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Successful treatment of lipofibromatosis-like neural tumor of the lumbar spine with an NTRK-fusion inhibitor

Successful treatment of lipofibromatosis-like neural tumor of the lumbar spine with an... Background: Lipofibromatosis‑like neural tumors (LPF‑NT ) are a newly identified class of rare mesenchymal neo ‑ plasms. Current standard of care therapy is surgical resection alone; there are no chemotherapies or molecular tar‑ geted therapies that have been shown to be effective in patients who are not surgical candidates due to either tumor bulk or location. Most LPF‑NT harbor NTRK fusions, although the therapeutic significance of these fusions has not been previously demonstrated in this malignancy. Here, we present the first case of a patient with surgically‑unresect ‑ able LPF‑NT successfully treated with medical therapy, specifically the TRK fusion‑protein inhibitor entrectinib. Case presentation: The patient is a 21 year old man with no co‑morbidities who presented for evaluation due to intermittent abdominal pain and was found to have a mass spanning from T12‑L2. Biopsy revealed a mesenchymal spindle cell neoplasm and S100 positivity pointed to possible nerve sheath origin. The sample was ultimately found to have an LMNA‑NTRK1 fusion, confirming the diagnosis of LP ‑NFT. Unfortunately, due to the bulk and location of the tumor, surgery was felt to be exceptionally morbid and the patient was treated in a clinical trial with the NTRK inhibitor entrectinib. Surprisingly, he had such a robust clinical response that he was ultimately deemed a surgi‑ cal candidate and he was successfully taken to surgery. Post‑ operative pathology revealed > 95% necrosis, dem‑ onstrating exceptional sensitivity to the targeted therapy. The patient remains NED and on entrectinib 12 months post‑ operatively. Conclusions: The exceptional treatment response of this patient suggests that NTRK fusions are true drivers of the disease. Thus, all patients should be evaluated for NTRK fusions using sensitive methodologies and treatment with TRK fusion‑protein inhibitors should be considered in patients who are not candidates for oncologic resection. Keywords: Lipofibromatosis‑like neural tumors, LPF‑NT, NTRK, Entrectinib Background Lipofibromatosis-like neural tumors (LPF-NT) are a rare subset of typically superficial mesenchymal neoplasms initially described in 2016 [1]. While morphologically similar to lipofibromatosis in that they contain spindle cells involving fibroadipose tissue and are positive for *Correspondence: Jalivingston@mdanderson.org Department of Sarcoma Medical Oncology, University of Texas MD CD34 and SMA, they are also positive for S-100 protein Anderson Cancer Center, 1515 Holcombe Blvd. Unit 0450, Houston, TX which suggests neural differentiation. Importantly, LPF- 77030, USA NT typically contain a driver fusion protein involving Full list of author information is available at the end of the article © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Dupuis et al. Clin Sarcoma Res (2020) 10:14 Page 2 of 7 TRK, a family of neurotrophic receptor tyrosine kinases implications of NTRK fusions in a subset of soft tissue [1]. This molecular alteration distinguishes this neoplasm sarcomas, the WHO has recently reclassified all NTRK- from lipofibromatosis, which does not harbor a TRK rearranged soft tissue sarcoma into a new provisional fusion protein [1]. These tumors are locally invasive and entity labeled NTRK-rearranged spindle cell neoplasm can carry significant morbidity [1]. Currently, front-line [18]. This new classification encompasses LPF-NT as therapy for LPF-NT is surgery alone; if resection is not an well as other sarcomas harboring NTRK fusions. This option due to tumor bulk or location, there are no vali- move towards molecularly defined subtypes of soft tis - dated standardized treatments. Thus, a lack of effective sue sarcoma is reflective of the field and the evolving role pre-surgical therapies represents a significant gap in the of subtype specific diagnoses and treatments. However, field for this newly-described tumor. the significance and therapeutic implications of NTRK- In recent years, cancer treatments have dramatically fusions across various sarcoma subtypes may not be uni- changed due to identification of new, druggable, onco - form and thus warrants specific evaluation as in our case genic molecular drivers. One such target is the fusion of LPF-NT. product of the neurotrophic receptor tyrosine kinase Taken together, the above studies suggest that most genes NTRK1, NTRK2, and NTRK3 (encoding proteins LPF-NT harbor an NTRK fusion protein, a viable thera- TRK1, TRK2, and TRK3, respectively) with a variety of peutic target. Here, we report the first case of an LPF-NT genetic fusion partners [2]. These upstream fusion part - successfully treated with a TRK inhibitor prior to surgical ners contain oligomerization domains (such as coiled- resection, and discuss the implications for management coil, zinc finger, or WD domains) [3, 4] or have alternate of this rare entity. mechanisms of dimerization which activate TRK down- stream signaling; more than 50 upstream partners have been identified thus far [5]. NTRK fusions have been identified in tumors of more than 20 histologies [5]. Certain NTRK fusions, like ETV6- NTRK3, are represented in > 90% of secretory breast carcinomas [6], mammary analog of secretory carcino- mas (MASC) [7], congenital mesoblastic nephroma [8, 9], and infantile fibrosarcomas [10, 11]. These fusions are also found at lower incidences (5–25%) in tumors such as breast, lung, colon, and melanoma [2], leading to the 2018 basket trial in which 55 NTRK-fusion-positive patients with 17 different cancer types were treated with the first-generation TRK inhibitor larotrectinib [12]. This study ultimately resulted in the first tissue-agnostic US FDA approval for a molecular targeted therapy. Entrec- tinib, another first generation small-molecule inhibitor against TRKA/B/C, ROS1, and ALK, was recently