ECP 2022 Abstract Book

Virchows Archiv (2022) 481 (Suppl 1):S1–S364 13 while reducing manual labour. We find that our DigiKiPI score is significantly associated with high-grade disease and the presence of extra-pelvic metastasis. OFP-12 | Joint Oral Free Paper Session Molecular Pathology / Haematopathology OFP-12-001 The Nrf2-ARE pathway: a potential novel therapeutic target in papillary renal cancer patients S. Angori*, A. Banaei-Esfahani, K. Mühlbauer, A. Kahraman, V. Pietiäinen, S. Potdar, O. Kallionemi, P. Schraml, H. Moch *University Hospital Zurich, Switzerland Background & objectives: Nrf2-ARE signalling, a key sensor of oxidative stress in humans, is involved in papillary renal cell carcinoma (pRCC). We characterised Nrf2-ARE pathway over- activation in pRCCs and screen pathway inhibitors to identify targeted treatment for pRCC patients. Methods: Comprehensive characterisation of 60 formalin- fixed, paraffin-embedded pRCCs by copy number analysis and Whole Exome Sequencing allowed us to identify pRCC groups based on their genetic background. Protein expression of NQO1, the downstream target of the Nrf2-ARE pathway, was analysed in pRCCs by immunohistochemistry and activity assay. Newly established patient-derived cell models that resemble pRCC tumours were applied for drug profiling. Results: Immunohistochemical tissue microarray analysis of 119 pRCC correlated Nrf2-ARE pathway over-activation with worse patient outcome and higher tumour grade and stage. Secondly, based on the STRING network, we identified 15 members of the Nrf2-ARE pathway of which 4 genes NFE2L2, Keap1, CUL3 and Bach1 had mutations in 12% of all samples. The investigation of 9 matched pRCC samples and patient-derived tumour cell cultures demonstrated increased NQO1 mRNA and protein expression and activity in 56% of tumours. Finally, drug screening with 18 Nrf2- ARE pathway inhibitors using 6 pRCC PDCs with deregulated Nrf2-ARE pathway activation showed Brusatol and Convallatoxin, two Nrf2 inhibitors, had the most potent responses in our PDCs. Conclusion: pRCC is not a single disease but consists of at least two main subtypes with distinct molecular backgrounds and patient outcomes. We first characterised a subset of aggressive pRCCs with aberrant activation of the Nrf2-ARE pathway. Moreover, we showed that pharmacological inhibition of Nrf2 represents a promising therapeutic target for this tumour subtype. We anticipate that this will open up new possibilities for the clinical management of these patients. OFP-12-002 Improving the quality of cfDNA testing – results from two years of EQA J. Fairley*, M.H. Cheetham, S.J. Patton, Z.C. Deans *GenQA, United Kingdom Background & objectives: Testing of cfDNA for biomarkers is now a recognised part of clinical practice in lung cancer. EQA plays an important role in assessing and improving standards. The results from two global EQAs testing cfDNA in lung cancer are presented. Methods: Artificial plasma samples with cfDNA containing pre- scribed variants at defined allelic frequencies were distributed. Laboratories tested the samples according to their usual cfDNA protocols and reported the results in the context of specific clinical cases. Reports were peer-assessed, and feedback pro- vided to laboratories in the form of individual reports. Results: EQAs were provided in 2020 and 2021 with the number of laboratories submitting results increasing from 259 to 292. Both EQAs included assessment of EGFR testing and 2021 also included KRAS. The genotyping error rate decreased from 22% in 2020 to 11% in 2021. Common issues observed included the use of inappropriate methods for cfDNA testing and a lack of awareness available treatment for tumours with KRAS mutations, over-interpretation of the absence of a variant and failing to pro- vide sufficient details of the test methodology and limitations. Conclusion: The increase in the number of participants reflects the recognition for the need for EQA for cfDNA testing. These EQAs have shown a large variation of methodologies being used and variability in genotyping accuracy and interpretation of results being reported. This has the potential to adversely impact on patient care highlighting the clear need for education to improve testing methods and the clear reporting of the result. EQA is a key mechanism to deliver this knowledge. OFP-12-003 Common pitfalls in interpreting fusion testing results high- lighted by EQA J. Fairley*, Z.C. Deans *GenQA, United Kingdom Background & objectives: Testing of tumours for fusion tran- scripts by molecular methods is becoming increasingly wide- spread. GenQA has adapted to the change in testing strategies by including assessment of fusions by genomic testing into existing EQAs and the introduction of an NTRK EQA. Methods: Fusion -testing by molecular methods is assessed in the lung, thyroid and renal cancer, sarcoma and NTRK EQAs. FFPE tissue is provided to laboratories to test for fusions accord- ing to their usual procedures and report the results in the context of the clinical case provided. Returns are assessed by expert assessors and laboratories provided with individual reports of their results. Results: There has been a significant increase in the number of laboratories performing routine fusion transcript testing. Com- mon reporting errors across the EQAs were identified which resulted in the incorrect interpretation of the clinical relevance of detected transcripts. Laboratories reported the presence of multiple transcripts, described transcripts incorrectly and incor- rectly predicted the productive nature of transcript. Conclusion: The introduction of molecular testing for fusion transcript has the benefit that multiple targets can be examined using the same assay compared to techniques such as FISH and IHC. EQAs for the detection of fusion transcripts in FFPE tissue from solid tumours have identified issues with both interpretation and reporting of results. This could impact on patient care and therefore there is a need for continual assessment of this testing. OFP-12-004 The Geneva HRD test: clinical validation on 469 samples from the PAOLA-1 trial Y. Christinat*, L. Ho, S. Clément, C. Genestie, J. Sehouli, S. Cinieri, A. Gonzalez Martin, U. Denison, K. Fujiwara, I. Vergote, G. Tognon, S. Hietanen, E. Pujade-Lauraine, I. Ray-Coquard, T. McKee *Hôpitaux universitaires de Genève, Switzerland Background & objectives: The efficiency of the Myriad HRD test to guide use of PARP inhibitors has been demonstrated in S49