NTRK Fusions in Papillary Thyroid Cancer: Expanding Targetable Treatment Options
Papillary thyroid cancer (PTC), the most common type of thyroid cancer, has a 5-year survival rate of approximately 95% with currently available curative treatments, primarily surgery, thyroid hormone, and radioiodine therapy. A small number of PTCs, however, can evolve into more therapy-resistant, clinically aggressive variants that may be lethal.1
Receptor kinase fusion events are recognized as important genetic abnormalities across various cancers and typically involve the fusion of dimerization or other oligomerization domains from one gene with the tyrosine kinase portion of a receptor gene, resulting in the formation of an aberrant, constitutively activated signaling kinase.2 In-frame and potentially activating receptor kinase fusions, especially members of the neurotrophic tyrosine receptor kinase (NTRK) family, which encode the Trk proteins, have been shown to occur at a high frequency in thyroid cancer.3,4 Trks are a family of related receptor tyrosine kinases that normally mediate cellular signaling by the neurotrophic factors, including the nerve growth factor.5 The kinase proteins TrkA, TrkB, and TrkC are encoded by the genes NTRK1, NTRK2, and NTRK3, respectively.
The existence of NTRK fusions in a subset of PTC patients has added to the understanding of the genetic basis of thyroid cancer. Interest in genomic testing for PTC patients is expanding so as to identify those who may benefit from targeted therapy with Trk inhibitors.
Fusions in the oncogenes RET, NTRK1, and NTRK3 can play driving roles in PTC. In a 2010 review, Greco et al noted that while somatic rearrangements of the NTRK1 gene in PTC are less common than those involving the RET gene, NTRK1 fusions alone can occur at a frequency of up to 12%.6 In a cohort of post-Chernobyl papillary thyroid adult patients, the ETV6-NTRK3 fusion was detected in 9 of 62 radiation-exposed patients (14.5%) and in 3 of 151 sporadic PTC patients (2%).7 Among 26 Ukrainian patients with thyroid cancer who were younger than 10 years old and living in contaminated areas during the time of the Chernobyl nuclear reactor accident,5 (19%) had either an NTRK1 or NTRK3 fusion.8
More recently, a series of 27 consecutive pediatric PTCs without noted exposure to radiation was examined for genetic abnormalities. The investigators noted rearrangements of NTRK in 7 of 27 samples (26%), including rearrangements of NTRK3 and NTRK1. The authors noted the unusually high incidence of these NTRK rearrangements relative to other available studies of adult and sporadic PTC (2% and 3%, respectively) and radiation-induced pediatric PTCs (approximately 14%, from a post-Chernobyl population). The NTRK-rearranged tumors in the study were associated with several identifiable clinical characteristics, including large, nodular, and infiltrative pathology, advanced stage at presentation, and lymphovascular invasion.9
Less Favorable Outcome for NTRK Fusions in PTC Patients
Most correlation studies consider PTCs carrying RET and NTRK rearrangements to be a unique group with less favorable disease outcomes, strengthening the urgency for targeted therapy in this population.6 Bonarzone et al reported the association between RET and NTRK1 rearrangements with a young age at diagnosis and a less favorable disease outcome, as well as the lack of association with tumor subtype.10 Analysis of the survival rate of 13 PTC patients with an NTRK1 rearrangement demonstrated a worse prognosis when compared to patients with an RET rearrangement (15 cases) or without any rearrangement (89 cases).11
Targeted Therapies in Oncology spoke with Chia-Chi (Josh) Lin, MD, PhD, director of the Phase I Center and associate clinical professor in the School of Medicine at National Taiwan University Hospital, about molecular testing for patients with PTCs. “If you screen only BRAF wild-type papillary thyroid cancer, the incidence of NTRK1 rearrangements could be as high as 10% to 20%,” Lin said. An NTRK rearrangement may, therefore, be a potentially targetable molecular alteration in PTC, leading to the study of Trk inhibitors as targeted PTC therapy.
Entrectinib (RXDX-101) is an investigational agent that is a potent inhibitor of the Trk tyrosine kinases, as well as the ROS1 and ALK kinases.12 In phase I clinical studies, entrectinib demonstrated a 79% overall response rate in patients harboring NTRK, ROS1, or ALK fusions who were naïve to prior inhibitors of their target and who received an efficacious dose level. Responses were noted in a patient with metastatic colorectal cancer harboring an LMNA-NTRK1 rearrangement and in a patient with non–small cell lung cancer harboring an SQSTM1-NTRK1 rearrangement.13,14 The safety profile to date has been generally well tolerated with the most frequent adverse events (AEs) consisting of mild to moderate fatigue, altered taste, abnormal sensations in the nerves, nausea, and muscle aches.
An open-label, multicenter, global, phase II basket study of entrectinib (STARTRK-2) is now underway and is enrolling patients with tumors harboring gene rearrangements in NTRK, ROS1, or ALK, including those with PTC (NCT02568267). Lin is a principal investigator on the STARTRK-2 trial, which is ongoing in 16 countries across the United States, Europe, and Asia.
