Abstract
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.
Highlights
Target therapy has revolutionized the oncological approach to cancer patients carrying druggable molecular alterations [1]
A large-scale next generation sequencing (NGS) approach with large gene panels is desirable but at the moment, the costs and the low diffusion of the technology make it not realistically feasible [12]. Driven by these management difficulties, we have developed a diagnostic strategy based on large scale IHC screening of rare molecular alterations on tissue microarrays (TMAs) and Tissue Slice Arrays (TSAs) to select cancer patients for histologyagnostic therapies
The innovative workflow provides that malignant tumor samples are identified by histological examination and subdivided into large and small samples based on size, regardless of the type of malignancy, for further processing
Summary
Target therapy has revolutionized the oncological approach to cancer patients carrying druggable molecular alterations [1]. Some of the biomarkers for target therapy are frequent events in particular tumor types (eg RAS mutations in colorectal cancer or BRAF mutations in melanoma). In these cases, accurate identification of the molecular alteration with dedicated methods is feasible and the cost and time of analysis to find a positive patient is acceptable [3, 4]. The detection of rare mutations with a mono-marker test implies long time frames and high costs to identify a positive/druggable patient.
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