Detecting Gene Rearrangements in Patient Populations Through a 2-Step Diagnostic Test Comprised of Rapid IHC Enrichment Followed by Sensitive Next-Generation Sequencing

Murphy, Danielle; Ely, Heather A.; Shoemaker, Robert; Boomer, Aaron; Culver, Brady P.; Hoskins, Ian; Haimes, Josh; Walters, Ryan D.; Fernandez, Diane; Stahl, Joshua; Lee, Jeeyun; Kim, Kyoung‐Mee; Lamoureux, Jennifer; Christiansen, Jason

doi:10.1097/pai.0000000000000360

Cited by 79 publications

(77 citation statements)

References 23 publications

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“…Nonetheless, pan-TRK immunohistochemistry may still be useful for distinguishing between secretory carcinoma and acinic cell carcinoma, as the latter is entirely devoid of pan-TRK staining. The suboptimal sensitivity of pan-TRK immunohistochemistry for detecting TRK-positive tumours is also consistent with its published performance: pan-TRK staining is stronger in NTRK1/NTRK2-rearranged tumours but weaker and less consistent in NTRK3-rearranged tumours, [15][16][17][18] as noted in 88-89% of NTRK1/ NTRK2-rearranged tumours compared with 55% of NTRK3-rearranged tumours in a prior study. 18 Additional development of TRK immunohistochemistry is thus needed to optimise detection of NTRK3-rearranged tumours, which include most secretory carcinomas.…”

Section: Discussionsupporting

confidence: 83%

Immunohistochemistry with a pan‐TRK antibody distinguishes secretory carcinoma of the salivary gland from acinic cell carcinoma

Hung

Jo²,

Hornick³

2019

Histopathology

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Aims Secretory carcinoma (previously known as mammary analogue secretory carcinoma) is characterised by ETV6 rearrangements, most often ETV6–NTRK3 fusion. Given its histological overlap with other salivary gland tumours, secretory carcinoma can be difficult to diagnose without genetic confirmation. A recently developed pan‐TRK antibody shows promise for identifying tumours with NTRK fusions. The aim of this study was to evaluate the utility of pan‐TRK immunohistochemistry in distinguishing secretory carcinoma from mimics. Methods and results We examined whole‐tissue sections from 86 tumours, including 14 secretory carcinomas (12 parotid primaries and one buccal primary, and one metastasis; five with ETV6 rearrangement confirmed by fluorescence in‐situ hybridisation, and one with ETV6–NTRK3 fusion and one with ETV6–RET fusion detected by targeted sequencing), 14 acinic cell carcinomas, 18 polymorphous adenocarcinomas, 20 low‐grade mucoepidermoid carcinomas, and 20 pleomorphic adenomas. Immunohistochemistry was performed with a pan‐TRK rabbit monoclonal antibody. Pan‐TRK staining was detected in nine (64%) secretory carcinomas, all with a nuclear pattern and four with diffuse staining (>50% of cells). Among other tumour types, pan‐TRK immunoreactivity was observed in all (100%) pleomorphic adenomas (particularly myoepithelial cell‐rich, myxoid areas), 15 (83%) polymorphous adenocarcinomas, and four (20%) low‐grade mucoepidermoid carcinomas, all with predominantly membranous/cytoplasmic immunoreactivity; only six cases showed focal (<10%) nuclear staining. All acinic cell carcinomas were entirely negative. Conclusions Although pan‐TRK expression is not entirely sensitive or specific for secretory carcinoma, nuclear staining distinguishes secretory carcinoma from mimics. Acinic cell carcinomas are negative for pan‐TRK, though membranous expression of TRK is common in other salivary gland neoplasms. The lack of pan‐TRK immunoreactivity in a subset of secretory carcinomas may suggest non‐NTRK fusion partners.

