Cx. Incorporation of ctDNA analysis into routine follow-up for early detection of relapse may allow earlier initiation of alternate treatment modalities.
Legal entity responsible for the study: The National Committee on Health Research Ethics (#1302183), Denmark.
Funding: Novo Nordisk Foundation, Danish Cancer Society, Natera Inc San Carlos USA.
Disclosure: H. Sethi, S. Sharma, H-T. Wu, R. Swenerton, R. Salari, D. Hafez, R. Srinivasan, M. Balcioglu, S. Navarro, Z. Assaf, B. Zimmermann, J. Lin: Employee, stockownership or options to stock: Natera, Inc. All other authors have declared no conflicts of interest.
87P Distinct functional consequences of HER2 gene amplification in colorectal and lung adenocarcinomas
E.N. Imyanitov1 , T.N. Sokolova1 , G. Raskin2 , A.O. Ivantsov1 , A.G. Iyevleva1 , A.P. Sokolenko1 1
Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St. Petersburg, Russian Federation,2
Department of Pathology, A.M. Granov Russian Scientific Centre of Radiology and Surgical Technologies, St. Petersburg, Russian Federation
Background: HER2 oncogene amplification, being accompanied by its overexpression, is an established driver event in breast and gastric carcinomas. The functional role of HER2 in pathogenesis of other tumor types is less defined.
Methods: 2401 archival samples of lung carcinomas (LC) and 1969 samples of colorec-tal carcinomas (CRC) were subjected to HER2 copy number analysis. Selected tumors with amplification of this oncogene were further subjected to HER2 immunohisto-chemistry and mRNA quantitation. In addition, the expression levels of some neigh-bouring genes located in 17q12-21 amplicon were analyzed.
Results: Frequency of HER2 amplification was similar in both groups, being 100/2401 (4.2%) in LC and 84/1969 (4.3%) in CRC, respectively. 10 (82%) out of 12 analyzed HER2-amplified CRCs demonstrated clear evidence for HER2 protein and mRNA overexpression, while this estimate approached to only 3 (27%) out of 11 for LCs. Expression analysis of GRB7, STARD3, and LASP1 revealed a statistically significant correlation between HER2 and STARD3 levels [r¼ 0.571, Spearman test]. High STARD3 expression was observed in HER2-amplified CRCs but not LCs [p¼ 0.03]. Conclusions: HER2 amplification is frequently accompanied by gene overexpression in colorectal but not lung adenocarcinomas. STARD3 gene belonging to 17q12-21 amplicon demonstrates evidence for activation in HER2-amplified colorectal neo-plasms and therefore deserves further analysis.
Legal entity responsible for the study: Evgeny Imyanitov. Funding: Russian Science Foundation.
Disclosure: All authors have declared no conflicts of interest.
88P Role of AR-V7 and AR-FL in resistance to hormonal therapy in mCRPC: Independent actors or reciprocal drivers? A translational study by Meet-Uro group M. Del Re1 , S. Crucitta1 , A. Sbrana2 , E. Rofi3 , F. Paolieri3 , L. Galli4 , A. Falcone3 , R. van Schaik5 , G. Jenster6 , R. Morganti2 , S. Pignata7 , R. Danesi1 1
Clinical and Experimental Medicine, University of Pisa, Pisa, Italy,2
Medical Oncology 2 Unit, Azienda Ospedaliera Universitaria S. Chiara, Pisa, Italy,3
Medical Oncology, Azienda Ospedaliera Universitaria S. Chiara, Pisa, Italy,4
UO Oncologia Medica 2 Universitaria, Azienda Ospedaliero-Universitaria Pisana Istituto Toscano Tumori, Pisa, Italy,5
Clinical Chemistry, Erasmus University, Rotterdam, Netherlands,6
Josephine Nefkens Institute, Erasmus University, Rotterdam, Netherlands,7
Urology and Gynecology, Istituto Nazionale Tumori – I.R.C.C.S - Fondazione Pascale, Naples, Italy Background:The androgen receptor splice variant 7 (AR-V7) is strongly associated with resistance to hormonal therapy (HT) in castration-resistant prostate cancer (CRPC), although it is not implemented in clinical practice as a biomarker. The AR-full length (AR-FL) is also overexpressed in CRPC but its role has yet to be clarified. The aim of the present work was to investigate the role of AR-V7 and AR-FL as predictors of resistance to HT in plasma-derived exosomal RNA.
Methods:6 ml of blood were collected in EDTA tubes before the start of abiraterone/ enzalutamide; blood was centrifuged and plasma stored at -80C until analysis.
Exosomes isolation and RNA extraction were performed using the exoRNeasy kit (Qiagen) as per manufacturer instructions. The analysis of AR-FL and AR-V7 were per-formed by digital droplet PCR using the One-Step RT-ddPCR kit (BioRad). The abso-lute target concentration as copies/ml in samples was calculated by ddPCR QuantaSoft and statistical analyses were performed by SPSS v.24.
