A novel agnostic tumor: NTRKoma

Abstract

Precision medicine has revolutionized the cancer treatment and created the notion of tumor agnostic drug development. Agnostic tumor markers define a simple compound used against multiple tumor types. For instance, pembrolizumab for microsatellite instable tumors was the first tumor agnostic treatment approved by Food and Drug Administration (FDA) in 2017. Similarly, neurotrophic tyrosine kinase (NTRK) alterations are found across tumor types in a tumor agnostic manner. The normal physiological function of tropomyosin receptor kinase (Trk) includes the development of nervous system. Thus far, three genes NTRK1, NTRK2, and NTRK3 encoding TrkA, TrkB, and TrkC proteins, respectively, have been discovered. NTRK gene fusions are estimated to occur in approximately 1% of all solid tumors. Moreover, they are targetable driver genomic aberrations that proceed tumorigenesis through constitutive activation of MAPK, PI3K, and PKC signaling pathways. NTRK gene fusions are detected across various pediatric and adult tumor types, including breast secretory carcinoma, mammary analogue secretory carcinoma, infantile fibrosarcoma, congenital mesoblastic nephroma, spitzoid melanoma, and papillary thyroid carcinoma. NTRK gene fusions are classified according to the frequency detected. These are cancers enriched for TRK fusions (>90%), cancers harboring TRK fusions at lower frequencies (5–25%), and cancers harboring TRK fusions at very low frequency (<5%). Tumor agnostic treatments are based on the specific genomic abnormalities irrespective of the tumor histology. In contrast, traditional cancer therapies target genomic alterations in a given tumor type. Therefore, clinical trials for traditional cancer treatments include patients whose tumors originate from the body’s same anatomical site and share histological features. Given the increasing number of clinical trials for tumor agnostic therapies, molecular tumor boards established across cancer institutes to plan the state-ofart treatment options for patients sharing actionable genomic targets. Recently, NTRK gene fusions received an ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) Tier 1-C rating, which means a single genomic alteration and drug match can offer a substantial clinical benefit to patients whose tumors share a common driver mutation but are distinct in terms of tumor type. Even though NTRK alterations are rarely found in a specific tumor histology, they are widely distributed across tumor types. Increasing number of basket trials in which assess the clinical utility of NTRK inhibitors enables medical oncologists to be more precise in the management of cancers resistant to standard of care treatments. Previously, Dr. Hiroyuki Mano proposed to term all tumors harboring anaplastic lymphoma kinase (ALK) rearrangement as ALKoma. This yielded a substantial benefit to treating tumors with ALK rearrangement, in which ALK is an essential growth driver for the development of cancer. Defining gene rearrangements that drive tumorigenesis is one of the crucial steps in developing targeted therapy agents and enrolling patients in a basket trial if possible. Furthermore, precision medicine will allow health care providers to tailor treatment algorithms based on the genomic profile of patient’s tumor rather than targeting tumor histology or the organ involved. Therefore, we propose to term tumors harboring driver rearrangement on NTRK genes as NTRKoma. This term will enable clinicians to consider NTRK inhibitors (eg, entrectinib, larotrectinib) against cancers harboring NTRK gene rearrangements regardless of the histology, age, and fusion type.