devel- oped. It was designed to cross the blood–brain barrier to target brain metastases [13], and demonstrated efficacy Fig. 1 Imaging features of the lesion. a, b Axial and sagittal in multiple histologies including non-small cell lung can- post‑ contrast MRI demonstrates an avidly enhancing lesion in the cer [14, 15] as well as activity in adults and children with L1 pre‑ vertebral soft tissues. There is anterior displacement of the solid tumors harboring NTRK fusions [16]. These stud - aorta (Ao, black arrow) and inferior vena cava (IVC, white arrows). There is invasion of the L1 vertebral body, with cephalad and ies have led to its accelerated approval by the US FDA for caudad extension of disease and secondary pressure erosion of the adults with ROS-1 positive metastatic NSCLC and for ventral cortices of T12 (black arrowhead) and L2 (white arrowhead) adult and pediatric patients ≥ 12  years old with NTRK vertebral bodies. c Concurrent contrast‑ enhanced CT image at the fusion-positive solid tumors. level of L1 shows an avidly enhancing mass (between large black u Th s far, two papers have studied the incidence of arrows) with invasion of the L1 vertebral body. The CT shows rim of sclerosis in the vertebral body indicative of secondary invasion from NTRK fusion proteins in LPF-NT. In the 2016 paper a soft tissue mass. The aorta and inferior vena cava (black and white which first classified this tumor [1], they describe that arrows, respectively) are anteriorly displaced. d Contrast‑ enhanced 10/14 patients (71%) had NTRK1 fusions. In the sec- CT at end of therapy shows significant decrease in size and degree ond study [17], molecular studies showed 4/5 patients of enhancement of the mass (between large black arrows). Mass with LPF-NF were positive for NTRK1 rearrangement effect on the aorta and inferior vena cava (black and white arrows, respectively) has also decreased by FISH. Given the natural history and therapeutic D upuis et al. Clin Sarcoma Res (2020) 10:14 Page 3 of 7 PCR-based targeted next-generation sequencing (NGS) Case presentation RNA fusion panel that covers 485 exons from 81 genes The patient is a 21-year-old young man without signifi - and is optimized for formalin-fixed, paraffin-embedded cant past medical history. He initially presented with a (FFPE) samples, revealed a fusion between exon 2 of complaint of intermittent abdominal pain, and a CT scan LMNA (NM_005572.3; chr1:156100564) and exon 11 revealed an abnormal paraspinal lesion. He underwent of NTRK1 (NM_002529.3; chr1:156844698), predicted MRI which demonstrated the lesion extending from T12- to encode an in-frame LMNA-NTRK1 fusion protein L2 and measured 8.7 cm × 3.9 cm × 6.9 cm (Fig. 1a, b). retaining the C-terminal kinase domain of NTRK1 Subsequent biopsy revealed a spindle cell mesenchymal (Fig.  3a). The fusion transcripts were confirmed with tumor with monotonous, bland spindle cells admixed orthogonal RT-PCR and Sanger sequencing (Fig.  3b). with mature fat and occasional ectatic blood vessels Identification of this fusion reclassified the putative (Fig.  2). Neither necrosis nor brisk mitotic activity were diagnosis to an S-100 positive LPF-NT of the spine. noted. IHC studies demonstrated positivity for CD34, Due to size and location, primary surgical resec- pan-TRK, S-100 and SMA (not shown); the tumor was tion would have been exceedingly morbid. Thus, the negative for Pankeratin cocktail, STAT6, DOG1, desmin, patient was entered into a phase II basket trial enroll- TLE1, panmelanocytic cocktail, and Sox10. Scattered ing patients with NTRK 1/2/3, ROS1, or ALK gene cells labeled for SATB2 and H3K27me3. The tumor was rearrangements to be treated with entrectinib. He negative for MDM2 amplification or FUS gene rearrange- received a dose of 600  mg daily, and the only adverse ment using fluorescent in situ hybridization (FISH). effects were grade 1 diarrhea and taste alterations. The S-100 staining raised the possibility of a periph - Early response assessment after 1 month demonstrated eral nerve sheath origin. Given the pan-TRK immu- a near-complete loss of enhancement and density of the noreactivity, the diagnosis of LPF-NT was considered; mass, with the hounsfield units dropping from 200 on however, the site was unusual as it was not superficial. the initial scan to 55–60 at follow up (Figs. 1a, b, and 4). Thus, further molecular testing was performed. A cus - He had an excellent therapeutic response, with a 45% tom-designed, clinically-validated anchored multiplex Fig. 2 Pre‑treatment biopsy. a H&E sections demonstrate monotonous, bland, spindle cell proliferation admixed with mature fat and occasional ectatic blood vessel. Immunohistochemical studies reveal that areas of the tumor cells had reactivity for c S‑100, c CD34, and d pan‑trk. Measurement bars = 100 µm Dupuis et al. Clin Sarcoma Res (2020) 10:14 Page 4 of 7 Fig. 3 LMNA‑NTRK1 fusion confirmed by RT ‑PCR. a Schematic diagram showing the predicted in‑frame LMNA‑NTRK1 fusion protein joining the 5′ LMNA filament domain to an intact 3′ NTRK1 tyrosine kinase domain (KD). The red dashed lines denote the 1q chromosomal positions of LMNA and NTRK1, respectively. b RT‑PCR Sanger sequencing trace confirming the fusion breakpoint at chr1:156100564 (LMNA, NM_005572.3, exon 2) and chr1:156844698 (NTRK1, NM_002529.3, exon 11). LTD, lamin tail domain; Ig, Tyrosine‑protein kinase receptor C2 Ig‑like domain Fig. 4 Post treatment. Contrast‑ enhanced MR images demonstrating mass involving vertebrae (a) axial and (b) sagittal showing decrease in the size of the lesion compared to baseline (Fig. 1). c Gross specimen (sagittal) demonstrating a tan‑ white pink mass involving the paraspinal soft tissue and protruding into the underlying vertebrae body associated with sclerosis. Measurement bar = 1 cm reduction in tumor size by RECIST criteria, measuring into the vertebral body, with underlying bony sclerosis. 4.0 × 2.8  cm (Fig .  