Next generation sequencing of carcinoma of unknown primary reveals novel combinatorial strategies in a heterogeneous mutational landscape.

Ishwaria M Subbiah,David S Hong,Vivek Subbiah,Sinchita Roy-Chowdhuri,Apostolia Tsimberidou,Filip Janku

doi:10.18632/oncoscience.352

Ishwaria M Subbiah, David S Hong + Show 4 more

Open Access

https://doi.org/10.18632/oncoscience.352

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Abstract

BackgroundAdvanced carcinoma of unknown primary (CUP) has limited effective therapeutic options given the phenotypic and genotypic diversity. To identify future novel therapeutic strategies we conducted an exploratory analysis of next-generation sequencing (NGS) of relapsed, refractory CUP.MethodsWe identified patients in our phase I clinic where archival tissue was available for a targeted NGS CLIA-certified assay.ResultsOf 17 patients tested, 15 (88%) demonstrated genomic alterations (median 2 aberrations; range 0–8, total 59 alterations). Nine (53%) patients had altered cell signaling including the PI3K/AKT/MTOR (n=5, 29%) and MAPK pathways (n=3,18%); 7 (41%) patients demonstrated ≥1 alterations in tumor suppressor genes (TP53 in 5 patients), 8 (47%) had impaired epigenetic regulation and DNA methylation, 8 (47%) had aberrant cell cycle regulation, commonly in the cyclin dependent kinases. Ten (59%) patients had alterations in transcriptional regulators. Concurrent mutations affecting cell cycle regulation were noted to occur with aberrant epigenetic regulation (n=6, 35%) and MAPK/PI3K pathway (n=5, 29%).ConclusionEvery patient had a unique molecular profile with no two patients demonstrating an identical panel of mutations. We identify two emerging novel combinatorial strategies targeting impaired cell cycle arrest, first with epigenetic modifiers and, second, with MAPK/PI3K pathway inhibition.

Highlights

Carcinoma of unknown primary (CUP) remains a unique challenge to the clinician in a landscape where algorithms for the diagnosis, management and outcomes of cancers are often histology-dependent
Concurrent mutations affecting cell cycle regulation were noted to occur with aberrant epigenetic regulation (n=6, 35%) and MAPK/PI3K pathway (n=5, 29%)
Every patient had a unique molecular profile with no two patients demonstrating an identical panel of mutations

Summary

Introduction

Carcinoma of unknown primary (CUP) remains a unique challenge to the clinician in a landscape where algorithms for the diagnosis, management and outcomes of cancers are often histology-dependent. CUP is defined as a metastatic cancer without a clearly identified primary site despite an adequate standard workup including an in-depth pathologic analysis with concurrent detailed history, physical examination, and laboratory and radiologic assessments [4]. The preliminary categorization on microscopic evaluation classifies an overarching histology as adenocarcinomas (ranging from well, moderate, poor, or undifferentiated), which represent up to 90% of CUP cases; lesser prevalent characterizations include squamous cell carcinomas, undifferentiated neoplasm, melanoma, sarcoma, or lymphoma seen in the remaining 10% of cases [5, 6]. To identify future novel therapeutic strategies we conducted an exploratory analysis of nextgeneration sequencing (NGS) of relapsed, refractory CUP

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Conclusion