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Section: Discussionsupporting

confidence: 83%

Immunohistochemistry with a pan‐TRK antibody distinguishes secretory carcinoma of the salivary gland from acinic cell carcinoma

Hung

Jo²,

Hornick³

2019

Histopathology

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“…The resultant chimeric oncoprotein initiates and sustains downstream signaling resulting in tumor growth and proliferation. (2) As molecular profiling of tumors continues to migrate toward more comprehensive platforms, such as DNA-based next-generation sequencing and RNA-based anchored multiplex polymerase chain reaction (PCR), the number of these fusion events that are detectable in the clinic continues to rise substantially(3, 4). …”

Section: Introductionmentioning

confidence: 99%

Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1)

et al. 2017

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Entrectinib, a potent oral inhibitor of the tyrosine kinases TRKA/B/C, ROS1, and ALK, was evaluated in two Phase 1 studies in patients with advanced or metastatic solid tumors, including patients with active CNS disease. Here we summarize the overall safety and report the antitumor activity of entrectinib in a cohort of patients with tumors harboring NTRK1/2/3, ROS1, or ALK gene fusions, naïve to prior TKI treatment targeting the specific gene, and who were treated at doses that achieved therapeutic exposures consistent with the RP2D. Entrectinib was well tolerated, with predominantly Grades 1/2 adverse events that were reversible with dose modification. Responses were observed in NSCLC, colorectal cancer, mammary analog secretory carcinoma, melanoma, and renal cell carcinoma, as early as 4 weeks after starting treatment and lasting as long as > 2 years. Notably, a complete CNS response was achieved in a patient with SQSTM1-NTRK1-rearranged lung cancer.

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“…Although comprehensive at the time, this table does not contain the complete list of fusions known today, in 2019. IHC has been used as an initial screening tool to inform highly sensitive but less available and more expensive molecular testing methodologies . However, it is now clear that IHC does not have sufficient sensitivity to detect all existing NTRK fusion‐encoded proteins, meaning that tumor samples should certainly be assayed using FISH or NGS from the get‐go .…”

Section: Biomarker Testing In the Clinicmentioning

confidence: 99%

“…IHC has been used as an initial screening tool to inform highly sensitive but less available and more expensive molecular testing methodologies. [29][30][31] However, it is now clear that IHC does not have sufficient sensitivity to detect all existing NTRK fusion-encoded proteins, meaning that tumor samples should certainly be assayed using FISH or NGS from the get-go. 18 In conclusion, clinicians need to be aware of all 3 TRK targets and arrange adequate testing for all of them.…”

Section: Neurotrophic Receptor Tyrosine Kinasementioning

confidence: 99%

The current state of molecular testing in the treatment of patients with solid tumors, 2019

El‐Deiry

Goldberg

Lenz

et al. 2019

CA A Cancer J Clinicians

220

171

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The world of molecular profiling has undergone revolutionary changes over the last few years as knowledge, technology, and even standard clinical practice have evolved. Broad molecular profiling is now nearly essential for all patients with metastatic solid tumors. New agents have been approved based on molecular testing instead of tumor site of origin. Molecular profiling methodologies have likewise changed such that tests that were performed on patients a few years ago are no longer complete and possibly inaccurate today. As with all rapid change, medical providers can quickly fall behind or struggle to find up‐to‐date sources to ensure he or she provides optimum care. In this review, the authors provide the current state of the art for molecular profiling/precision medicine, practice standards, and a view into the future ahead.

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Detecting Gene Rearrangements in Patient Populations Through a 2-Step Diagnostic Test Comprised of Rapid IHC Enrichment Followed by Sensitive Next-Generation Sequencing

Abstract: Supplemental Digital Content is available in the text.

Cited by 79 publications

References 23 publications

Immunohistochemistry with a pan‐TRK antibody distinguishes secretory carcinoma of the salivary gland from acinic cell carcinoma

Immunohistochemistry with a pan‐TRK antibody distinguishes secretory carcinoma of the salivary gland from acinic cell carcinoma

Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1)

The current state of molecular testing in the treatment of patients with solid tumors, 2019

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