Comprehensive genomic and epigenomic analysis in cancer of unknown primary guides molecularly-informed therapies despite heterogeneity

Abstract

The benefit of molecularly-informed therapies in cancer of unknown primary (CUP) is unclear. Here, we use comprehensive molecular characterization by whole genome/exome, transcriptome and methylome analysis in 70 CUP patients to reveal substantial mutational heterogeneity with TP53, MUC16, KRAS, LRP1B and CSMD3 being the most frequently mutated known cancer-related genes. The most common fusion partner is FGFR2, the most common focal homozygous deletion affects CDKN2A. 56/70 (80%) patients receive genomics-based treatment recommendations which are applied in 20/56 (36%) cases. Transcriptome and methylome data provide evidence for the underlying entity in 62/70 (89%) cases. Germline analysis reveals five (likely) pathogenic mutations in five patients. Recommended off-label therapies translate into a mean PFS ratio of 3.6 with a median PFS1 of 2.9 months (17 patients) and a median PFS2 of 7.8 months (20 patients). Our data emphasize the clinical value of molecular analysis and underline the need for innovative, mechanism-based clinical trials.

Single Nucleus RNA Sequencing of Remnant Kidney Biopsies and Urine Cell RNA Sequencing Reveal Cell Specific Markers of Covid-19 Acute Kidney Injury

“…LRP1B encodes a member of the low-density lipoprotein receptor (LDL) family. These receptors play a vital role in normal cell development and function and disruption of LRP1B has been reported in various cancer types 17 . Case reports show patients with respiratory failure from SARS-CoV2 experienced substantial benefits with a PDE3-inhibitor intervention.…”

Implementation of Whole-Genome and Transcriptome Sequencing Into Clinical Cancer Care

“…Patients with CUP particularly benefited from comprehensive molecular profiling, in terms of more precise diagnostic classification and individually tailored therapy, which was associated with a particularly large prolongation of intrapatient PFS. 32 , 34 In contrast, WGTS did not provide additional benefit in other entities such as bone sarcomas, 32 suggesting that more comprehensive analyses of WGTS data are needed in addition to other levels of characterization of these patients. In the Drug Rediscovery Protocol (DRUP), 500 patients started one of the available drugs and were evaluated for treatment outcomes.…”

Retrospective analysis of clinical characteristics and outcomes of patients with carcinoma of unknown primary from three tertiary centers in Australia

“…Further, relying on ICD codes may have missed identification of all CUP patients, especially in instances where clinicians may have assigned a tissue of origin despite patients satisfying the diagnostic criteria for CUP. Finally, given the time period and location in which our study was conducted, we did not have sufficient statistical power to evaluate the impact of early molecular testing and actionable treatment alterations, which has been suggested as a means to improve outcomes and rationalize treatment options, including targeted and immunotherapies for this patient population 16,33 . Such testing is likely to become increasingly relevant with further advent of molecularly guided and tumor agnostic treatment strategies.…”