Characterizing NTRK gene fusions helps to drive progress in precision oncology

Today, a few ultra-rare molecular alterations constitute some of the most promising therapeutic targets in precision oncology. Large repositories of molecular tumor profiles, allow us to better describe the genomic and molecular landscape of cancers defined by such rare alterations.

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Precision medicine is a rapidly evolving healthcare concept aiming to provide personalized care based on the features of the individual and their disease.1 At the core of precision medicine lies the identification of key biomarkers combined with molecular insights which can aid in selecting treatment strategies that target disease drivers and are thus tailored to the patient’s tumor profile. Investigation of large patient cohorts by comprehensive genomic tumor profiling can also drive innovation by identifying additional targets for drug development; this offers hope for the future of healthcare, as these drugs could provide further benefit to patients and increase the number of personalized treatments.

With the adoption of precision medicine into clinical practice, biomarkers have had an increasing role in clinical decision making. This is particularly true in oncology; however, so far this has been largely limited to individual tumor types (e.g. use of multiple molecular agents addressing various therapeutic targets (EGFR, ROS1, ALK, MET, KRAS) in non-small cell lung cancer [NSCLC]). Recent so-called “tumor-agnostic” drug approvals represent a paradigm shift in the treatment of cancer. Tumor-agnostic treatments target specific oncogenic drivers linked to defined biomarkers, rather than a specific tumor type. As these biomarkers are found at various frequencies across a broad range of tumors, drugs that have received a tumor-agnostic approval are licensed for the treatment of any tumor type that harbors the biomarker of interest (Figure 1, top). Importantly, the biomarkers for which drugs have received tumor-agnostic approvals (high microsatellite instability [MSI-H]; NTRK gene fusions; high tumor-mutational burden [TMB-H]) and those undergoing clinical trial evaluation in a tumor-agnostic indication (e.g. RET fusions, KRAS G12C mutations, BRAF mutations etc.) are just a subset of all driver alterations, suggesting that many more targets may be amenable to this approach.2

NTRK1/2/3 gene fusions are oncogenic rearrangements that lead to the constitutive activation of chimeric TRKA/B/C proteins and have been found in many cancer types. Although NTRK gene fusions are generally very rare (0.3% of cases), frequencies vary by cancer type; their prevalence is >90% in (very) rare cancers such as mammary analogue secretory carcinoma and secretory breast cancer.3,4 NTRK genes are associated with a range of different fusion partners, and it is likely that many more are yet to be identified. However, due to their rarity, limited data are available describing the distribution of NTRK fusions, the genomic context of these events, and the nature of the fusion partners in cancer.

In this study, we interrogated a large real-world database of comprehensive genomic profiling (CGP) data built on a harmonized testing approach from >295,000 adult and pediatric patients, looking at the prevalence of NTRK fusions in different cancer types/histologies, their associated fusion partners, and their co-occurrence with other relevant biomarkers/oncogenic drivers. NTRK fusions were found in 0.30% of the patients (0.28% in adults aged ≥18 years and 1.34% in pediatric patients) confirming prior reports3,4 — and across 134 distinct histological subtypes from 45 cancer types. Within the adult NTRK fusion-positive cohort, NSCLC, breast cancer and soft tissue sarcoma were the most common tumor types (Figure 1, middle). Interestingly, NTRK fusion prevalence decreased with increasing age: the highest prevalence was observed in children aged <5 years. NTRK fusions were mutually exclusive with other pathogenic mutations, suggesting that these are the primary drivers in the tumor.

Importantly, our study provided novel insights into the range of NTRK fusion partners. Indeed, >65% of the 88 different fusion partners we identified had not been reported previously (Figure 1, bottom). These results strongly emphasize the importance of using large real-world datasets to capture the variety of NTRK fusions, and to identify rare fusions that would have had little chance of being discovered in a clinical trial dataset of just a few hundred patients.

Further underscoring the power of large datasets, we identified a rare subgroup of colorectal cancers (CRCs). These CRC cases were defined as both NTRK+ and MSI-H CRC. Importantly, in these cases, which were mostly deemed spontaneous MSI-H cases, mutual exclusivity with BRAF alterations was observed. With this background information, screening for NTRK alterations in patients with CRC could be optimized.

In summary, owing to the size and quality of the harmonized CGP database, we were able to describe the largest cohort of NTRK fusion-positive tumors, to date. Next-generation sequencing, now recommended by ESMO guidelines5 as the first-line method for detecting NTRK fusions in clinical practice, allowed us to discover many previously unknown NTRK fusion pairs. This could eventually lead to the identification of more patients who could benefit from TRK-targeted therapies. Interrogating large datasets drives better understanding of the characteristics and prevalence of very rare molecular biomarkers of cancer. These data will inform future testing practices and drug development, eventually helping clinical decision making by providing tailored, more effective care to patients.

 

References:

  1. Yates L.R., et al. The European Society for Medical Oncology (ESMO) Precision Medicine Glossary. Ann Oncol 29, 30–35, doi:10.1093/annonc/mdx707 (2018).
  2. Photopoulos J. A hopeful revolution in cancer care. Nature 585, S16–S18, doi: https://doi.org/10.1038/d41586-020-02679-6 (2020).
  3. Okamura R., et al. Analysis of NTRK alterations in pan-cancer adult and pediatric malignancies: implications for NTRK-targeted therapeutics. JCO Precis Oncol 2, 1–20, https://doi.org/10.1200/PO.18.00183 (2018).
  4. Cocco E., et al. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol 15, 731–747, https://doi.org/10.1038/s41571-018-0113-0 (2018).
  5. Marchió C., et al. ESMO recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research. Ann Oncol 30, 1417–1427. https:// doi:10.1093/annonc/mdz204 (2019).

Ben Westphalen

Medical Lead Precision Oncology, University of Munich Cancer Center