FISH is a better predictor of trastuzumab uptake than standard HER2 classification. The wide range of 64Cu-DOTA-trastuzumab uptake among HER2+ patients correlates with variable tumor HER2 expression driven by variations in gene amplification. However, HER2 expression/gene amplification is not the only significant determinant of trastuzumab uptake. RESEARCH SUPPORT. DOD 1024511.