The hormonal nexus in PIK3CA-mutated meningiomas: implications for targeted therapy and clinical trial design

Abstract

The presence of hormonal receptors in meningiomas has been known for decades. More recently, evidence has shown increased prevalence of meningiomas in patients taking certain types of hormonal treatments, such as oral contraceptives, progestins or hormone replacement therapy. Epidemiological evidence suggests that patients undergoing hormonal therapy harbor higher mutational rates of the oncogene PIK3CA. Due to the relative paucity of literature describing the intersection of hormone therapy and mutated PIK3CA pathways in meningioma, we have conducted a narrative review on this topic. Similarly, the clinical trial landscape for hormonal therapies for meningioma currently focuses on somatostatin receptor-targeted therapies and peptide receptor radionucleotide therapy, and the PIK3CA-hormonal signaling axis has not been explicitly targeted. Given the role of PIK3CA mutations in promoting cancer progression in other hormone-sensitive tumors, such as breast and prostate cancer, exploring this axis could inform drug repurposing including hormonal therapy specifically for these tumors.

Introduction

The majority of meningiomas are benign (80–90%), with a smaller fraction displaying more aggressive histopathological features [1]. Malignant and metastatic forms remain rare. For decades, a relationship between sex hormones and meningiomas has been postulated, driven by several converging lines of evidence. Epidemiologically, meningiomas occur more frequently in women and show enhanced aggressiveness during pregnancy and among breast cancer patients [2]. Additionally, men who receive antiandrogen treatments display increased meningioma risks [3].

Hormone receptor expression in meningiomas has been documented for nearly half a century. Numerous studies consistently demonstrate expression of progesterone (up to 90%), androgen (up to 88%), and estrogen receptors (up to 30%) in meningioma tissues [4]. This robust and long-recognized association between meningiomas and hormonal factors poses several clinical questions. These include the feasibility of leveraging hormone receptor expression for targeted combination therapies, potential repurposing of existing endocrine therapies, and possible retrospective analyses of clinical trials for genotypic characterization and clinical effect quantification. Additionally, effect modification mediated by specific hormone receptor expression profiles demands further investigation. These clinical questions have recently led to cross-disciplinary collaborative guidelines suggesting decision-trees for managing meningioma patients who require oral contraceptives, menopausal hormonal treatments, progestins, or gender-affirming hormonal therapies [5].

To address these questions comprehensively, it is crucial to understand the specific genetic mutations underpinning meningioma pathogenesis. Recent advances have highlighted a complex genetic landscape in meningiomas [6, 7]. prominently featuring mutations in the NF2 tumor suppressor gene. Beyond NF2, additional alterations are described within key tumorigenic pathways, including the PI3K-AKT-mTOR axis, TRAF7, and SMO involved in the Hedgehog signaling pathway, highlighting extensive molecular crosstalk. Mutation frequency and spectrum vary by tumor grade, with higher-grade meningiomas often exhibiting a greater mutational burden and more complex genomic alterations, including chromosomal instability and TERT promoter mutations. CITE Recent guidelines further stress molecular profiling as essential for optimal therapeutic selection [8]. As glioblastoma and other CNS tumors now integrate molecular and immunophenotypic profiling at diagnosis [9, 10], adopting a comparable framework in meningiomas is imperative for precision therapeutics and stratified care.

A comparatively rare but significant pathogenic variant occurs in the gene encoding phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α, or PIK3CA. The p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K), encoded by the PIK3CA gene, was first identified as mutated in 78 meningioma tumor specimens [11]. PIK3CA mutations have been identified in both low- and higher-grade meningiomas, though evidence linking them consistently to aggressive behavior remains inconclusive [7, 12, 13]. Recent epidemiological, animal-model, and pharmacological evidence collectively suggests that PIK3CA mutations may be important drivers and potential therapeutic targets in a specific subset of meningiomas. Specifically, these mutations are enriched in non-NF2 meningiomas, particularly those localized to the skull base and convexity, and have been shown to co-occur with mutations in AKT1 and SMO within the PI3K-AKT-mTOR and Hedgehog signaling pathways. A large molecular study identified PIK3CA mutations in approximately 7–9% of non-NF2 tumors, with increased frequency in WHO grade I lesions of meningothelial or transitional histology. They typically report hormone receptor positivity for progesterone and are most commonly detected in middle-aged women, suggesting a hormonally controlled oncogenic pathway that is treatable by endocrine or PI3K pathway-targeted therapies [7, 14].

