<p>C. PET uptake in one kidney per patient. On X axis the different PET moments: 2, 4 and 7 days post injection. On the Y axis the SUVmax per patient.</p>
<p>Suppl. Table 3. Best clinical response and cause of progression for all patients. NE = not evaluable. SD = stable disease. PD = progressive disease. CR = clinical response. PR = partial response.</p>
<div>AbstractPurpose:<p>PET with 16α-[<sup>18</sup>F]-fluoro-17β-estradiol ([<sup>18</sup>F]FES) allows assessment of whole body estrogen receptor (ER) expression. The aim of this study was to investigate [<sup>18</sup>F]-fluorodeoxyglucose ([<sup>18</sup>F]FDG) and [<sup>18</sup>F]FES PET/CT imaging for response prediction and monitoring of drug activity in patients with metastatic ER-positive breast cancer undergoing treatment with the selective estrogen receptor downregulator (SERD) rintodestrant.</p>Experimental Design:<p>In this trial (NCT03455270), PET/CT imaging was performed at baseline ([<sup>18</sup>F]FDG and [<sup>18</sup>F]FES), during treatment and at time of progression (only [<sup>18</sup>F]FES). Visual, quantitative, and mutational analysis was performed to derive a heterogeneity score (HS) and assess tracer uptake in lesions, in relation to the mutation profile. The primary outcome was progression-free survival (PFS).</p>Results:<p>The HS and PFS in the entire group did not correlate (<i>n</i> = 16, Spearman's rho, <i>P</i> = 0.06), but patients with a low HS (< 25.0%, <i>n</i> = 4) had a PFS of > 5 months whereas patients with no [<sup>18</sup>F]FES uptake (HS 100.0%, <i>n</i> = 3) had a PFS of < 2 months. [<sup>18</sup>F]FES uptake was not affected by estrogen receptor 1 (<i>ESR1</i>) mutations. On-treatment [<sup>18</sup>F]FES PET/CT scans showed no [<sup>18</sup>F]FES uptake in any of the baseline [<sup>18</sup>F]FES-positive lesions. At progression, [<sup>18</sup>F]FES uptake remained blocked in patients scanned ≤ 1–2 half-lives of rintodestrant whereas it restored in patients scanned ≥ 5 days after end of treatment.</p>Conclusions:<p>Absence of ER expression on [<sup>18</sup>F]FES PET is a predictor for no response to rintodestrant. [<sup>18</sup>F]FES uptake during treatment and at time of progression is useful to monitor the (reversible) effect of therapy and continued mode of action of SERDs.</p><p><i><a href="https://aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-23-0393" target="_blank">See related commentary by Linden and Mankoff, p. 2015</a></i></p></div>
// Robin W. Jansen 1 , Paul van Amstel 1 , Roland M. Martens 1 , Irsan E. Kooi 2 , Pieter Wesseling 3, 4 , Adrianus J. de Langen 5 , Catharina W. Menke-Van der Houven van Oordt 6 , Bernard H.E. Jansen 1 , Annette C. Moll 7 , Josephine C. Dorsman 2 , Jonas A. Castelijns 1 , Pim de Graaf 1 and Marcus C. de Jong 1 1 Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands 2 Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands 3 Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands 4 Department of Pathology, Princess Máxima Center for Pediatric Oncology and University Medical Center Utrecht, Utrecht, The Netherlands 5 Department of Respiratory Diseases, VU University Medical Center, Amsterdam, The Netherlands 6 Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands 7 Department of Ophthalmology, VU University Medical Center, Amsterdam, The Netherlands Correspondence to: Marcus C. de Jong, email: mc.dejong@vumc.nl Keywords: radiogenomics; non-invasive; genotyping; biomarker; precision medicine Received: August 11, 2017 Accepted: February 26, 2018 Published: April 13, 2018 ABSTRACT With targeted treatments playing an increasing role in oncology, the need arises for fast non-invasive genotyping in clinical practice. Radiogenomics is a rapidly evolving field of research aimed at identifying imaging biomarkers useful for non-invasive genotyping. Radiogenomic genotyping has the advantage that it can capture tumor heterogeneity, can be performed repeatedly for treatment monitoring, and can be performed in malignancies for which biopsy is not available. In this systematic review of 187 included articles, we compiled a database of radiogenomic associations and unraveled networks of imaging groups and gene pathways oncology-wide. Results indicated that ill-defined tumor margins and tumor heterogeneity can potentially be used as imaging biomarkers for 1p/19q codeletion in glioma, relevant for prognosis and disease profiling. In non-small cell lung cancer, FDG-PET uptake and CT-ground-glass-opacity features were associated with treatment-informing traits including EGFR -mutations and ALK -rearrangements. Oncology-wide gene pathway analysis revealed an association between contrast enhancement (imaging) and the targetable VEGF-signalling pathway. Although the need of independent validation remains a concern, radiogenomic biomarkers showed potential for prognosis prediction and targeted treatment selection. Quantitative imaging enhanced the potential of multiparametric radiogenomic models. A wealth of data has been compiled for guiding future research towards robust non-invasive genomic profiling.