Results:52 patients (pts) were enrolled; AR-FL was detected in all pts (median: 700 copies/ml), while 15 subjects (28.8%) were AR-V7þ (median: 310 copies/ml) at base-line. The amount of AR-FL was significantly higher in pts AR-V7þ vs AR-V7- (6700 vs 490 copies/ml, p < 0.0001). Median PFS and OS were longer in AR-V7- vs AR-V7þ pts (median PFS 25 vs 4 mo, p < 0.0001; median OS 38 vs 9 mo, p < 0.0001). A ROC curve was calculated for AR-FL in the overall population and 950 copies/ml was identified as
cut-off value. Pts were then stratified across this value and it was found that PFS was 22 mo in pts with <950 AR-FL copies/ml vs 4 mo in pts with950 copies/ml (p¼ 0.0003). In 12/15 AR-V7þ pts the AR-FL expression was 950 copies/ml while in 3/15 AR-V7þ pts, AR-FL expression was <950 copies/ml; however, their PFS reflected the AR-V7 better than AR-FL status, being, respectively 6, 10, 4 mo. No other clinical variables were correlated with worse PFS at the univariate analysis (i.e. Gleason score 7 vs > 7, age).
Conclusions:This study demonstrates that resistance to HT may be predicted by AR-V7, making it a clinically relevant biomarker. AR-FL over-expression may contribute to hormone resistance although AR-V7 plays a primary role.
Legal entity responsible for the study:Romano Danesi. Funding:University of Pisa.
Disclosure:All authors have declared no conflicts of interest.
89P Validation of a 90-gene assay for tissue origin diagnosis of brain metastases Y. Zheng1 , Y. Ding1 , C. Xiao1 , W. Zhong2 , X. Teng2 , Q. Gao2 , Q. Wang3 , Y. Sun4 , C. Chen4 , L. Chen4 , J. Zhu4 , Q. Xu4 , N. Xu1 1
Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China,2
Department of Pathology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China,3
Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China,4
Research and Development, Canhelp Genomics Ltd., Hangzhou, China
Background: Brain metastases (BM) are the most common intracranial tumors affecting about 8-10% of all cancer patients. Morphology and immunohistochemical staining are two common approaches used to identify the primary sites of BM samples, but morphol-ogy fails to identify poorly differentiated tumors and IHC markers usually lack specificity. About 2% to 14% of BM patients still present with unknown primary sites. A 90-gene assay, proposed in our previous study, is an RNA-based gene expression test to identify the tissue of origin in poorly differentiated and undifferentiated tumors. This study aims to evaluate the performance of the 90-gene assay in determining the primary sites for BM samples. Methods: The sequence-based gene expression profiles of 708 primary brain tumors (PBT) collected from The Cancer Genome Atlas database were performed by a 90-gene expression signature, with a similarity score for each of 21 tumor types. We used Optimal Binning algorithm to generate a threshold for separating PBT from BM. Eighteen PBT samples from Fudan University Shanghai Cancer Center were analyzed to substantiate reliability of the threshold. In addition, the performance of the 90-gene assay for identifying the tissue of origin was validated in a cohort of 48 BM samples with known origin from The First Affiliated Hospital, Zhejiang University. For each BM sample, the tumor type with the highest similarity score was considered tissue of origin. When a sample was diagnosed as PBT but the similarity score below the thresh-old, the second prediction was considered as primary site.
Results: A threshold of the similarity score, 70, was identified to discriminate PBT from BM (PBT: 70, BM: < 70) with an accuracy of 99% (703/708). Eighteen PBT and 44 BM were performed by the 90-gene assay. The results of 18 PBT samples matched refer-ence diagnosis with a concordance rate of 100% and all similarity scores were above 70. Of 44 BM samples, the 90-gene assay accurately predicted primary sites in 89% (39/44, 95%CI: 0.75-0.96) of the cases.
Conclusions: The 90-gene assay showed promising discriminatory ability to separate PBT from BM and identify the primary site of BM. Our findings demonstrated the potential that 90-gene assay can serve as a powerful tool for accurately identifying the tissue of origin for BM samples.
Legal entity responsible for the study: Yulong Zheng. Funding: Has not received any funding.
Disclosure: Y. Sun, C. Chen, L. Chen, J. Zhu: Employment: Canhelp Genomics Co. Ltd. Q. Xu: Employment, stock ownership: Canhelp Genomics Co. Ltd. All other authors have declared no conflicts of interest.
90P Development of a pan-cancer biomarker panel for improved detection of MSI across all cancer types
J. Bacher1 , R. Halberg2 , P. Ward3 , E. Udho1 , K. Murphy4 , M. Uhr5 , L. Dubeau3 , J. Pettersson3 , D. Storts1 , S. Gallinger6 , D. Buchanan7 , M. Jenkins7 , N. Lindor8 , J. Eshleman9 1
RD Nucleic Acid Technologies Group, Promega Corporation, Madison, WI, USA, 2
Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA,3 USC Keck School of Medicine, University of Southern California, Los Angeles, CA, USA, 4
Pathology, ProPath, Dallas, TX, USA,5
RD Protein & Nucleic Acids, Promega Corporation, Madison, WI, USA,6
Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada,7
Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia,8
Health Science Research, Mayo Clinic, Scottsdale, AZ, USA,9
Pathology, Johns Hopkins University, Baltimore, MD, USA
Background: A new multiplexed biomarker panel is being developed for detection of microsatellite instability (MSI) that is more sensitive than currently available systems. Preliminary research data shows increased MSI sensitivity for colon polyps and
