One of the activities was the Lab Talk led by Dr. Kurt Schalper from Yale School of Medicine, which explored NRG1 testing in cancer patients. The session covered the clinical utility of NRG1 fusions as a poor prognostic factor across tumor types, exploring NRG1+ tumors’ metastatic potential and histological features. Dr. Kurt Schalper also approached the challenges for detecting NRG1 fusions, considering that conventional methods often fail to detect these fusions. 

Key learnings from the series that can be implemented in routine diagnostics to ensure that patients with NRG1+ tumors are properly and timely identified:

Pathogenic gene fusions are key oncogenic drivers and actionable biomarkers in precision oncology

NRG1 fusions have been identified across many tumor types, with NRG1+ tumors being associated with aggressive features and poor outcomes in cancer patients

Conventional methods like RT-PCR, FISH, and IHC may fall short of detecting pathogenic gene fusions and have limitations in screening NRG1 fusions

Although NGS can detect a broad range of genomic alterations, DNA-based NGS alone can miss pathogenic gene fusions

Comprehensive testing with RNA-based NGS, including both DNA and RNA sequencing, is recommended to capture these fusions that DNA-based NGS might miss

The detection of NRG1 fusions is particularly difficult without RNA-based NGS due to the diversity of gene fusion partners, varying breakpoints, and large intronic regions

Proper testing for pathogenic gene fusions is necessary to maximize the identification of potentially eligible patients to benefit from targeted therapies

Poorer outcomes were observed in patients with pathogenic gene fusions who were not matched to an FDA-approved fusion-targeted therapy

Ultimately, RNA-based NGS can enable oncologists to match eligible patients with targeted therapy to the driving fusion, which wouldn’t have otherwise been identified, potentially leading to improved outcomes

Register interest

Thank you for joining us during our NRG1 fusions testing series!

Diaceutics organized a series of digital engagement activities focused on the clinical relevance of pathogenic gene fusions, specifically NRG1 fusions, for cancer patients.

NRG1 is a pathogenic fusion receiving increasing attention, as it is associated with multiple poor prognostic factors

 NRG1 fusions are genetic alterations that involve the NRG1 gene being abnormally fused with another gene. These fusions are heterogeneous and have many different gene partners and breakpoints. NRG1 fusions result in increased cell signaling and growth and can lead to uncontrolled growth and cancer.

NRG1 fusions have been identified across many tumor types and generally occur in the absence of other driver mutations. The overall frequency of NRG1 fusions varies across tumor types, with the highest being found in lung cancer (0.3%-1.7%) and pancreatic cancer (0.5%-1.8%), with other tumor types having <1%.

Importantly, there is a significant enrichment in NRG1 fusions in invasive mucinous lung adenocarcinoma (27%-31%) and in KRAS wild-type pancreatic cancer (up to 6%).

Methods like RT-PCR, FISH, and IHC may fall short of detecting pathogenic gene fusions and have limitations in screening NRG1 fusions. Detection of NRG1 fusions poses challenges, as DNA-based NGS alone can miss pathogenic gene fusions and lead to false-negative and false-positive results. Comprehensive testing with RNA-based NGS, including both DNA and RNA sequencing, is recommended to capture these fusions that DNA-based NGS might miss. The detection of NRG1 fusions is particularly difficult without RNA-based NGS due to the diversity of gene fusion partners, varying breakpoints, and large intronic regions.

To learn more about NRG1 fusions and RNA-based testing please visit

Next week we will be inviting you to join our latest Lab Talk with Dr. Kurt Shalper from Yale School of Medicine. During this session Dr. Shalper will discuss pathogenic gene fusions as oncogenic drivers and actionable biomarkers in precision oncology, focusing on NRG1 fusions.

