Oncogenic Fusion Detection - Bridging the Gap from Clinic to Lab

Why Are Fusions Critical in Cancer?

An oncogenic fusion is a hybrid gene formed when a portion of one gene fuses with a portion of another, often resulting from structural variants such as translocations or inversions at the DNA level. This leads to a chimeric, aberrant protein.

In lung cancer, these fusions are often the "driver mutation" of the tumour. Identifying these drivers is crucial because effective, targeted treatments exist for fusions such as ALK, ROS1, and RET. Dr. Saxena emphasises that if testing isn't performed, patients miss out on these treatments. For example, studies on ALK-targeted therapy in metastatic lung cancer showed that after five years, the median progression-free survival had not yet been reached, highlighting the amazing, life-changing responses possible if the fusion is detected.¹

It is standard practice to test for these fusions in virtually all patients with non-small cell lung cancer (NSCLC), particularly those with stage four or metastatic disease, or those with lung adenocarcinomas, as effective therapies are available.

The Evolution of Fusion Detection

The discussion highlights the diverse methodologies available for detection. While low-throughput methods like Immunohistochemistry (IHC) and Fluorescent In Situ Hybridization (FISH) are used, more comprehensive approaches are becoming standard.

• IHC is widely available and provides fast results, which can be useful for quickly informing decisions (such as what not to give, like immunotherapy in ALK-positive patients). However, IHC is generally better used as a screening tool for many fusions (except ALK) and requires confirmatory testing.

• Sequencing methods offer higher throughput. DNA-based sequencing can be challenging because fusion breakpoints often occur in large intronic regions that are difficult to cover.

• RNA sequencing is highly recommended and often utilized, as it sequences the expressed RNA transcripts after the intronic regions have been spliced out. This method demonstrates a clear benefit: a highly cited study by Reema K. Benayed et al.², found that performing RNA sequencing detected a previously undetected driver alteration in up to approximately 14% of cases that were DNA sequencing negative.

Comprehensive panels often include both DNA and RNA sequencing simultaneously to maximize detection capability. Dr. Solomon notes that comprehensive sequencing helps detect rare and novel fusions.

Communication and Reporting

The clinical relevance of testing necessitates clear and rapid communication between the lab and the treating physician. Turnaround time (TAT) is constantly being optimized as it is crucial for patient management.

To facilitate treatment decisions, reports must be clear and concise. Oncologists, like Dr. Saxena, appreciate reports that prioritize FDA-approved or known relevant mutations upfront. Both experts agreed that having descriptive blurbs that provide context and knowledge about the specific mutation (e.g., efficacy data or clinical trial status) is very useful, rather than just positive/negative listings. Pathologists often rely on vast knowledge bases (like OncoKB^TM) to ensure accuracy and relevance when drafting these interpretations.

The Future of Fusion Detection

Molecular pathology is rapidly changing. Although common fusions (ALK, ROS1) are well-established, newer fusions like NTRK and NRG1 are seen in very small percentages of cases (less than 1% to 2%).^3,4 Dr. Solomon believes that increased, comprehensive RNA sequencing on more tumours will lead to the recognition of additional targetable fusions.

Ultimately, better testing enables better treatment.

Listen to the full episode of the Diaceutics "Better Testing, Better Treatment" podcast now!

1. Solomon BJ, Liu G, Felip E, Mok TSK, Soo RA, Mazieres J, Shaw AT, de Marinis F, Goto Y, Wu YL, Kim DW, Martini JF, Messina R, Paolini J, Polli A, Thomaidou D, Toffalorio F, Bauer TM. Lorlatinib Versus Crizotinib in Patients With Advanced ALK-Positive Non-Small Cell Lung Cancer: 5-Year Outcomes From the Phase III CROWN Study. J Clin Oncol. 2024 Oct 10;42(29):3400-3409.
2. Benayed R, Offin M, Mullaney K, Sukhadia P, Rios K, Desmeules P, Ptashkin R, Won H, Chang J, Halpenny D, Schram AM, Rudin CM, Hyman DM, Arcila ME, Berger MF, Zehir A, Kris MG, Drilon A, Ladanyi M. High Yield of RNA Sequencing for Targetable Kinase Fusions in Lung Adenocarcinomas with No Mitogenic Driver Alteration Detected by DNA Sequencing and Low Tumor Mutation Burden. Clin Cancer Res. 2019 Aug 1;25(15):4712-4722.
3. O’Haire, S., Franchini, F., Kang, YJ. et al. Systematic review of NTRK 1/2/3 fusion prevalence pan-cancer and across solid tumours. Sci Rep 13, 4116 (2023).
4. Sushma Jonna; Rebecca A. Feldman; Jeffrey Swensen; Zoran Gatalica; Wolfgang M. Korn; Hossein Borghaei; Patrick C. Ma; Jorge J. Nieva; Alexander I. Spira; Ari M. Vanderwalde; Antoinette J. Wozniak; Edward S. Kim; Stephen V. Liu. Detection of NRG1 Gene Fusions in Solid Tumors. Clin Cancer Res (2019) 25 (16): 4966–4972.