Aggressive pituitary tumours and pituitary carcinomas: molecular insights guiding management and the role of precision oncology.

Available online 5 June 2025, 112598

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Genome instability and mutations determine aggressive pituitary tumour behaviour

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The immune microenvironment in altered in aggressive pituitary tumours

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Proliferative markers, genomic variations and mutations are prognostic biomarkers

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Molecular and immune targeted therapies are options for treatment

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Molecular profiling to be considered as part of a personalised therapeutic approach

ABSTRACT

Aggressive pituitary neuroendocrine tumours and pituitary carcinomas are associated with high morbidity and mortality and have limited treatment options. Increased understanding of the molecular pathogenesis of pituitary tumours has led to identification of molecular drivers of aggressive behaviour and prognostic markers, as well as identification of therapeutic targets. Mechanisms for pituitary tumourigenesis include chromosomal genomic instability, defective DNA repair, loss of cell cycle control, epigenetic changes, dysregulation of intracellular signalling pathways and alterations within the pituitary tumour immune microenvironment. Novel therapeutic treatment options including VEGF targeted therapies and immune checkpoint inhibitors have been used with varied responses. The application of precision oncology platforms to identify therapeutic targets is well described in other cancers and should be considered in the management of aggressive pituitary tumours and pituitary carcinomas. Histopathological analysis of established prognostic markers should be included in routine clinical practice.

Section snippetsINTRODUCTION

Pituitary neuroendocrine tumours (PitNETs; also known as pituitary adenomas) are the most common intracranial tumours with a reported prevalence of 16.7% of the population when autopsy and radiological data are considered(1). The prevalence of clinically significant PitNETs is much lower, occurring in around 1 per 1000 of the population2, 3. While the majority are slow growing these tumours can still cause significant morbidity through hormonal dysfunction and mass effect. Furthermore, often

DEFECTIVE DNA REPAIR IS COMMON IN AGGRESSIVE PITUITARY TUMOURS

DNA repair is essential for maintaining genomic integrity and defects in these mechanisms can predispose to tumour development and are also commonly exploited by cancer cells for survival and resistance to therapy.

LOSS OF CELL CYCLE CONTROL IS IMPORTANT FOR PITUITARY TUMOUR PROGRESSION

Alterations in cell cycle components, such as pRB, p16, p21, p27, cyclin D1, and cyclin E, contribute to PitNET pathogenesis and aggressiveness. Reduction or absence of tumor suppressors like p21, p27, Rb and nm23 is not infrequent among APTs, particularly carcinomas 58, 59, 60. Increased expression of the proto-oncogene, cyclin D1, may also indicate potential for aggressive behaviour of pituitary tumours and cyclin E expression is increased in corticotroph PitNETs(61).

Cell cycle-targeted

EPIGENETIC CHANGES CONTRIBUTE TO PITUITARY TUMOUR PROGRESSION

Epigenetic changes, including DNA methylation and histone modifications, play a key role in PitNET tumorigenesis. Promoter hypermethylation is a frequent event in PitNETs, most commonly involving CDKN2A (p14/p16) in up to 82% of PitNETs 65, 66. Methylation events are less well described among APT, although RASSF1A involved in intracellular signalling exhibits higher rates of promoter methylation while TERT promoter methylation has been associated with disease progression and shorter progression

MORE PRONOUNCED EXPRESSION OF GROWTH FACTOR AND INTRACELLULAR SIGNALLING PATHWAYS IN AGGRESSIVE PITUITARY TUMOURS

Growth factors and their respective membrane tyrosine kinase receptors play a well-described role in pituitary tumorigenesis(76). In APTs there is an exaggerated upregulation however thresholds for predicting aggression are lacking. Targeting these pathways has been utilised for managing APT with mixed results.

THE IMMUNE MICROENVIRONMENT IS ALTERED IN AGGRESSIVE PITUITARY TUMOURS

The immune microenvironment of PitNETs has recently gained attention as novel immune targeted therapies are considered for the management of APTs. However, how the immune microenvironment is altered during PitNET transformation into an APT is not well understood. Certainly, pro-tumorigenic M2-type macrophages, are implicated in PitNET growth and invasiveness and association with expression of immune checkpoint markers such as PD-L1 suggest they contribute to an immunosuppressive environment85,

THE ROLE FOR THERANOSTICS IN THE MANAGEMENT OF AGGRESSIVE PITUITARY TUMOURS

Peptide receptor radionuclide therapy (PRRT) comprises a radionuclide bound to a somatostatin receptor ligand and is designed to selectively deliver cytotoxic radiation therapy to tumour cells expressing somatostatin receptors (SSTRs)(126). The most used radiotherapeutics in PRRT are 90Yttrium-DOTA-TOC and 177Lu-DOTA-TATE which both have a predominant affinity for SSTR2(127). The expression of all five SSTR subtypes on normal pituitary as well as PitNETs provides a rationale for the use of PRRT

THE ERA OF MOLECULAR TESTING FOR AGGRESSIVE PITUITARY TUMOURS HAS ARRIVED

In a recent study, whole exome analysis was performed on 125 PitNETs (not specifically APTs) with the aim to identify clinically actionable therapies. There was a heterogeneity of somatic mutations across these tumours including genes involved in cell cycle and a variety of signalling pathways important for cancer. 48 existing drugs were considered, 21 of which were FDA-approved and 27 in phase 1-3 clinical trials(129). 28% of the patients in the series had tumours with a potentially actionable

CONCLUSIONS

Increased understanding of the molecular basis for PitNETs provides important prognostic insights as well as identifying potential therapeutic targets, particularly for the management of APTs and PCs. Somatic mutations of importance in pituitary tumourigenesis have been identified, for example TP53 and ATRX which are associated with aggressive behaviour in corticotroph tumours. Growth factors, their receptors and downstream intracellular signalling pathways play a role in pituitary tumour

CRediT authorship contribution statement

AI McCormack: Writing – review & editing, Supervision, Conceptualization. S Ramus: Writing – review & editing, Supervision. HW Sim: Writing – review & editing, Supervision. Lydia Lamb: Writing – original draft

Uncited reference

56.; 57.; 127.; 133..

AGGRESSIVE PITUITARY TUMOURS FREQUENTLY DEMONSTRATE CHROMOSOMAL GENOMIC INSTABILITY

Chromosomal instability is a hallmark of cancer, including PitNETs, resulting in significant genetic disruption (15). Functional PitNETs, such as corticotroph and lactotroph subtypes, are linked to higher chromosomal disruption (e.g., copy-number variations, CNVs) compared to non-functional types 16, 17, 18, 19, 20 (Table 1, Figure 1(21)). Notably, corticotroph and lactotroph tumours account for the majority of APTs(22). Genomically disrupted tumours more frequently exhibit higher Ki-67

Declaration of Competing Interest

☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

ACKNOWLEDGEMENTS

Dr Lydia Lamb is supported by a scholarship from the University of New South Wales.

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