Concurrent Germline-Somatic Alterations and Associations with Cancer Outcomes: A Systematic Review of Concurrent Data...

Despite routine clinical collection of germline and somatic data in patients diagnosed with cancer, little is known about how these data concurrently associate with outcomes. The purpose of this review is to map the landscape of concurrent germline-somatic alterations and their associations with translational and clinical outcomes to identify addressable gaps in reporting and considerations for future research.

All studies in patients with cancer published through February 2024 were included that contained both germline and somatic data and associations of concurrent germline and somatic attributes with outcomes (e.g. in silico, predictive, prognostic, and clinical measures). Information abstracted from each study included publication date, study design, patient population characteristics, treatment regimen if applicable, germline data type, somatic data type, statistical interactions if performed, and reported associations.

Of the 8,613 studies screened, 197 met inclusion criteria. The most common concurrent germline-somatic alterations studied with respect to outcomes were germline BRCA2/somatic TP53 and germline BRCA1/somatic TP53 (n=40 and n=38 studies, respectively). Statistical testing was performed in 41.6% (n=82) of studies to determine associations between concurrent germline-somatic alterations and outcomes, with other studies providing solely descriptive or enumerative analysis. Among studies reporting direction of effect, 31 showed benefit associated with concurrent germline and somatic alterations relative to germline-only or somatic-only, while 28 showed harm.

These findings suggest that planning for concurrent germline-somatic data analysis during the initial design of a translational or clinical study could meaningfully improve current applications in cancer genetics.