<p>Gene set enrichment analysis on Hallmark gene sets, on genes ranked based on the correlation between gene expression and FDG-PET uptake described by SUVmax (positive normalized enrichment score – NES – for positive correlation, negative NES for negative correlation).</p>
<p>Gene set enrichment analysis on Reactome gene sets, comparing, within the 89Zr-trastuzumab class “high”, metabolic response (positive normalized enrichment score – NES) and lack of metabolic response (negative NES).</p>
Abstract Background: Resection of colorectal cancer liver metastasis (CRCLM) with curative intent is beneficial in approximately 30% of cases, indicating the need for prognostic biomarkers to improve clinical management of CRCLM patients. Protein expression levels of epidermal growth factor receptor (EGFR) and prostaglandin-endoperoxide synthase 2 (PTGS2; also known as cyclooxygenase-2 or COX2) have been associated with carcinogenesis, metastases and survival. EGFR and PTGS2 are targets for molecular drugs and exhibit complex molecular interactions. Aim: We aimed to determine the prognostic value of EGFR and PTGS2 expression in CRCLM of patients who underwent liver resection. Patients and methods: Formalin-fixed paraffin-embedded CRCLM tissue and corresponding primary tumor specimens from a multi-institutional cohort of patients who underwent liver resection between 1990 and 2010 were incorporated into tissue microarrays (TMAs). TMAs were stained for EGFR and PTGS2 by immunohistochemistry and a hazard rate ratio (HRR) for the association between expression in CRCLM and overall survival (OS) was calculated. Results were validated by 500-fold cross-validation. Results: EGFR expression could be evaluated in 323 patients and PTGS2 expression in 351 patients. EGFR expression in CRCLM was associated with poor prognosis in both univariate analysis (average HRR 1.47; P=0.03) and multivariate analysis with standard clinicopathological prognostic variables (average HRR 1.54; P=0.02). PTGS2 expression was also associated with poor prognosis in both univariate (average HRR 1.63; P<0.01) and multivariate analysis (average HRR 1.59; P=0.01). Stratification for systemic therapy demonstrated prognostic value for EGFR and PTGS2 only in the subgroup of patients who were not treated (HRR 1.78; P<.01 and HRR 1.64; P=0.04, respectively), with worst prognosis when both EGFR and PTGS2 were highly expressed (HRR 3.08; P<.01). CRCLM expression of PTGS2 was concordant in 69.2% of matched primary tumors (P=0.02), while there was no such correlation for EGFR expression (P=0.51). Conclusion: EGFR and PTGS2 expression are prognostic molecular biomarkers with added value to standard clinicopathological variables for patients with CRCLM. Citation Format: Jeroen A.C.M. Goos, Annemieke C. Hiemstra, Veerle M.H. Coupé, Begoña Diosdado, Wendy Kooijman, Pien M. Delis-van Diemen, Cemile Karga, Jeroen A.M. Beliën, C. Willemien Menke-van der Houven van Oordt, Albert A. Geldof, Gerrit A. Meijer, Otto S. Hoekstra, Remond J.A. Fijneman. Epidermal growth factor receptor (EGFR) and prostaglandin-endoperoxide synthase 2 (PTGS2) are prognostic biomarkers for metastatic colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2853. doi:10.1158/1538-7445.AM2014-2853