5). Although the patient was not ini- Histologically, there was extensive treatment response tially a surgical candidate due to unacceptable morbid- (> 95%) with decreased cellularity, marked hyalinization ity, his response to therapy was so exceptional that he and focal areas of viable tumor cells (Fig.  6). The tumor ultimately qualified for surgical resection. focally involved soft tissue margins however bone mar- Therefore, he underwent vertebrectomy, which gins were tumor-free. The patient has continued on revealed a 7.0 × 5.2 × 3 cm mass with tan-white pink cut entrectinib following surgery and remains without evi- surface involving paraspinal soft tissue and protruding dence of recurrence at 7 months. D upuis et al. Clin Sarcoma Res (2020) 10:14 Page 5 of 7 partners remains incompletely understood [2, 5], and their systematic classification may yield information about their biologic behavior. In the broader sarcoma field, the significance of NTRK fusions has emerged. As previously mentioned, ETV6- NTRK3 fusions are practically pathognomonic for the diagnosis of infantile fibrosarcoma [11] and NTRK fusions have also been implicated as the defining feature of a subset of unclassified uterine sarcoma with spin - dle cell morphology [21]. However, incidence of NTRK fusions is variable between different sarcoma subtypes. Fig. 5 Response to therapy as assessed by RECIST 1.1. Response Recently, position papers released from the Journal of plateau was achieved at week 12, with 45% decrease in size of the Clinical Pathology [22] and ESMO [23] propose stand- lesion ardized algorithms for testing for NTRK fusions. Both propose essentially the same method: for tumors with a high incidence of NTRK fusions (such as MASC), any Discussion and conclusions detection method is sufficient; however, in tumors with LPF-NT is a rare tumor of mesenchymal origin first low incidence, an NGS panel should be used upfront with described in 2016. Prior to then, LPF-NT was likely positivity confirmed via IHC. If, however, no standard characterized as atypical lipofibromatosis, malignant NGS panel is available, then IHC screening may be used peripheral nerve sheath tumor (MPNST), or spindle cell upfront, with NGS confirmation. tumors. Given its recent classification, there is a paucity For poor quality specimens, a highly sensitive and ver- of data regarding management and outcomes. Currently, satile assay able to test for NTRK and other fusions is only 26 patients with LPF-NT are described in the litera- needed to confirm the diagnosis. Anchored multiplex ture [1, 17, 19]; our case, which met classification criteria PCR NGS allows for detection of multiple gene fusions for LPF-NT given positive S100 and CD34 staining, rep- in a single assay with minimal RNA input, which has high resents the 27th patient. diagnostic yield in sarcomas and other spindle cell lesions Importantly, his tumor was positive for a LMNA- [24]. NTRK1 fusion, which was the most common type of As these fusions have been identified, the opportunity NTRK fusion seen in the initial case series [1]. The for targeted therapy has also become apparent. In 2015, authors also separately report a single case of a patient a patient with metastatic soft-tissue sarcoma harboring with LPF-NT and LMNA-NTRK1 fusion with lung an LMNA-NTRK1 fusion protein was enrolled phase I metastasis, potentially secondary to a delay in surgical clinical trial with larotrectinib and had nearly complete resection rather than the specific NTRK fusion partner. regression of the lung tumors. In the 2018 basket trial Another case report has also implicated the LMNA- evaluating larotrectinib, 21/55 patients had sarcomas and NTRK1 fusion in a patient with metastatic sarcoma all but 2 experienced at least a partial response [12]. In [20]. However, the significance of specific NTRK fusion 2018, an integrated analysis of two phase I clinical trials Fig. 6 Post‑treatment histological changes. a H&E sections demonstrate marked hyalinization and decreased cellularity with scattered foci of b residual tumor cells admixed with lymphocytes. Measurement bars = 100 µm Dupuis et al. Clin Sarcoma Res (2020) 10:14 Page 6 of 7 Author details and one phase II clinical trial revealed that entrectinib Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, had a 57% ORR among 54 patients with NTRK fusions Houston, TX, USA. Department of Pathology & Immunology, Baylor College [15]. Entrectinib was well tolerated, produced durable of Medicine and Texas Children’s Hospital, Houston, TX, USA. Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, systemic responses, and was FDA-approved based on USA. Department of Diagnostic Imaging, University of Texas MD Anderson these data. Cancer Center, Houston, TX, USA. Department of Neurosurgery, Univer‑ In LPF-NT, the frontline therapy is surgical resection. sity of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Sarcoma Medical Oncology, University of Texas MD Anderson Cancer However, in patients for whom surgery is not an option Center, 1515 Holcombe Blvd. Unit 0450, Houston, TX 77030, USA. Depart‑ due to location or bulk of tumor, no chemotherapies or ment of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, molecular therapies have successfully reduced tumor TX, USA. burden. To our knowledge, this case represents the first Received: 9 April 2020 Accepted: 30 July 2020 successful treatment of LPF-NT with an NTRK-fusion inhibitor prior to surgery. Our patient had an excel- lent response to entrectinib, allowing him to proceed to surgical resection. Importantly, post-operative pathol- References ogy revealed > 95% necrosis, consistent with exqui- 1. Agaram NP, Zhang L, Sung YS, et al. Recurrent NTRK1 gene fusions define a novel subset of locally aggressive lipofibromatosis‑like neural tumors. site inhibitor sensitivity. These results suggest that all Am J Surg Pathol. 2016;40:1407–16. patients with a presumed diagnosis of LPF-NT should 2. Amatu A, Sartore‑Bianchi A, Siena S. NTRK gene fusions as novel be screened for NTRK fusions using sensitive method- targets of cancer therapy across multiple tumour types. ESMO Open. 2016;1:e000023. ologies, and that treatment with a TRK fusion-protein 3. Coulier F, Martin‑Zanca D, Ernst M, et al. Mechanism of activation of the inhibitor is a rational therapeutic option for patients human trk oncogene. Mol Cell Biol. 1989;9:15–23. who are not up-front surgical candidates. 