Development of new oncology drugs has increased since the improved understanding of cancer's complex biology. The oncology field has become the top therapeutic research area for new drugs. However, only a limited number of drugs entering clinical trials will be approved for use as the standard of care for cancer patients. Molecular imaging is increasingly perceived as a tool to support go/no-go decisions early during drug development. It encompasses a wide range of techniques that include radiolabeling a compound of interest followed by visualization with SPECT or PET. Radiolabeling can be performed using a variety of radionuclides, which are preferably matched to the compound on the basis of size and half-life. Imaging can provide information on drug behavior in vivo, whole-body drug target visualization, and heterogeneity in drug target expression. This review focuses on current applications of molecular imaging in the development of small molecules, antibodies, and antihormonal anticancer drugs.

Introduction: Estrogen receptor (ER) expression largely determines the therapy choice for patients diagnosed with metastatic breast cancer (MBC). Given potential conversion of ER-status, the current golden standard for ER assessment is by immunohistochemistry (IHC) on metastatic tissue. Since a biopsy is cumbersome and sometimes not feasible, ER-status assessments by means of [18F]-fluorestradiol (FES)-PET or circulating tumor cells (CTCs) might be potential alternatives. We hypothesize that FES-PET or CTCs can determine ER status in patients with MBC, in a more efficient and patient friendly way than IHC. Methods: In the Dutch multicenter IMPACT-MBC trial (NCT01832051) patients with non-rapidly progressive MBC at first presentation, regardless of subtype, underwent extensive molecular imaging (including FES-PET, 89Zr-trastuzumab-PET and serial [18F]-fluorodeoxyglucose (FDG)-PET), a metastasis biopsy and blood sampling to obtain a whole body molecular profile of their disease. ER-status on the metastasis biopsy was evaluated by IHC and considered positive if ≥10% of the tumor cells showed ER expression. The FES-PET was considered positive when the maximum standardized uptake value (SUVmax) of at least one lesion was ≥ 1.5. Reverse transcription polymerase chain reaction was used to quantify the ESR1 expression in CTCs. ER-positivity was defined as an ESR1 mRNA ΔCq level ≥ -7.86, corrected for background healthy donor blood signal, only in samples with ≥5 CTCs/7.5ml and a sufficient mRNA signal of reference and epithelial genes. Sensitivity, specificity, positive and negative predictive values were calculated (PPV and NPV). Results: From 178 patients of 201 evaluable patients both metastasis IHC and FES-PET could be assessed. 129 of these 178 patients had an IHC ER positive metastasis (72%) and 133 patients had a positive FES-PET (75%). The PPV and NPV for IHC by FES-PET were 91% and 82%, respectively. From 54 of the 178 patients, blood samples contained sufficient CTCs for ESR1 analysis, allowing combined assessment of IHC, FES-PET and CTCs. ER positive CTCs were present in 45 patients (83%). Table 1 Metastasis ER positive (n=42)Metastasis ER negative (n=12)Sensitivity(%)PPV(%)Specificity(%)NPV(%)FES-PET positive4159889  CTC ER positive3879084  FES-PET and CTC positive3849090  FES-PET negative17  5888CTC ER negative45  4256FES-PET and CTC negative14  3380 Conclusion: In newly diagnosed patients with MBC, ER-status in metastatic lesions could be predicted by means of non-invasive FES-PET scan or CTCs. Prediction was most optimal with FES-PET compared to CTCs, and combining FES-PET with CTCs did not essentially improve this. Furthermore, CTCs were not detectable in most of these patients with non-rapidly progressive MBC, limiting their applicability for the present purpose. However, as CTC assessment is most patient friendly, CTCs might be considered as first step in determining MBC ER-status. If ER positive CTCs are detected, ER positive disease is very likely; if no- or ER negative CTCs are detected, MBC ER-status needs to be further assessed by means of tissue confirmation or FES-PET. Funding: Dutch Cancer Society grant RUG 2012-5565, project EMCR 16-8196 Citation Format: Eisses B, Angus L, van der Vegt B, Sieuwerts AM, Kraan J, Martens JW, Glaudemans AW, Brouwers AH, Hoekstra OS, Oyen W, Emmering J, Gerritse S, Menke-van der Houven van Oordt CW, Boon E, van Herpen CM, Jager A, Sleijfer S, de Vries EG, Schröder CP. Non-invasive estrogen receptor assessment by [18F]-fluorestradiol(FES)-PET or circulating tumor cells predicts receptor status in patients with metastatic breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD4-09.

Purpose: Watchful waiting (WW) can be considered for patients with metastatic clear cell renal cell carcinoma (mccRCC) with good or intermediate prognosis, especially those with <2 International Metastatic RCC Database Consortium criteria and ≤2 metastatic sites (referred to as watch and wait ("W&W")-criteria). The IMPACT-RCC study objective was to assess the predictive value of [18F]FDG- and [89Zr]Zr-DFO-girentuximab-PET/CT for WW-duration in patients with mccRCC. Patients and methods:Between February 2015 and March 2018, 48 patients were enrolled, including 40 evaluable patients with good (n=14) and intermediate (n=26) prognosis. Baseline ceCT, [18F]FDG and [89Zr]Zr-DFO-girentuximab-PET/CT were performed. Primary endpoint was the time to disease progression warranting systemic treatment. Maximum standardized uptake values (SUVmax) were measured using lesions on CT-images co-registered to PET/CT. High and low-uptake groups were defined based on median geometric mean SUVmax of RECIST-measurable lesions across patients. Results: The median WW-time was 16.1 months (95%CI 9.0-31.7). The median WW-period was shorter in patients with high [18F]FDG-tumor-uptake than those with low-uptake(9.0 versus 36.2 months, HR 5.6;95%CI 2.4-14.7;p<0.001). Patients with high [89Zr]Zr-DFO-girentuximab-tumor-uptake had a median WW-period of 9.3 months versus 21.3 months with low-uptake (HR 1.7;95%CI 0.9-3.3;p=0.13). Patients with "W&W-criteria" had a longer median WW-period of 21.3 compared with patients without:9.3 months(HR 1.9;95%CI0.9-3.9;pone-sided=0.034). Adding [18F]FDG-uptake to the "W&W-criteria" improved the prediction of WW-duration(p<0.001);whereas [89Zr]Zr-DFO-girentuximab did not (p=0.53). Conclusions: In patients with good or intermediate risk mccRCC, low [18F]FDG-uptake is associated with prolonged WW. This study shows the predictive value of the "W&W-criteria" for WW duration and shows the potential of [18F]FDG-PET/CT to further improve this.