Refresh your knowledge with this precision oncology clinical topic update from pathologist Prof. Fernando López-Ríos.

Prof. López-Ríos gives an overview of gene fusions in solid tumours, methods for identification and the different tumour types harbouring gene fusions. He highlights the need to search for actionable fusions and the implications for treatment.

Clinical takeaways

  • Several fusions are now actionable in solid tumours
  • Most of them were initially studied in NSCLC (ALK, ROS1 and RET), but many are now being developed in a tumour-agnostic manner (NTRK, RET, FGFR)
  • The gold standard for detecting fusions is RNA-based NGS, but IHC, FISH and real-time PCR can also be used

Educational objectives

  • Understand what a gene fusion is and the different types of genetic variations used in precision oncology

  • Know why gene fusions are oncogenic and how to identify them

  • Have an awareness of the different types of gene fusions, their distribution across tumour types and key data related to associated treatments

López-Ríos F, Illei PB, Rusch V, Ladanyi M. Multiple lines of evidence against a role for SV40 infection in human mesotheliomas and high risk of false-positive SV40 PCR results due to presence of SV40 sequences in common laboratory plasmids. Lancet 2004; 364: 1157-1166. Conde E, Angulo B, Tang M, Morente M, Torres-Lanzas J, López-Encuentra A, López-Ríos F, Sánchez-Céspedes M. Molecular context of the epidermal growth factor receptor mutations: evidence for the activation of mTOR/S6K signalling. Clin Cancer Res 2006; 12: 710-717. López-Ríos F, Chuai S, Flores R, Shimizu S, Ohno T, Wakahara K, Illei PB, Hussain S, Krug L, Zakowski MF, Rusch V, Olshen AB, Ladanyi M. Global gene expression profiling of pleural mesotheliomas. Overexpression of aurora kinases and P16/CDKN2A deletion as prognostic factors and critical evaluation of microarray-based prognostic prediction. Cancer Res 2006; 66: 2970-2979. López-Ríos F, Sánchez-Aragó M, García-García E, Ortega AD, Berrendero JR, Pozo-Rodríguez F, López-Encuentra A, Ballestín C, Cuezva JM. Loss of the mitochondrial bioenergetic capacity underlies the glucose avidity of Carcinomas. Cancer Res 2007; 67: 9013-9017. Angulo B, Suarez-Gauthier A, López-Ríos F, Medina PP, Conde E, Tang M, Soler G, Lopez-Encuentra A, Cigudosa JC, Sanchez-Cespedes M. Expression signatures in lung cancer reveal a profile for EGFR-mutant tumours and identify selective PIK3CA overexpression by gene amplification. J Pathol 2008; 214: 347-356. Agulló-Ortuño MT, López-Ríos F, Paz-Ares L. Lung cancer genomic signatures. J Thorac Oncol 2010; 5: 1673-1691. Thunnissen E, Bubendorf L, Dietel M, Elmberger G, Kerr K, Lopez-Rios F, Moch H, Olszewski W, Pauwels P, Penault-Llorca F, Rossi G. EML4-ALK testing in non-small cell carcinomas of the lung: a review with recommendations. Virchows Arch 2012; 461: 245-257. Conde E, Angulo B, Izquierdo E, Muñoz L, Suárez-Gauthier A, Plaza C, Dominguez N, Torres M, Madrigal L, Rubio-Viqueira B, Belda-Iniesta C, Hidalgo M, López-Ríos F. The ALK translocation in advanced non-small-cell lung carcinomas: preapproval testing experience at a single cancer centre. Histopathology 2013; 62: 609-616. Conde E, Suárez-Gauthier A, Benito A, Garrido P, García-Campelo R, Biscuola M, Paz-Ares L, Hardisson D, de Castro J, Camacho MC, Rodriguez-Abreu D, Abdulkader I, Ramirez J, Reguart N, Salido M, Pijuán L, Arriola E, Sanz J, Folgueras V, Villanueva N, Gómez-Román J, Hidalgo M, López-Ríos F. Accurate identification of ALK positive lung carcinoma patients: novel FDA-cleared automated fluorescence in situ hybridization scanning system and ultrasensitive immunohistochemistry. PLoS One 2014; 9: e107200. Bubendorf L, Büttner R, Al-Dayel F, Dietel M, Elmberger G, Kerr K, López-Ríos F, Marchetti A, Öz B, Pauwels P, Penault-Llorca F, Rossi G, Ryška A, Thunnissen E. Testing for ROS1 in non-small cell lung cancer: a review with recommendations. Virchows Arch 2016; 469: 489-503. Kerr KM, López-Ríos F. Precision medicine in NSCLC and pathology: how does ALK fit in the pathway? Ann Oncol. 2016: Suppl 3:iii16-iii24. Büttner R, Gosney JR, Skov BG, Adam J, Motoi N, Bloom KJ, Dietel M, Longshore JW, López-Ríos F, Penault-Llorca F, Viale G, Wotherspoon AC, Kerr KM, Tsao MS. Programmed Death-Ligand 1 Immunohistochemistry Testing: A Review of Analytical Assays and Clinical Implementation in Non-Small-Cell Lung Cancer. J Clin Oncol 2017; 35: 3867-3876. Conde E, Caminoa A, Dominguez C, Calles A, Walter S, Angulo B, Sánchez E, Alonso M, Jimenez L, Madrigal L, Hernando F, Sanz-Ortega J, Jimenez B, Garrido P, Paz-Ares L, de Castro J, Hernandez S, Lopez-Rios F. Aligning digital CD8(+) scoring and targeted next-generation sequencing with programmed death ligand 1 expression: a pragmatic approach in early-stage squamous cell lung carcinoma. Histopathology 2018; 72: 270-284. Yatabe Y, Dacic S, Borczuk AC, Warth A, Russell PA, Lantuejoul S, Beasley MB, Thunnissen E, Pelosi G, Rekhtman N, Bubendorf L, Mino-Kenudson M, Yoshida A, Geisinger KR, Noguchi M, Chirieac LR, Bolting J, Chung JH, Chou TY, Chen G, Poleri C, Lopez-Rios F, Papotti M, Sholl LM, Roden AC, Travis WD, Hirsch FR, Kerr KM, Tsao MS, Nicholson AG, Wistuba I, Moreira AL. Best Practices Recommendations for Diagnostic Immunohistochemistry in Lung Cancer. J Thorac Oncol 2019; 14: 377-407. Büttner R, Longshore JW, López-Ríos F, Merkelbach-Bruse S, Normanno N, Rouleau E, Penault-Llorca F. Implementing TMB measurement in clinical practice: considerations on assay requirements. ESMO Open 2019; 4: e000442.

Prof. Fernando López-Ríos has received financial support/sponsorship for research support, consultation, or speaker fees from the following companies:

AstraZeneca, Bayer, BMS, Lilly, MSD, Pfizer, Roche, Takeda and Thermo Fisher. 

 

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This educational programme is supported by an Independent Medical Education Grant from Bayer.
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PRECISION ONCOLOGY CONNECT is an initiative of COR2ED, supported by Independent Medical Educational Grants from AstraZeneca, Amoy Diagnostics and Bayer.

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