Targeted Therapies Necessary for Patients With Rearrangements
Lin explained current treatment options for patients with PTC that is refractory to standard therapy and how targeted therapies may compare. “The standard therapy for radioactive iodine-refractory papillary thyroid cancer is sorafenib or lenvatinib,” Lin said, although neither of these agents have demonstrated papillary thyroid activity in a subpopulation driven by NTRK, ROS1, ALK, or other driver mutations. He also noted that the safety profiles of these agents are not trivial. For example, with sorafenib, Lin cited some of the treatment-emergent AEs (any grade) that occurred in over 98% of the patients in the DECISION trial, most commonly hand-foot skin reaction, diarrhea, alopecia, and rash or desquamation;15 similarly, with lenvatinib in the SELECT trial, treatment-emergent AEs (any grade) occurred in over 40% of the patients, including hypertension, diarrhea, fatigue/asthenia, decreased appetite, decreased weight, and nausea.16
He emphasized that growth-promoting proto-oncogenes and growth-inhib- iting tumor suppressor genes have been detected in PTCs. “Activation of the MAP kinase pathway is a feature of most papillary carcinomas, and can occur by either fusions of RET (20%-40%), NTRK1 (5%-10%), or activating mutations in BRAF V600E (45%-70%).”
“Targeted therapy against these molecules is as effective, or more effective, than sorafenib or lenvatinib, which are multi-targeted tyrosine kinase inhibitors inclusive of vascular endothelial growth factor receptor,” he said. As such, Lin believes that targeted therapy against these molecules could lead to fewer side effects, as compared with sorafenib or lenvatinb.
Emerging results from clinical trials may pave the way for more targeted treatment for patients with PTC whose tumors harbor NTRK rearrangements. Likewise, the availability of these targeted therapies will likely expand the use of molecular testing in PTC to identify important subgroups of patients who may be eligible for these trials and may benefit from these targeted treatments.
- Shi X, Liu R, Basolo F, et al. Di erential clinicopathological risk and prognosis of major papillary thyroid cancer variants. J Clin Endocrinol Metab. 2016;101:264–7
- Shaw AT, Hsu PP, Awad MM, et al. Tyrosine kinase gene rearrangements in epithelial malignancies. Nat Rev Cancer. 2013;13(11):772-787.
- Yoshihara K, Wang Q, Torres-Garcia W, et al. The landscape and therapeutic relevance of cancer-associated transcript fusions. Oncogene. 2015; 34(37):4845-4854.
- Nakagawara A. Trk receptor tyrosine kinases: a bridge between cancer and neural development. Cancer Lett. 2001; 169(2):107-114.
- Thiele CJ, Li Z, McKee AE. On Trk--the TrkB signal transduction pathway is an increasingly important target in cancer biology. Clin Cancer Res. 2009;15(19):5962-5967.
- Greco A, Miranda C, Pierotti MA. Rearrangements of NTRK1 gene in papillary thyroid carcinoma. Mol Cell Endocrinol. 2010; 321(1):44-9.
- Leeman-Neill RJ, Kelly LM, Liu P, et al. ETV6-NTRK3 is a common chromosomal rearrangement in radiation-associated thyroid cancer. Cancer. 2014; 120(6):799-807.
- Ricarte-Filho JC, Li S, Garcia-Rendueles ME, et al. Identi cation of kinase fusion oncogenes in post-Chernobyl radiation- induced thyroid cancers. J Clin Invest. 2013;123(11):4935-44.
- Prasad ML, Vyas M, Horne MJ, et al. NTRK fusion oncogenes in pediatric papillary thyroid carcinoma in northeast United States. Cancer. 2016;122(7):1097-1107.
- Bongarzone I, Pierotti MA, Monzini N, et al. High frequency of activation of tyrosine kinase oncogenes in human papil- lary thyroid carcinoma. Oncogene. 1989; 4:1457-1462
- Musholt TJ, Musholt PB, Khaladj N, et al. Prognostic signi cance of RET and NTRK1 rearrangements in sporadic papil- lary thyroid carcinoma. Surgery. 2000; 128:984-993.
- Drilon A, De Braud FG, Siena S, et al. Entrectinib, an oral pan-Trk, ROS1, and ALK inhibitor in TKI-naïve patients with advanced solid tumors harboring gene rearrangements—updated phase 1 results. Presented at: 2016 AACR Annual Meet- ing; April 16-20, 2016; New Orleans, LA. Abstract CT007.
- Sartore-Bianchi A, Ardini E, Bosotti R, et al. Sensitivity to Entrectinib Associated With a Novel LMNA-NTRK1 Gene Fusion in Metastatic Colorectal Cancer. J Natl Cancer Inst. 2015;108(1).
- Farago AF, Le LP, Zheng Z, et al. Durable Clinical Response to Entrectinib in NTRK1-Rearranged Non-Small Cell Lung Cancer. J Thorac Oncol. 2015;10(12):1670-1674.
- Brose MS, Nutting CM, Jarzab B, et al.; DECISION investigators. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic di erentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet. 2014;384(9940):319-328.
- Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015;372(7):621-630.