A comparison of DNA sequencing and gene expression profiling to assist tissue of origin diagnosis in cancer of unknown primary

Abstract

Cancer of unknown primary (CUP) is a syndrome defined by clinical absence of a primary cancer after standardised investigations. Gene expression profiling (GEP) and DNA sequencing have been used to predict primary tissue of origin (TOO) in CUP and find molecularly guided treatments; however, a detailed comparison of the diagnostic yield from these two tests has not been described. Here, we compared the diagnostic utility of RNA and DNA tests in 215 CUP patients (82% received both tests) in a prospective Australian study. Based on retrospective assessment of clinicopathological data, 77% (166/215) of CUPs had insufficient evidence to support TOO diagnosis (clinicopathology unresolved). The remainder had either a latent primary diagnosis (10%) or clinicopathological evidence to support a likely TOO diagnosis (13%) (clinicopathology resolved). We applied a microarray (CUPGuide) or custom NanoString 18-class GEP test to 191 CUPs with an accuracy of 91.5% in known metastatic cancers for highmedium confidence predictions. Classification performance was similar in clinicopathology-resolved CUPs -80% had high-medium predictions and 94% were concordant with pathology. Notably, only 56% of the clinicopathology-unresolved CUPs had high-medium confidence GEP predictions. Diagnostic DNA features were interrogated in 201 CUP tumours guided by the cancer type specificity of mutations observed across 22 cancer types from the AACR Project GENIE database (77,058 tumours) as well as mutational signatures (e.g. smoking). Among the clinicopathology-unresolved CUPs, mutations and mutational signatures provided additional diagnostic evidence in 31% of cases. GEP classification was useful in only 13% of cases and oncoviral detection in 4%. Among CUPs where genomics informed TOO, lung and biliary cancers were the most frequently identified types, while kidney tumours

A qualitative study of patients with Cancer of Unknown Primary: Perceptions of communication, understanding of diagnosis and genomic testing, and information needs

“…SUPER is a national cohort study aiming to: (a) improve diagnostic assessment; (b) integrate new diagnostic approaches, specifically, genomic testing for likely site‐of‐origin and actionable molecular targets; and (c) understand psychosocial needs of patients. Details of the testing and impact on care have been previously reported 13 …”

“…Advancements in precision oncology driven by genomic analysis provide new hope with regards to identification of the site of origin as well as molecularly‐guided treatment opportunities for CUP patients 12,13 . Genomic testing may identify multiple types of molecular abnormalities, which can help guide clinical recommendations regarding cancer treatment and diagnosis 13 .…”

“…[3][4][5][6][7][8][9][10][11] Advancements in precision oncology driven by genomic analysis provide new hope with regards to identification of the site of origin as well as molecularly-guided treatment opportunities for CUP patients. 12,13 Genomic testing may identify multiple types of molecular abnormalities, which can help guide clinical recommendations regarding cancer treatment and diagnosis. 13 While genomic testing holds great potential to improve outcomes for CUP patients, understanding of genomic results could potentially be challenging for many patients and lead to increased confusion, uncertainty, and psychological distress.…”

“…12,13 Genomic testing may identify multiple types of molecular abnormalities, which can help guide clinical recommendations regarding cancer treatment and diagnosis. 13 While genomic testing holds great potential to improve outcomes for CUP patients, understanding of genomic results could potentially be challenging for many patients and lead to increased confusion, uncertainty, and psychological distress. 14,15 A recent UK large-scale national study of unmet needs among over four thousand cancer patients revealed a higher percentage of CUP patients expressed a wish to be better informed about their condition compared with matched non-CUP sample.…”

Immune and genomic biomarkers of immunotherapy response in cancer of unknown primary

“…Response to ICI treatment was assessed by the treating medical oncologist using the Response Evaluation Criteria in Solid Tumors V.1.1 (RECIST) scoring system for solid tumors: complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). 17 As previously described, 16 the diagnostically unresolved CUPs were classified into the Memorial Sloan Kettering OncoTree classes for CUP, 18 modified to incorporate immunohistochemistry (IHC) stains for cytokeratin (CK) 7 and 20 and p16INK4A. Four patients included in the current study were not a part of the previous cohort and not diagnostically evaluated.…”