4. Schram AM, Chang MT, Jonsson P, et al. Fusions in solid tumours: diag‑ nostic strategies, targeted therapy, and acquired resistance. Nat Rev Clin Oncol. 2017;14:735–48. 5. Cocco E, Scaltriti M, Drilon A. NTRK fusion‑positive cancers and TRK inhibi‑ Abbreviations tor therapy. Nat Rev Clin Oncol. 2018;15:731–47. LPF‑NT: Lipofibromatosis‑like neural tumor; NTRK: Neurotrophic receptor 6. Tognon C, Knezevich SR, Huntsman D, et al. Expression of the ETV6‑ tyrosine kinase; MASC: Mammary analog of secretory carcinoma; NSCLC: Non‑ NTRK3 gene fusion as a primary event in human secretory breast carci‑ small cell lung cancer; NGS: Next generation sequencing; MPNST: Malignant noma. Cancer Cell. 2002;2:367–76. peripheral nerve sheath tumor. 7. Drilon A, Li G, Dogan S, et al. What hides behind the MASC: clinical response and acquired resistance to entrectinib after ETV6‑NTRK3 identi‑ Acknowledgements fication in a mammary analogue secretory carcinoma (MASC). Ann Oncol. Not applicable. 2016;27:920–6. 8. Davis JL, Lockwood CM, Albert CM, et al. Infantile NTRK‑associated mes‑ Authors’ contributions enchymal tumors. Pediatr Dev Pathol. 2018;21:68–78. MD participated in conception of the report and the major drafting of the 9. Halalsheh H, McCarville MB, Neel M, et al. Dramatic bone remodeling manuscript as well as all revisions; YS, CC, JM, W‑LW, JR, AR, KF, acquired and following larotrectinib administration for bone metastasis in a patient interpreted data in regards to the immunohistochemistry and molecular with TRK fusion congenital mesoblastic nephroma. Pediatr Blood Cancer. testing of the sample leading to the accurate diagnosis. BA acquired and 2018;65:e27271. interpreted imaging data including RECIST criteria; LR performed the surgery 10. Pavlick D, Schrock AB, Malicki D, et al. Identification of NTRK fusions in and participated in the conception of the manuscript; AC participated in con‑ pediatric mesenchymal tumors. Pediatr Blood Cancer. 2017;64:e26433. ception of the manuscript, data analysis, and was a major contributor to the 11. Laetsch TW, DuBois SG, Mascarenhas L, et al. Larotrectinib for paediatric manuscript; JAL conceived of the manuscript, data analysis, and was a major solid tumours harbouring NTRK gene fusions: phase 1 results from a contributor to the manuscript and subsequent revisions of the manuscript. All multicentre, open‑label, phase 1/2 study. Lancet Oncol. 2018;19:705–14. authors read and approved the final manuscript. 12. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion‑positive cancers in adults and Children. N Engl J Med. Funding 2018;378:731–9. No funding was directly used to write or prepare this case report. 13. Ardini E, Menichincheri M, Banfi P, et al. Entrectinib, a Pan‑ TRK, ROS1, and ALK inhibitor with activity in multiple molecularly defined cancer indica‑ Availability of data tions. Mol Cancer Ther. 2016;15:628–39. Not applicable. 14. Farago AF, Le LP, Zheng Z, et al. Durable clinical response to entrec‑ tinib in NTRK1‑rearranged non‑small cell lung cancer. J Thorac Oncol. Ethics approval and consent to participate 2015;10:1670–4. Enrollment of the patient in a clinical trial was completed in compliance with 15. Demetri GD, Paz‑Ares L, Farago AF, et al. Efficacy and safety of entrectinib our institution’s ethics committee and institutional review board. in patients with NTRK fusion‑positive tumors: pooled analysis of STAR‑ TRK‑2, STARTRK ‑1 and ALKA‑372‑001. Munich: ESMO Congress; 2018. Consent for publication 16. Robinson GW, Gajjar AJ, Gauvain KM, et al. Phase 1/1B trial to assess Consent for publication was obtained from the patient using our institution’s the activity of entrectinib in children and adolescents with recurrent or consent policy and will be provided upon request. refractory solid tumors including central nervous system (CNS) tumors. Am Soc Clin Oncol. 2019;33(15):10009. Competing interests 17. Lao IW, Sun M, Zhao M, et al. Lipofibromatosis‑like neural tumour: a clin‑ AC receives research funding from Ignyta and Genentech for the conduct of icopathological study of ten additional cases of an emerging novel entity. the entrectinib study, and provides consulting for Genentech and scientific Pathology. 2018;50:519–23. advisement for Deciphera; no other authors have competing interests to 18. WHO. Classification of tumors: soft tissue and bone tumors. 5th ed. declare. Geneva: WHO; 2020. D upuis et al. Clin Sarcoma Res (2020) 10:14 Page 7 of 7 19. Bartenstein DW, Coe TM, Gordon SC, et al. Lipofibromatosis‑like neural 23. Marchio C, Scaltriti M, Ladanyi M, et al. ESMO recommendations on the tumor: case report of a unique infantile presentation. JAAD Case Rep. standard methods to detect NTRK fusions in daily practice and clinical 2018;4:185–8. research. Ann Oncol. 2019;30:1417–27. 20. Wong V, Pavlick D, Brennan T, et al. Evaluation of a congenital infan‑ 24. Lam SW, Cleton‑ Jansen AM, Cleven AHG, et al. Molecular analysis of gene tile fibrosarcoma by comprehensive genomic profiling reveals an fusions in bone and soft tissue tumors by anchored multiplex PCR‑based LMNA‑NTRK1 gene fusion responsive to crizotinib. J Natl Cancer Inst. targeted next‑ generation sequencing. J Mol Diagn. 2018;20:653–63. 2016;108(1):307. https ://doi.org/10.1093/jnci/djv30 7. 21. Chiang S, Cotzia P, Hyman DM, et al. NTRK fusions define a novel uterine Publisher’s Note sarcoma subtype with features of fibrosarcoma. Am J Surg Pathol. Springer Nature remains neutral with regard to jurisdictional claims in pub‑ 2018;42:791–8. lished maps and institutional affiliations. 22. Penault‑Llorca F, Rudzinski ER, Sepulveda AR. Testing algorithm for identi‑ fication of patients with TRK fusion cancer. J Clin Pathol. 2019;72:460–7. Ready to submit your research ? 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Successful treatment of lipofibromatosis-like neural tumor of the lumbar spine with an NTRK-fusion inhibitor