Given the limited existing research on the specific intersection of PIK3CA mutations and hormonal exposure in meningiomas, we aimed to comprehensively review this important niche. Due to lack of a coherent mechanism and translational evidence for the involvement of hormonal signaling in PIK3CA-mutated meningiomas, a focused systematic review would restrict inclusion criteria in a way that risks the omission of studies with conceptual importance, under a variety of methodological paradigms. For this reason we chose to proceed with a narrative review frame to bring together clinical, molecular, and epidemiologic data, allowing us to make a hypothesis generating assembly of biologically conceivable associations. It allows a more detailed questioning of new topics which are not yet developed enough for systematic review.

This narrative review addresses several critical aspects: first, we clarify the clinical landscape of PIK3CA-mutant meningiomas. Next, we evaluate epidemiological and clinical evidence of hormonal risks in patients harboring PIK3CA mutations, particularly focusing on tumor burden in hormonal therapy users. Furthermore, we assess human and animal-model data linking PIK3CA mutations, meningioma development, and hormonal treatments. Given the sparse literature on certain aspects, we also discuss completed and ongoing clinical trials evaluating hormonal therapies in meningioma, interrogating the potential role of PIK3CA mutations. Lastly, we extrapolate insights from hormone-sensitive cancers (breast and prostate cancer), where the relationship between hormonal therapies and PIK3CA mutations is more thoroughly elucidated, outlining possible future directions for this meningioma research niche (Tables 1, 2 and 3).

Table 1.

Summary of hormonal influence and genetic insights in meningiomas

Aspect	Key Findings	Implications
Epidemiological Evidence	-Higher incidence of meningiomas in women than men. - Aggressive behavior noted during pregnancy and in breast cancer patients. - Antiandrogen therapy linked to increased meningioma risk in men.	Suggests hormonal factors play a critical role in meningioma pathogenesis and progression, necessitating consideration in therapeutic strategies.
Hormonal Receptor Expression	- Up to 90% express progesterone receptors (PR). - Up to 88% express androgen receptors (AR). - Up to 30% express estrogen receptors (ER).	Potential for hormone receptor-targeted therapies in meningiomas and a need to correlate receptor profiles with clinical outcomes and molecular subtypes.
Molecular Pathogenesis	- Key mutations: NF2, TRAF7, SMO, PIK3CA, AKT1, and KLF4. - Crosstalk between pathways: PI3K-AKT-mTOR and Hedgehog signaling. - Genotypical complexity identified.	Highlights the need for molecular testing to refine treatment strategies and to develop targeted, patient-specific therapies.
PIK3CA Mutation Characteristics	- Occurs in ~ 4.7% of meningiomas (7.4% in non-NF2 cases). - Predominantly in women and localized to the skull base. - Often co-occurs with TRAF7 mutations but is exclusive of AKT1 and SMO.	Identifies PIK3CA as a distinct molecular subgroup with therapeutic relevance, particularly for stratifying patient populations for targeted interventions.
Clinical Decision-Making	- Recent guidelines emphasize counseling patients on hormone use, including oral contraceptives, menopause therapies, progestins, and gender-affirming treatments.	Suggests a need for cross-specialty collaboration and personalized medicine approaches to mitigate risks and guide therapy.

Table 2.

