Research Papers:

An innovative diagnostic strategy for the detection of rare molecular targets to select cancer patients for tumor-agnostic treatments

Antonio Marchetti, Alessia Di Lorito, Lara Felicioni and Fiamma Buttitta

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Oncotarget. 2019; 10:6957-6968. https://doi.org/10.18632/oncotarget.27343

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Antonio Marchetti1,2,3, Alessia Di Lorito2, Lara Felicioni3 and Fiamma Buttitta1,2,3

1 Laboratory of Diagnostic Molecular Oncology, Center for Advanced Studies and Technology (CAST), University of Chieti, Chieti, Italy

2 Department of Medical and Oral Sciences and Biotechnologies, University of Chieti, Chieti, Italy

3 Department of Pathology, SS Annunziata Clinical Hospital, Chieti, Italy

Correspondence to:

Antonio Marchetti,email: [email protected]

Keywords: tumor-agnostic treatments; microsatellite instability (MSI); neurotrophic receptor tyrosine kinase (NRTK); tissue microarrays (TMAs); tissue slice arrays (TSAs)

Received: August 22, 2019     Accepted: October 26, 2019     Published: December 10, 2019


Targeted therapies are playing an increasing role in oncology. Among them, particular attention is nowadays reserved to histology-agnostic treatments. Rare molecular alterations affecting different neoplastic forms, such as Microsatellite Instability (MSI), Neurotropic Tyrosine Receptor Kinase (NTRK) gene fusions, etc., can allow efficient treatments, irrespective of the histologic type. Developing an effective testing strategy for the detection of rare molecular alterations is challenging.

We report an innovative diagnostic strategy for a rapid and economically affordable detection of this uncommon targets. Malignant tumor samples are selected at the time of histopathological diagnosis and further processed for simultaneous analysis of multiple samples on Tissue Micro Arrays (TMAs) and Tissue Slice Arrays (TSAs). The TSA approach was specifically designed for large scale screening of small biopsies. TMA sections and TSA were first screened by immunohistochemistry (IHC) for the expression of mismatch repair and TRK proteins. Positive cases were subjected to confirmation tests (fragment analysis/FISH/NGS).

In a series of 1865 malignant tumors, 48 (2.6%) MSI cases and 6 (0.3%) NTRK fusion cases were detected in 9 and 4 different tumor forms, respectively. On average, the TMA/TSA screening approach enabled IHC analysis of about 20 patients simultaneously with significant saving of time and costs. In addition, we have shown that multiplex IHC can further increment the throughput. A detailed procedure for application of this diagnostic approach in clinical practice is reported.

The strategy described may allow an efficient and sustainable selection of tumors carrying rare molecular targets, not to leave behind patients for effective agnostic treatments.

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