1. Gao Qet al. Cell Rep. 2018;23(1):227-238.e3. doi:10.1016/j.celrep.2018.03.050. 2. Latyshevaet al.Nucleic Acids Res. 2016;44(10):4487-4503. doi:10.1093/nar/gkw282. 3. Heyer EEet al. Nat Commun. 2019;10(1):1388. doi:10.1038/s41467-019-09374-9. 4. Liu SV. Future Oncol. 2022;18(26):2865-2870. doi:10.2217/fon-2022-0073. 5. Drilon Aet al. J Clin Oncol. 2021;39(25):2791-2802. doi:10.1200/JCO.20.03307. 6. Rosas D et al. Cancers (Basel). 2021;13(20):5038. doi:10.3390/cancers13205038. 7. Laskin J et al. Ann Oncol. 2020;31(12):1693-1703. doi:10.1016/j.annonc.2020.08.2335. 8. Zhang C et al. BiochimBiophys Acta Rev Cancer. 2022;1877(3):188707. doi:10.1016/j.bbcan.2022.188707. 9. Drilon A et al. J Clin Oncol. 2021;39(25):2791-2802. doi:10.1200/JCO.20.03307. 10. Schram AM et al. Cancer Discov. 2022;12(5):1233-1247. doi:10.1158/2159-8290.CD-21-1119. 11. Geuijen CAW et al. Cancer Cell. 2018;33(5):922-936. doi:10.1016/j.ccell.2018.04.003. 12. Liu SV. Plain language summary of NRG1 fusions in cancer: current knowledge and treatment with afatinib and other drugs. Future Oncol. 2022;18(26):2865-2870. doi:10.2217/fon-2022-0073. 13. Drilon A, Somwar R, Mangatt BP, et al. Response to ERBB3-directed targeted therapy in NRG1-rearranged cancers. Cancer Discov. 2018;8(6):686-695. doi:10.1158/2159-8290.CD-17-1004. 14. Jones MR et al. Clin Cancer Res. 2019;25(15):4674-4681. doi:10.1158/1078-0432.CCR-19-0191. 15. Liu SV et al. Future Oncol. 2022;18(26):2865-2870. doi:10.2217/fon-2022-0073. 16. Drilon A et al. Cancer Discov. 2018;8(6):686-695. doi:10.1158/2159-8290.CD-17-1004. 17. Jones MR et al. Clin Cancer Res. 2019;25(15):4674-4681. doi:10.1158/1078-0432.CCR-19-0191. 18. Bruno R et al. Diagnostics (Basel). 2020;10(8):521. doi:10.3390/diagnostics10080521. 19. Su D et al. J Exp Clin Cancer Res. 2017;36(1):121. doi:10.1186/s13046-017-0591-4. 20. Benayed R et al. Clin Cancer Res. 2019;25(15):4712-4722. doi:10.1158/1078-0432.CCR-19-0225. 21. Heydt C et al. BMC Med Genomics. 2021;14(1):62. doi:10.1186/s12920-021-00909-y

Fusions can occur across different tumor types, being a contributing factor in 1 in 6 cancers and accountable for approximately 20% of cancer morbidity. Among 9624 patients who had their tumors genetically tested with RNA-based sequencing, pathogenic gene fusions were found in 16.5% of samples.

FGFR3 alterations play a pivotal role in the development and progression of bladder cancer. Its frequent mutations and fusions make it a key biomarker for targeted therapy in bladder cancer patients.

FGFR inhibitors have shown efficacy in treating FGFR3-altered urothelial cancer

, but identifying patients who will benefit most from FGFR3-targeted therapies requires reliable and comprehensive molecular testing.

Gene mutations and fusions of FGFR3 are important for diagnosing bladder cancer. As such, RNA samples may be required. Tissue biopsy (TURBT - transurethral resection of urothelial tumour) is the gold standard for FGFR3 testing in metastatic urothelial carcinoma.

 However, TURBT can result in heterogeneous samples, thus impacting the tissue quality available for biomarker testing. If fresh biopsies are not feasible, tumor tissues archived via formalin fixed and paraffin embedded (FFPE), using fresh or flash frozen methods from diagnosis can be used. 

Additionally, urine testing (urine cytology and tissue marker tests) has the potential to assist in clinical decision-making due to its ease of sampling, potentially reducing the need for invasive procedures.