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Abstract

Background: Lipofibromatosis‑like neural tumors (LPF‑NT ) are a newly identified class of rare mesenchymal neo ‑ plasms. Current standard of care therapy is surgical resection alone; there are no chemotherapies or molecular tar‑ geted therapies that have been shown to be effective in patients who are not surgical candidates due to either tumor bulk or location. Most LPF‑NT harbor NTRK fusions, although the therapeutic significance of these fusions has not been previously demonstrated in this malignancy. Here, we present the first case of a patient with surgically‑unresect ‑ able LPF‑NT successfully treated with medical therapy, specifically the TRK fusion‑protein inhibitor entrectinib. Case presentation: The patient is a 21 year old man with no co‑morbidities who presented for evaluation due to intermittent abdominal pain and was found to have a mass spanning from T12‑L2. Biopsy revealed a mesenchymal spindle cell neoplasm and S100 positivity pointed to possible nerve sheath origin. The sample was ultimately found to have an LMNA‑NTRK1 fusion, confirming the diagnosis of LP ‑NFT. Unfortunately, due to the bulk and location of the tumor, surgery was felt to be exceptionally morbid and the patient was treated in a clinical trial with the NTRK inhibitor entrectinib. Surprisingly, he had such a robust clinical response that he was ultimately deemed a surgi‑ cal candidate and he was successfully taken to surgery. Post‑ operative pathology revealed > 95% necrosis, dem‑ onstrating exceptional sensitivity to the targeted therapy. The patient remains NED and on entrectinib 12 months post‑ operatively. Conclusions: The exceptional treatment response of this patient suggests that NTRK fusions are true drivers of the disease. Thus, all patients should be evaluated for NTRK fusions using sensitive methodologies and treatment with TRK fusion‑protein inhibitors should be considered in patients who are not candidates for oncologic resection. Keywords: Lipofibromatosis‑like neural tumors, LPF‑NT, NTRK, Entrectinib Background Lipofibromatosis-like neural tumors (LPF-NT) are a rare subset of typically superficial mesenchymal neoplasms initially described in 2016 [1]. While morphologically similar to lipofibromatosis in that they contain spindle cells involving fibroadipose tissue and are positive for *Correspondence: Jalivingston@mdanderson.org Department of Sarcoma Medical Oncology, University of Texas MD CD34 and SMA, they are also positive for S-100 protein Anderson Cancer Center, 1515 Holcombe Blvd. Unit 0450, Houston, TX which suggests neural differentiation. Importantly, LPF- 77030, USA NT typically contain a driver fusion protein involving Full list of author information is available at the end of the article © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Dupuis et al. Clin Sarcoma Res (2020) 10:14 Page 2 of 7 TRK, a family of neurotrophic receptor tyrosine kinases implications of NTRK fusions in a subset of soft tissue [1]. This molecular alteration distinguishes this neoplasm sarcomas, the WHO has recently reclassified all NTRK- from lipofibromatosis, which does not harbor a TRK rearranged soft tissue sarcoma into a new provisional fusion protein [1]. These tumors are locally invasive and entity labeled NTRK-rearranged spindle cell neoplasm can carry significant morbidity [1]. Currently, front-line [18]. This new classification encompasses LPF-NT as therapy for LPF-NT is surgery alone; if resection is not an well as other sarcomas harboring NTRK fusions. This option due to tumor bulk or location, there are no vali- move towards molecularly defined subtypes of soft tis - dated standardized treatments. Thus, a lack of effective sue sarcoma is reflective of the field and the evolving role pre-surgical therapies represents a significant gap in the of subtype specific diagnoses and treatments. However, field for this newly-described tumor. the significance and therapeutic implications of NTRK- In recent years, cancer treatments have dramatically fusions across various sarcoma subtypes may not be uni- changed due to identification of new, druggable, onco - form and thus warrants specific evaluation as in our case genic molecular drivers. One such target is the fusion of LPF-NT. product of the neurotrophic receptor tyrosine kinase Taken together, the above studies suggest that most genes NTRK1, NTRK2, and NTRK3 (encoding proteins LPF-NT harbor an NTRK fusion protein, a viable thera- TRK1, TRK2, and TRK3, respectively) with a variety of peutic target. Here, we report the first case of an LPF-NT genetic fusion partners [2]. These upstream fusion part - successfully treated with a TRK inhibitor prior to surgical ners contain oligomerization domains (such as coiled- resection, and discuss the implications for management coil, zinc finger, or WD domains) [3, 4] or have alternate of this rare entity. mechanisms of dimerization which activate TRK down- stream signaling; more than 50 upstream partners have been identified thus far [5]. NTRK fusions have been identified in tumors of more than 20 histologies [5]. Certain NTRK fusions, like ETV6- NTRK3, are represented in > 90% of secretory breast carcinomas [6], mammary analog of secretory carcino- mas (MASC) [7], congenital mesoblastic nephroma [8, 9], and infantile fibrosarcomas [10, 11]. These fusions are also found at lower incidences (5–25%) in tumors such as breast, lung, colon, and melanoma [2], leading to the 2018 basket trial in which 55 NTRK-fusion-positive patients with 17 different cancer types were treated with the first-generation TRK inhibitor larotrectinib [12]. This study ultimately resulted in the first tissue-agnostic US FDA approval for a molecular targeted therapy. Entrec- tinib, another first generation small-molecule inhibitor against TRKA/B/C, ROS1, and ALK, was recently devel- oped. It was designed to cross the blood–brain barrier to target brain