Completed clinical trials of hormonal therapies in meningioma

Study	Drug	Histology	Location	Grade	Receptors Tested	Receptor Positive (%)	Receptor Detection Method	Primary Outcome
Markwalder (1985)	Tamoxifen	1 fibrous	1 skull base; 1 parasagittal	Not specified	1	0	Not specified	1 non-specific response, two stable, 1 progressed
Goodwin (1993)	Tamoxifen	Not specified	Not specified	Not specified	1	0	Not specified	1 partial response, 2 minor responses, 6 stable, 10 progressed
Grunberg (1990)	Megestrol acetate	6 meningothelial; 2 fibrous; 1 anaplastic	8 skull base; 1 convexity	8 WHO I; 1 WHO III	2	0	Not specified	2 stable, 7 progressed
Grunberg (2006)	Mifepristone	13 meningothelial	22 skull base; 4 spinal; 2 convexity	13 WHO I; 2 WHO III	0	0	Not specified	5 minor responses, 3 clinical improvements without radiographic change, 2 progressed
Touat (2014)	Mifepristone	1 transitional	3 multifocal	1 WHO I	3	33%	Immunohistochemistry (IHC)	100% had > 20% volume reduction
Ji (2015)	Mifepristone	17 atypical	Not specified	17 WHO II	84	75%	Immunohistochemistry (IHC)	HR 1.02 (95% CI: 0.72–1.48); adjusted P = 0.9
Chamberlain (2007)	Octreotide (Sandostatin LAR)	Not specified	7 skull base; 6 convexity; 3 multifocal	8 WHO I; 3 WHO II; 5 WHO III	16	100%	Radioimaging	Disease control: stable response in receptor-positive cases
Norden (2015)	Octreotide (Pasireotide LAR)	Not specified	Not specified	18 WHO I; 18 WHO II/III	34	100%	Immunohistochemistry (IHC)	Disease control in receptor-positive cases
Hrachova (2020)	Octreotide (Sandostatin LAR)	5 atypical; 6 anaplastic	23 skull base; 15 convexity; 5 mixed	32 WHO I; 5 WHO II; 6 WHO III	43	100%	Radioimaging	Disease control: better outcomes in WHO I tumors

Table 3.

Ongoing hormonal therapy trials for meningioma

Study	Drug	Grade	Receptors Required	Detection Method	Dose	Design	Participants	Primary Outcome	NCT Number
Cordier (2021)	177Lu-DOTA-JR11	Not specified	SSTR	Radioimaging	IV 4.5 GBq 177Lu-DOTA-JR11 once, repeat at 8 weeks	Prospective cohort	18	Progression-free survival (PFS)	NCT04997317
Merrell (2020)	177Lu-DOTATATE	WHO I	SSTR	Radioimaging	IV lutetium Lu 177 dotatate q8w for up to 6 months	Prospective cohort	41	Disease control rate	NCT04082520
Salloum (2022)	Lutathera	WHO II/III	SSTR	Radioimaging	IV lutetium Lu 177 dotatate q8w for 8 months	Phase I/II cohort	65	PFS	NCT05278208
Kaley (2021)	Lutetium-DOTA	WHO I/II/III	SSTR	Radioimaging	IV Lutetium-DOTA radionuclide infusion, repeat dosing every 8 weeks	Phase II cohort	30	Tumor response and safety profile	NCT03971461
Kumthekar (2020)	Lutetium-DOTATATE	WHO I/II	SSTR	Radioimaging	IV lutetium Lu 177 dotatate, repeat q8w for up to 4 cycles	Phase II cohort	27	Tumor response and quality-of-life outcomes	NCT04082520

PIK3CA meningioma

Mutations in PIK3CA constitutively activate PI3 kinase, particularly through mutations at hotspot residues (H1047R, E542K, E545K) [14]. Approximately 4.7% of meningiomas harbor PIK3CA mutations, rising to 7.4% in the NF2-negative subgroup [7]. These mutations predominantly affect primary benign tumors (WHO Grade I) in women, primarily localized at the skull base [7]. PIK3CA mutations frequently co-occur with TRAF7 mutations but remain mutually exclusive with AKT1 and SMO mutations, favoring transitional and meningothelial histologies [7, 15]. Angiomatous meningiomas also exhibit exon variants in PIK3CA [15]. Studies of anterior skull-base and convexity meningiomas report PI3K pathway mutations in up to 19% of cases, including PIK3CA mutations in approximately 6% [15]. Additionally, PIK3CA mutations have been identified in 6.5% of foramen magnum meningiomas [16], contributing to the hypothesis that they have a preferential localization within middle cranial and medial anterior cranial fossae.