There are 3 major diagnostic pitfalls that labs should consider when testing for FGFR3 in bladder cancer:

 The choice of test may depend on the clinical context, available resources, and specific FGFR3 alterations of interest. For instance, NGS provides comprehensive data but may not be necessary for detecting a known single mutation, where RT-PCR could suffice.

 The accuracy of FGFR3 testing depends on the quality of the sample. Adequate tumor content in tissue biopsies or sufficient DNA/RNA quantity and quality from urine samples are essential.

 Positive results for FGFR3 genetic alterations can help in prognostication and selecting patients for FGFR-targeted therapies. Negative results, particularly from highly sensitive methods like NGS or RT-PCR, mean a patient is not eligible for the targeted therapy.

1. Helsten T et al. Clin Cancer Res 2016;22(1):259–267. 2. Necchi A et al. Eur Urol Focus 2019;5(4):689–692. 3. Wang Z et al. npj Precis Onc 2023;7(70). 4. Benjamin DJ et al. Front Immunol. 2023;14:1258388. 5. Mazzucchelli R et al. Front Surg. 2021 Dec 2;8:754741.

                                                Approval code: EM-162587

Up to 20% of patients with advanced urothelial carcinoma may have FGFR alterations, with FGFR3 mutations and fusions being predominant in bladder and upper tract urothelial tumours.

The prevalence of FGFR3 mutations and fusions is approximately 80% in non-muscle-invasive bladder cancer (NMIBC) patients, compared to 20% in muscle-invasive bladder cancer (MIBC) patients.

 To ensure eligible patients receive targeted therapies specific to FGFR3 alterations, accurate testing of FGFR3 gene is essential.

Over the past 6 months, Diaceutics have delivered a series of digital  activities focused on the new and emerging perspectives on the classification of HER2 in breast cancer. 

Our aim is to raise awareness of the new perspectives emerging on HER2 testing and expression, particularly in relation to recognizing low levels of HER2 in breast cancer patients. 

Catch-up on the activities in this series to: 

 about the importance of recognizing HER2 low and HER2 negative patients and how this can be implemented in your lab

 to Key Opinion Leader, Professor Dr Abeer Shaaban, discuss her perspective on HER2 expression during the Lab Talk,

 A new perspective on HER2 testing- Evolving the lab practices to match clinical advances

the HER2 Report Checklist from the series and share with colleagues or print and display in your labs for ease of reference 

, we highlighted that up to 60% of breast cancers classed as HER2 negative have detectable levels of HER2 expression

. This has created a need for a consistent assessment standard that recognizes HER2 biomarker expression as a spectrum of negative, low and positive, encouraging labs to re-think what they know about determining HER2 expression and how this can impact patients.  

 with Professor Dr Abeer Shaaban MSc, PhD, FRCPath. During this session, Prof. Dr Shaaban discussed the clinical utility of HER2 testing, HER2 scoring and the spectrum of expression and the technical factors to be considered, including analytical and pre-analytical. 

Register interest 

1.  Schettini  F, et  al.  NPJ  Breast  Cancer.  2021;7:1-13.

This  content  is  organized and funded  by  AstraZeneca. This content  is  intended  for  healthcare  professionals  only. Z4-62779. DOP July 2024.

Diese digitalen Dialoge unterstreichen die Bedeutung von KIT D816V für die Diagnose und therapeutische Entscheidungsfindung, sowie die Notwendigkeit einer optimalen Patientenidentifizierung.

Informieren Sie sich über die Aktivitäten in dieser Reihe und:

Sie mehr über die Bedeutung von KIT D816V, den Weg eines SM-Patienten vom Verdacht bis zur Diagnose und Faktoren, die zu Fehldiagnosen führen können

 Sie von unserem Experten Prof. Dr. med. Hans Michael Kvasnicka, mehr über KIT D816V und die positiven Auswirkungen, die ein effiziente Diagnose auf Patienten haben kann

Sie das DiagnosetoolKIT für Systemische Mastozytose, die FAQs und die Folien des Lab Talks herunter, die Sie gerne auch an Kollegen weitergeben oder für Ihr Labor ausdrucken und als schnell zugängliche Informationsquelle aushängen können.

