2318P - Value of broad molecular profiling for cancer diagnosis

Background

Molecular techniques have improved cancer diagnosis and treatment. Due to limited availability and costs, broad molecular profiling, i.e., analysis of whole genomes/exomes, transcriptomes, and methylomes, is rarely performed upfront in clinical practice and mostly confined to research settings. However, in contrast to more readily available focussed analyses of, e.g., the few genes seemingly relevant for a suspected diagnosis, broad molecular profiling may yield unsuspected findings pertinent to diagnosis and/or treatment.

Methods

This analysis is based on patients enrolled in the MASTER program of DKFZ, NCT Heidelberg/Dresden, and DKTK, a nationwide precision oncology network applying genome/exome, transcriptome, methylome, and – more recently – proteome analysis in young adults with advanced malignancies and patients with rare cancers to inform clinical decision-making and the design of molecularly stratified clinical trials. Cases with molecular findings suggestive of an alternative diagnosis are subjected to clinical, molecular, and pathologic revaluation.

Results

In 99 of 3,092 patients (3.2%), the molecular profile warranted revaluation of the clinical diagnosis. The most frequent presenting diagnoses were cancer of unknown primary (n=21); various sarcomas (n=50), e.g., sarcoma not otherwise specified (n=4), malignant peripheral nerve sheath tumor (n=5), and undifferentiated sarcoma (n=6); and melanoma (n=4). Molecular findings suggesting an alternative diagnosis were based on genome/exome, transcriptome, and methylome analysis in 30, 78, and 41 cases, respectively. Potential clinical consequences were classified as changes in diagnosis without relevance for treatment (n=22), relevant for routine treatment (n=58), and prompting molecular alteration-specific treatment (n=19). The molecularly suspected diagnosis was confirmed in a major subset of cases for which sufficient material for histopathologic review was available. The clinically most relevant findings were EWSR1::WT1 fusions and diagnosis of desmoplastic small round cell tumor (n=9) and druggable gene fusions involving FGFR2 (n=4), ALK (n=4), and NTRK3 (n=1).

Conclusions

Broad molecular profiling is a useful adjunct to routine cancer diagnostics, especially in rare entities.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

DKFZ.

Funding

NCT Molecular Precision Oncology Program, German Cancer Consortium.

Disclosure

C.E. Heilig: Financial Interests, Institutional, Funding: AstraZeneca, Pfizer, PharmaMar, Roche. S. Bauer: Financial Interests, Institutional, Research Funding: Blueprint Medicines, Incyte, Novartis; Financial Interests, Personal, Other, Honoraria: PharmaMar, Eli Lilly & Co, Novartis; Financial Interests, Personal, Advisory Board: Adcendo, Bayer, Blueprint Medicines, Boehringer Ingelheim, Cogant, Daiichi Sankyo, Deciphera, GSK, Exelixis, Nanobiotix, Novartis, Roche; Financial Interests, Personal, Other, travel support: PharmaMar. D.T. Rieke: Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Other, Honoraria: Lilly, BMS, Roche, Bayer; Financial Interests, Personal, Other, Travel or accommodation expenses: Bayer. P. Horak: Financial Interests, Personal, Advisory Board: Platomics; Financial Interests, Personal, Other, Consulting: Platomics; Financial Interests, Personal, Other, Honoraria: Platomics, Roche, Trillium. S. Fröhling: Financial Interests, Personal, Advisory Board: Bayer, Illumina, Roche; Financial Interests, Personal, Invited Speaker: Amgen, Eli Lilly, Illumina, PharmaMar, Roche. All other authors have declared no conflicts of interest.