Intra-image referencing for simplified assessment of HER2-expression in breast cancer metastases using the Affibody molecule ABY-025 with PET and SPECT

Abstract

PurposeIn phase I/II-studies radiolabelled ABY-025 Affibody molecules identified human epidermal growth factor receptor 2 (HER2) expression in breast cancer metastases using PET and SPECT imaging. Here, we wanted to investigate the utility of a simple intra-image normalization using tumour-to-reference tissue-ratio (T/R) as a HER2 status discrimination strategy to overcome potential issues related to cross-calibration of scanning devices.MethodsTwenty-three women with pre-diagnosed HER2-positive/negative metastasized breast cancer were scanned with [111In]-ABY-025 SPECT/CT (n = 7) or [68Ga]-ABY-025 PET/CT (n = 16). Uptake was measured in all metastases and in normal spleen, lung, liver, muscle, and blood pool. Normal tissue uptake variation and T/R-ratios were established for various time points and for two different doses of injected peptide from a total of 94 whole-body image acquisitions. Immunohistochemistry (IHC) was used to verify HER2 expression in 28 biopsied metastases. T/R-ratios were compared to IHC findings to establish the best reference tissue for each modality and each imaging time-point. The impact of shed HER2 in serum was investigated.ResultsSpleen was the best reference tissue across modalities, followed by blood pool and lung. Spleen-T/R was highly correlated to PET SUV in metastases after 2 h (r = 0.96, P < 0.001) and reached an accuracy of 100% for discriminating IHC HER2-positive and negative metastases at 4 h (PET) and 24 h (SPECT) after injection. In a single case, shed HER2 resulted in intense tracer retention in blood. In the remaining patients shed HER2 was elevated, but without significant impact on ABY-025 biodistribution.ConclusionT/R-ratios using spleen as reference tissue accurately quantify HER2 expression with radiolabelled ABY-025 imaging in breast cancer metastases with SPECT and PET. Tracer binding to shed HER2 in serum might affect quantification in the extreme case.Electronic supplementary materialThe online version of this article (doi:10.1007/s00259-017-3650-3) contains supplementary material, which is available to authorized users.

Kinetic analysis of HER2-binding ABY-025 Affibody molecule using dynamic PET in patients with metastatic breast cancer

“…HER2 imaging provides an extended scale to the degree of expression contrary to traditional IHC that incorporates the entire range of positive lesions into the ordinal HER2 3+, as shown in the previous studies [11,12,27].…”

Same-Day Imaging Using Small Proteins: Clinical Experience and Translational Prospects in Oncology

“…Comparison with immunohistochemical staining of biopsy material demonstrated that the measurement of the maximal uptake value at 2-4 h after injection permits clear discrimination between metastases with 31 and 21 levels of HER2 expression (21). Furthermore, the spleen can be used as an within-image reference tissue to calculate tumorto-spleen ratios, permitting a simple and robust discrimination between metastases with high and low HER2 expression using both PET and SPECT (23) and thus making the diagnosis independent of external hardware calibrations.…”

(Radio)Theranostic Patient Management in Oncology Exemplified by Neuroendocrine Neoplasms, Prostate Cancer, and Breast Cancer

“…SPECT and PET imaging using anti-HER2 Affibody ® molecule [177][178][179][180][181][182] demonstrated the potential of safe, whole-body, and non-invasive "biopsy", allowing receptor expression heterogeneity profiling (Figure 11), in clinical trials with ongoing multicenter Phase II/III one (NCT03655353) [5,[183][184][185][186][187]. [ 68 Ga]Ga-ABY-025 PET-CT presents advantages over [ 111 In]In-ABY-025/SPECT/CT in terms of simpler logistics, higher resolution, higher detection rate, dynamic scanning, and accurate quantification [5,183] potentially allowing staging, prognosis, patient selection, quantification of the receptor expression and therapeutic drug dose estimation, early monitoring of the treatment response and resistance, residual disease, follow-up, and relapse.…”

“…Extraordinary receptor shedding was observed after the start of HER2-targeted therapy wherein most probably the on-going treatment had executed a rapid cytotoxic impact on the metastases with HER2 debris leaking into the blood stream [186]. Liver biopsy after PET examination showed fibrosis and no sign of remaining cancer cells.…”

“…The In order to facilitate standardized multicenter trials and to enable dissemination of this diagnostic methodology for routine clinical use, it is necessary to provide data evaluation methods that are independent on the variation of PET scanner characteristics. Intra-image normalization such as tumor-to-reference tissue ratio (T/R) was investigated and spleen was found the most accurate approach providing a simple and robust semi-quantification of HER2 expression [186]. The spleen T/R ratio met the selection criteria such as correlation with biopsy analysis results, low variation of radioactivity uptake, and low probability of hosting metastases from breast cancer on spleen.…”