Unser erster Lab Alert konzentrierte sich auf die fortgeschrittene Systemische Mastozytose (AdvSM) und wir haben dabei hervorgehoben, dass 90-95 % der AdvSM Patienten KIT D816V-positiv

 sind und welche entscheidende Rolle diese Mutation sowohl bei der diagnostischen Abklärung bei SM-Verdachtspatienten als auch bei Behandlungsentscheidungen spielt. 

, um den vollständigen Artikel zu lesen und das DiagnosetoolKIT für systemische Mastozytose herunterzuladen.

Anschließend fand ein Lab Talk mit Prof. Dr. med. Hans Michael Kvasnicka statt, in dem er den Weg des SM-Patienten bis zur Diagnose, die klinische Bedeutung von KIT D816V bei Patienten mit systemischer Mastozytose, einschließlich fortgeschrittener SM (AdvSM) und indolenter SM (ISM) beschrieb. Weiterhin wurden die Faktoren, die zu Fehldiagnosen führen können, und die aktuellen Richtlinien erörtert. Klicken Sie 

, um die Aufzeichnung anzusehen und die FAQs zu diesem Seminar herunterzuladen.

Vielen Dank, dass Sie uns bei der Serie begleitet haben. Die Folien des Lab Talk können Sie über den unten stehenden Link herunterladen.

Download, Lab Talk Vortrag

Die FAQs zu der KIT D816V Testung sind jetzt zum Download verfügbar

Wenn Sie Fragen zu dieser Serie haben oder mehr über das DXRX-Netzwerk erfahren möchten, wenden Sie sich bitte an help@dxrx.io.  

1. William  Shomali,  Jason  Gotlib;  The  new  tool  “KIT”  in  advanced  systemic  mastocytosis.  Hematology  Am  Soc  Hematol  Educ  Program  2018;  2018  (1):  127–136.

In den vergangenen sechs Monaten hat Diaceutics eine Reihe digitaler Aktivitäten durchgeführt, die sich auf die Bedeutung der Detektion von KIT D816V bei Patienten mit Verdacht auf SM konzentrierten.

This series of digital engagements highlighted the importance of rapid and accurate BRAF V600E testing in mCRC patients to guide therapeutic strategy for optimal patient outcomes.

As we wrap up this series, catch-up on various activities to:

 into the molecular biology of BRAF V600E mutation in mCRC and explore its clinical relevance

to Professor Matteo Fassan discuss the current diagnostic scenario, focusing on different molecular techniques during the Lab Talk 

 the FAQs from the series and the slides from the Lab Talk. These can be printed for ease of reference.

 article sheds light on the significant clinical utility of BRAF testing in mCRC due to the strong prognostic impact of the V600E mutation and its relevance in informing the therapeutic strategy. However, the heterogeneous diagnostic landscape stresses the need for hospitals and labs to optimise BRAF testing in mCRC.

, Head, Department of Pathology, ULSS2 Marca Trevigiana, Italy, exploring the molecular biology and role of BRAF mutations in mCRC. To further support labs in BRAF testing, Prof. Fassan discussed the current diagnostic scenario and compared and analysed different molecular techniques for optimal testing and reporting.

Thank you for joining us during this series. We want to bring you more information on this and other relevant topics in precision medicine. 

Take 2 minutes to complete the survey below and access the Lab Talk slides led by Professor Fassan.

 Your participation will enhance our ability to fulfil our mission of better testing, better treatment.

Fill out this short survey and access the Lab Talk slides.

If you have any questions on this series or would like to learn more about the DXRX Network, contact help@dxrx.io.

Over the past few months, Diaceutics have delivered a series of digital activities focusing on the clinical significance of BRAF testing in mCRC. 

Insights

Catch-up on the series: NRG1 fusions testing

Pathogenic gene fusions are key actionable biomarkers in precision oncology

The clinical relevance of FGFR3 testing in bladder cancer

Catch-up on the series: HER2 Testing in Breast Cancer

KIT D816V Testung bei Systemischer Mastozytose (SM) kompakt dargestellt

BRAF testing in metastatic colorectal cancer series at a glance