metastases [13], and demonstrated efficacy Fig. 1 Imaging features of the lesion. a, b Axial and sagittal in multiple histologies including non-small cell lung can- post‑ contrast MRI demonstrates an avidly enhancing lesion in the cer [14, 15] as well as activity in adults and children with L1 pre‑ vertebral soft tissues. There is anterior displacement of the solid tumors harboring NTRK fusions [16]. These stud - aorta (Ao, black arrow) and inferior vena cava (IVC, white arrows). There is invasion of the L1 vertebral body, with cephalad and ies have led to its accelerated approval by the US FDA for caudad extension of disease and secondary pressure erosion of the adults with ROS-1 positive metastatic NSCLC and for ventral cortices of T12 (black arrowhead) and L2 (white arrowhead) adult and pediatric patients ≥ 12  years old with NTRK vertebral bodies. c Concurrent contrast‑ enhanced CT image at the fusion-positive solid tumors. level of L1 shows an avidly enhancing mass (between large black u Th s far, two papers have studied the incidence of arrows) with invasion of the L1 vertebral body. The CT shows rim of sclerosis in the vertebral body indicative of secondary invasion from NTRK fusion proteins in LPF-NT. In the 2016 paper a soft tissue mass. The aorta and inferior vena cava (black and white which first classified this tumor [1], they describe that arrows, respectively) are anteriorly displaced. d Contrast‑ enhanced 10/14 patients (71%) had NTRK1 fusions. In the sec- CT at end of therapy shows significant decrease in size and degree ond study [17], molecular studies showed 4/5 patients of enhancement of the mass (between large black arrows). Mass with LPF-NF were positive for NTRK1 rearrangement effect on the aorta and inferior vena cava (black and white arrows, respectively) has also decreased by FISH. Given the natural history and therapeutic D upuis et al. Clin Sarcoma Res (2020) 10:14 Page 3 of 7 PCR-based targeted next-generation sequencing (NGS) Case presentation RNA fusion panel that covers 485 exons from 81 genes The patient is a 21-year-old young man without signifi - and is optimized for formalin-fixed, paraffin-embedded cant past medical history. He initially presented with a (FFPE) samples, revealed a fusion between exon 2 of complaint of intermittent abdominal pain, and a CT scan LMNA (NM_005572.3; chr1:156100564) and exon 11 revealed an abnormal paraspinal lesion. He underwent of NTRK1 (NM_002529.3; chr1:156844698), predicted MRI which demonstrated the lesion extending from T12- to encode an in-frame LMNA-NTRK1 fusion protein L2 and measured 8.7 cm × 3.9 cm × 6.9 cm (Fig. 1a, b). retaining the C-terminal kinase domain of NTRK1 Subsequent biopsy revealed a spindle cell mesenchymal (Fig.  3a). The fusion transcripts were confirmed with tumor with monotonous, bland spindle cells admixed orthogonal RT-PCR and Sanger sequencing (Fig.  3b). with mature fat and occasional ectatic blood vessels Identification of this fusion reclassified the putative (Fig.  2). Neither necrosis nor brisk mitotic activity were diagnosis to an S-100 positive LPF-NT of the spine. noted. IHC studies demonstrated positivity for CD34, Due to size and location, primary surgical resec- pan-TRK, S-100 and SMA (not shown); the tumor was tion would have been exceedingly morbid. Thus, the negative for Pankeratin cocktail, STAT6, DOG1, desmin, patient was entered into a phase II basket trial enroll- TLE1, panmelanocytic cocktail, and Sox10. Scattered ing patients with NTRK 1/2/3, ROS1, or ALK gene cells labeled for SATB2 and H3K27me3. The tumor was rearrangements to be treated with entrectinib. He negative for MDM2 amplification or FUS gene rearrange- received a dose of 600  mg daily, and the only adverse ment using fluorescent in situ hybridization (FISH). effects were grade 1 diarrhea and taste alterations. The S-100 staining raised the possibility of a periph - Early response assessment after 1 month demonstrated eral nerve sheath origin. Given the pan-TRK immu- a near-complete loss of enhancement and density of the noreactivity, the diagnosis of LPF-NT was considered; mass, with the hounsfield units dropping from 200 on however, the site was unusual as it was not superficial. the initial scan to 55–60 at follow up (Figs. 1a, b, and 4). Thus, further molecular testing was performed. A cus - He had an excellent therapeutic response, with a 45% tom-designed, clinically-validated anchored multiplex Fig. 2 Pre‑treatment biopsy. a H&E sections demonstrate monotonous, bland, spindle cell proliferation admixed with mature fat and occasional ectatic blood vessel. Immunohistochemical studies reveal that areas of the tumor cells had reactivity for c S‑100, c CD34, and d pan‑trk. Measurement bars = 100 µm Dupuis et al. Clin Sarcoma Res (2020) 10:14 Page 4 of 7 Fig. 3 LMNA‑NTRK1 fusion confirmed by RT ‑PCR. a Schematic diagram showing the predicted in‑frame LMNA‑NTRK1 fusion protein joining the 5′ LMNA filament domain to an intact 3′ NTRK1 tyrosine kinase domain (KD). The red dashed lines denote the 1q chromosomal positions of LMNA and NTRK1, respectively. b RT‑PCR Sanger sequencing trace confirming the fusion breakpoint at chr1:156100564 (LMNA, NM_005572.3, exon 2) and chr1:156844698 (NTRK1, NM_002529.3, exon 11). LTD, lamin tail domain; Ig, Tyrosine‑protein kinase receptor C2 Ig‑like domain Fig. 4 Post treatment. Contrast‑ enhanced MR images demonstrating mass involving vertebrae (a) axial and (b) sagittal showing decrease in the size of the lesion compared to baseline (Fig. 1). c Gross specimen (sagittal) demonstrating a tan‑ white pink mass involving the paraspinal soft tissue and protruding into the underlying vertebrae body associated with sclerosis. Measurement bar = 1 cm reduction in tumor size by RECIST criteria, measuring into the vertebral body, with underlying bony sclerosis. 4.0 × 2.8  cm (Fig .  