Endocrine Abstracts

Background: Sporadic non-functioning pituitary adenomas (NFPAs) are described as having quiet mutational landscapes. Genes with recurrent somatic alterations have not been identified by previous studies examining heterogeneous pituitary tumour populations. Existing biomarkers have limited ability to discriminate NFPAs with a predisposition for regrowth from those that will follow a more indolent course after primary surgery. We undertook somatic sequencing, in an enriched cohort of NFPAs with a propensity for recurrence, in order to identify variants with potential prognostic or therapeutic utility.

Methods: 36 formalin-fixed paraffin-embedded NFPA tumour samples from 21 patients that had required multiple therapeutic interventions (revision surgery and/or radiotherapy) or demonstrated radiological recurrence / regrowth following primary surgery (median time to recurrence 31.5 months), were recruited. Tumour and paired germline DNA samples were sequenced using a custom 92 gene ‘pan-endocrine and oncology’ panel. Variants were filtered for non-synonymous changes and a driver variant was defined as a pathogenic or likely pathogenic variant with a VAF >5%.

Results: 12 of 40 potential driver variants were within genes relating to the PI3K/AKT signalling pathway (PIK3CA, PTEN, HRAS, NRAS, EGFR, SRC). 7 of 36 [19.4%] tumour samples were identified to have a potential somatic driver variant within constituents of the PI3K/AKT signalling pathway, 4 within PIK3CA. Amongst patients with recurrent tumours, those with variants in PI3K/AKT pathway constituents in the first resected tumour sample, had a tendency to a longer median time to progression (41.3 months [24.2 – 58.3]) vs 30.2 [22.5 – 40.0]), although this did not reach statistical significance.

Discussion: In NFPAs with a predisposition for regrowth following primary surgery, variants in the PI3K/AKT pathway are commonly encountered. Further studies will help to elucidate the potential prognostic and/or therapeutic value of this finding.