5). Although the patient was not ini- Histologically, there was extensive treatment response tially a surgical candidate due to unacceptable morbid- (> 95%) with decreased cellularity, marked hyalinization ity, his response to therapy was so exceptional that he and focal areas of viable tumor cells (Fig.  6). The tumor ultimately qualified for surgical resection. focally involved soft tissue margins however bone mar- Therefore, he underwent vertebrectomy, which gins were tumor-free. The patient has continued on revealed a 7.0 × 5.2 × 3 cm mass with tan-white pink cut entrectinib following surgery and remains without evi- surface involving paraspinal soft tissue and protruding dence of recurrence at 7 months. D upuis et al. Clin Sarcoma Res (2020) 10:14 Page 5 of 7 partners remains incompletely understood [2, 5], and their systematic classification may yield information about their biologic behavior. In the broader sarcoma field, the significance of NTRK fusions has emerged. As previously mentioned, ETV6- NTRK3 fusions are practically pathognomonic for the diagnosis of infantile fibrosarcoma [11] and NTRK fusions have also been implicated as the defining feature of a subset of unclassified uterine sarcoma with spin - dle cell morphology [21]. However, incidence of NTRK fusions is variable between different sarcoma subtypes. Fig. 5 Response to therapy as assessed by RECIST 1.1. Response Recently, position papers released from the Journal of plateau was achieved at week 12, with 45% decrease in size of the Clinical Pathology [22] and ESMO [23] propose stand- lesion ardized algorithms for testing for NTRK fusions. Both propose essentially the same method: for tumors with a high incidence of NTRK fusions (such as MASC), any Discussion and conclusions detection method is sufficient; however, in tumors with LPF-NT is a rare tumor of mesenchymal origin first low incidence, an NGS panel should be used upfront with described in 2016. Prior to then, LPF-NT was likely positivity confirmed via IHC. If, however, no standard characterized as atypical lipofibromatosis, malignant NGS panel is available, then IHC screening may be used peripheral nerve sheath tumor (MPNST), or spindle cell upfront, with NGS confirmation. tumors. Given its recent classification, there is a paucity For poor quality specimens, a highly sensitive and ver- of data regarding management and outcomes. Currently, satile assay able to test for NTRK and other fusions is only 26 patients with LPF-NT are described in the litera- needed to confirm the diagnosis. Anchored multiplex ture [1, 17, 19]; our case, which met classification criteria PCR NGS allows for detection of multiple gene fusions for LPF-NT given positive S100 and CD34 staining, rep- in a single assay with minimal RNA input, which has high resents the 27th patient. diagnostic yield in sarcomas and other spindle cell lesions Importantly, his tumor was positive for a LMNA- [24]. NTRK1 fusion, which was the most common type of As these fusions have been identified, the opportunity NTRK fusion seen in the initial case series [1]. The for targeted therapy has also become apparent. In 2015, authors also separately report a single case of a patient a patient with metastatic soft-tissue sarcoma harboring with LPF-NT and LMNA-NTRK1 fusion with lung an LMNA-NTRK1 fusion protein was enrolled phase I metastasis, potentially secondary to a delay in surgical clinical trial with larotrectinib and had nearly complete resection rather than the specific NTRK fusion partner. regression of the lung tumors. In the 2018 basket trial Another case report has also implicated the LMNA- evaluating larotrectinib, 21/55 patients had sarcomas and NTRK1 fusion in a patient with metastatic sarcoma all but 2 experienced at least a partial response [12]. In [20]. However, the significance of specific NTRK fusion 2018, an integrated analysis of two phase I clinical trials Fig. 6 Post‑treatment histological changes. a H&E sections demonstrate marked hyalinization and decreased cellularity with scattered foci of b residual tumor cells admixed with lymphocytes. Measurement bars = 100 µm Dupuis et al. Clin Sarcoma Res (2020) 10:14 Page 6 of 7 Author details and one phase II clinical trial revealed that entrectinib Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, had a 57% ORR among 54 patients with NTRK fusions Houston, TX, USA. Department of Pathology & Immunology, Baylor College [15]. Entrectinib was well tolerated, produced durable of Medicine and Texas Children’s Hospital, Houston, TX, USA. Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, systemic responses, and was FDA-approved based on USA. Department of Diagnostic Imaging, University of Texas MD Anderson these data. Cancer Center, Houston, TX, USA. Department of Neurosurgery, Univer‑ In LPF-NT, the frontline therapy is surgical resection. sity of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Sarcoma Medical Oncology, University of Texas MD Anderson Cancer However, in patients for whom surgery is not an option Center, 1515 Holcombe Blvd. Unit 0450, Houston, TX 77030, USA. Depart‑ due to location or bulk of tumor, no chemotherapies or ment of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, molecular therapies have successfully reduced tumor TX, USA. burden. To our knowledge, this case represents the first Received: 9 April 2020 Accepted: 30 July 2020 successful treatment of LPF-NT with an NTRK-fusion inhibitor prior to surgery. Our patient had an excel- lent response to entrectinib, allowing him to proceed to surgical resection. Importantly, post-operative pathol- References ogy revealed > 95% necrosis, consistent with exqui- 1. Agaram NP, Zhang L, Sung YS, et al. Recurrent NTRK1 gene fusions define a novel subset of locally aggressive lipofibromatosis‑like neural tumors. site inhibitor sensitivity. These results suggest that all Am J Surg Pathol. 2016;40:1407–16. patients with a presumed diagnosis of LPF-NT should 2. Amatu A, Sartore‑Bianchi A, Siena S. NTRK gene fusions as novel be screened for NTRK fusions using sensitive method- targets of cancer therapy across multiple tumour types. ESMO Open. 2016;1:e000023. ologies, and that treatment with a TRK fusion-protein 3. Coulier F, Martin‑Zanca D, Ernst M, et al. Mechanism of activation of the inhibitor is a rational therapeutic option for patients human trk oncogene. Mol Cell Biol. 1989;9:15–23. who are not up-front surgical candidates. 4. Schram AM, Chang MT, Jonsson P, et al. Fusions in solid tumours: diag‑ nostic strategies, targeted therapy, and acquired resistance. Nat Rev Clin Oncol. 2017;14:735–48. 5. Cocco E, Scaltriti M, Drilon A. NTRK fusion‑positive cancers and TRK inhibi‑ Abbreviations tor therapy. Nat Rev Clin Oncol. 2018;15:731–47. LPF‑NT: Lipofibromatosis‑like neural tumor; NTRK: Neurotrophic receptor 6. Tognon C, Knezevich SR, Huntsman D, et al. Expression of the ETV6‑ tyrosine kinase; MASC: Mammary analog of secretory carcinoma; NSCLC: Non‑ NTRK3 gene fusion as a primary event in human secretory breast carci‑ small cell lung cancer; NGS: Next generation sequencing; MPNST: Malignant noma. Cancer Cell. 2002;2:367–76. peripheral nerve sheath tumor. 7. Drilon A, Li G, Dogan S, et al. What hides behind the MASC: clinical response and acquired resistance to entrectinib after ETV6‑NTRK3 identi‑ Acknowledgements fication in a mammary analogue secretory carcinoma (MASC). Ann Oncol. Not applicable. 2016;27:920–6. 8. Davis JL, Lockwood CM, Albert CM, et al. Infantile NTRK‑associated mes‑ Authors’ contributions enchymal tumors. Pediatr Dev Pathol. 2018;21:68–78. MD participated in conception of the report and the major drafting of the 9. Halalsheh H, McCarville MB, Neel M, et al. Dramatic bone remodeling manuscript as well as all revisions; YS, CC, JM, W‑LW, JR, AR, KF, acquired and following larotrectinib administration for bone metastasis in a patient interpreted data in regards to the immunohistochemistry and molecular with TRK fusion congenital mesoblastic nephroma. Pediatr Blood Cancer. testing of the sample leading to the accurate diagnosis. BA acquired and 2018;65:e27271. interpreted imaging data including RECIST criteria; LR performed the surgery 10. Pavlick D, Schrock AB, Malicki D, et al. Identification of NTRK fusions in and participated in the conception of the manuscript; AC participated in con‑ pediatric mesenchymal tumors. Pediatr Blood Cancer. 2017;64:e26433. ception of the manuscript, data analysis, and was a major contributor to the 11. Laetsch TW, DuBois SG, Mascarenhas L, et al. Larotrectinib for paediatric manuscript; JAL conceived of the manuscript, data analysis, and was a major solid tumours harbouring NTRK gene fusions: phase 1 results from a contributor to the manuscript and subsequent revisions of the manuscript. All multicentre, open‑label, phase 1/2 study. Lancet Oncol. 2018;19:705–14. authors read and approved the final manuscript. 12. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion‑positive cancers in adults and Children. N Engl J Med. Funding 2018;378:731–9. No funding was directly used to write or prepare this case report. 13. Ardini E, Menichincheri M, Banfi P, et al. Entrectinib, a Pan‑ TRK, ROS1, and ALK inhibitor with activity in multiple molecularly defined cancer indica‑ Availability of data tions. Mol Cancer Ther. 2016;15:628–39. Not applicable. 14. Farago AF, Le LP, Zheng Z, et al. Durable clinical response to entrec‑ tinib in NTRK1‑rearranged non‑small cell lung cancer. J Thorac Oncol. Ethics approval and consent to participate 2015;10:1670–4. Enrollment of the patient in a clinical trial was completed in compliance with 15. Demetri GD, Paz‑Ares L, Farago AF, et al. Efficacy and safety of entrectinib our institution’s ethics committee and institutional review board. in patients with NTRK fusion‑positive tumors: pooled analysis of STAR‑ TRK‑2, STARTRK ‑1 and ALKA‑372‑001. Munich: ESMO Congress; 2018. Consent for publication 16. Robinson GW, Gajjar AJ, Gauvain KM, et al. Phase 1/1B trial to assess Consent for publication was obtained from the patient using our institution’s the activity of entrectinib in children and adolescents with recurrent or consent policy and will be provided upon request. refractory solid tumors including central nervous system (CNS) tumors. Am Soc Clin Oncol. 2019;33(15):10009. Competing interests 17. Lao IW, Sun M, Zhao M, et al. Lipofibromatosis‑like neural tumour: a clin‑ AC receives research funding from Ignyta and Genentech for the conduct of icopathological study of ten additional cases of an emerging novel entity. the entrectinib study, and provides consulting for Genentech and scientific Pathology. 2018;50:519–23. advisement for Deciphera; no other authors have competing interests to 18. WHO. Classification of tumors: soft tissue and bone tumors. 5th ed. declare. Geneva: WHO; 2020. D upuis et al. Clin Sarcoma Res (2020) 10:14 Page 7 of 7 19. Bartenstein DW, Coe TM, Gordon SC, et al. Lipofibromatosis‑like neural 23. Marchio C, Scaltriti M, Ladanyi M, et al. ESMO recommendations on the tumor: case report of a unique infantile presentation. JAAD Case Rep. standard methods to detect NTRK fusions in daily practice and clinical 2018;4:185–8. research. Ann Oncol. 2019;30:1417–27. 20. Wong V, Pavlick D, Brennan T, et al. Evaluation of a congenital infan‑ 24. Lam SW, Cleton‑ Jansen AM, Cleven AHG, et al. Molecular analysis of gene tile fibrosarcoma by comprehensive genomic profiling reveals an fusions in bone and soft tissue tumors by anchored multiplex PCR‑based LMNA‑NTRK1 gene fusion responsive to crizotinib. J Natl Cancer Inst. targeted next‑ generation sequencing. J Mol Diagn. 2018;20:653–63. 2016;108(1):307. https ://doi.org/10.1093/jnci/djv30 7. 21. Chiang S, Cotzia P, Hyman DM, et al. NTRK fusions define a novel uterine Publisher’s Note sarcoma subtype with features of fibrosarcoma. Am J Surg Pathol. Springer Nature remains neutral with regard to jurisdictional claims in pub‑ 2018;42:791–8. lished maps and institutional affiliations. 22. Penault‑Llorca F, Rudzinski ER, Sepulveda AR. Testing algorithm for identi‑ fication of patients with TRK fusion cancer. J Clin Pathol. 2019;72:460–7. Ready to submit your research ? 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Published: Aug 6, 2020

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