Furthermore, although PIK3CA gene is a member of the PI3K-AKT-mTOR-pathway, we specifically highlight this gene in the current review in light of its progressively recognized significance in hormone-related meningioma subtypes, and the fact that it can potentially be targeted pharmacologically with isoform-specific inhibitors. This gene has attracted particular interest not only because of unique mutation ‘hot spots’ scattered across its sequence, but also because it is crossed by progesterone and estrogen signaling in non-NF2 mutant tumors [17–19]. However, these mutations in PIK3CA, AKT1 and MTOR may converge functionally yet diverge in terms of spatial distribution and enrichment in histological subtype and hormone receptor expression for mutations in AKT1 and mTOR.

Hormonal risks to meningioma

Several hormonal drug classes—including progestins, oral contraceptives (OCs), hormone replacement therapy (HRT), and feminizing hormone therapy—can potentially modulate meningioma risk. Prescribed progestins have been epidemiologically associated with increased meningioma risk. However, their mechanisms of action are pleiotropic, spanning progesterone agonism, androgen antagonism, and glucocorticoid receptor modulation, making it unclear which pathways mediate this association. Cyproterone acetate (CPA), a potent synthetic progestogen and antiandrogen, significantly elevates meningioma risk in a dose-dependent manner, with lesion regression following CPA withdrawal [3, 20]. Similar findings are reported for nomegestrol and chlormadinone, though with somewhat lower risk ratios [21]. A recent update expanded the evidence to additional progestins, demonstrating elevated risks primarily with medrogestone, medroxyprogesterone, and promegestone [22]. Cyproterone acetate’s (CPA) association with meningioma is now recognized in regulatory guidelines, which explicitly contraindicate its use in patients with a personal history of meningioma, reflecting growing clinical awareness of its dose-dependent tumorigenic potential [3].

Oral contraceptives, widely prescribed globally, show weaker associations. Most studies, including meta-analyses, indicate no statistically significant risk increase [23]. Similarly, the relationship between HRT and meningioma remains inconclusive. While certain studies report significantly elevated risks (RR = 1.86; OR = 1.7) [24], others fail to reach statistical significance or indicate varied results based on hormonal formulation [25]. Despite variability, given the sheer prescription volume of OCs and HRT, even modest associations merit mechanistic exploration.

Furthermore, there is a known risk of meningioma progression during the time of pregnancy. This is thought to arise from the relatively large hormonal changes that occur during the pregnant period [26], arising from the presence of progesterone receptors, as well as VEGF, glucocorticoid and epidermal growth factor receptors. Further, the presence of prolactin receptors found on meningioma cells could similarly contribute to growth around pregnancy with associated pituitary hyperplasia and chiasmal compression [27, 28]. However, a case series of skull base meningiomas resected during pregnancy showed histopathological changes suggestive of reversible hemodynamic changes rather than pure cell proliferation driven exclusively by hormonal binding [29]. Similarly to the importance of counselling women on contraceptive use when diagnosed with meningioma, patient counselling is equally important during pregnancy or in those women planning to be pregnant after receiving the diagnosis of meningioma. In addition, this raises questions of whether a resective surgery, if indicated, should be performed antepartum or postpartum [30] (Fig 1).

Fig. 1.

Molecular, Immunological, and Therapeutic Landscape of PIK3CA-Mutant Meningiomas. The current figure recapitulates the molecular, immunological, and therapeutic landscape of PIK3CA-mutant meningiomas, integrating hormonal risk factors, immune modulation, and ongoing treatment strategies. Progestins, HRT, and ADT amplify PI3K-AKT signaling, suppressing immune responses (↑Tregs, ↓CD8 + T cells) and promoting tumor progression. The molecular subtype panel highlights PIK3CA (hormonal therapy association, tumor-suppressive TME), NF2 (high-grade, immune resistance), SMO (Hedgehog pathway, angiogenesis), and TRAF7 (skull base, PIK3CA/KLF4 co-mutation). The PI3K-AKT-mTOR pathway is a central driver of proliferation, survival, and therapy resistance, with progestins further enhancing immune suppression. The bottom section presents current and future therapeutic strategies, including SSTR-targeted therapy (Octreotide, Lutathera), PI3K inhibitors (Alpelisib, Buparlisib), and anti-progestin agents (Mifepristone), aiming to restore immune surveillance and target tumor growth. This figure synthesizes epidemiological, molecular, and immunological insights, providing a framework for therapeutic advancements in meningioma. Created with BioRender.com, accessed February 20th, 2025

Hormonal therapies and PIK3CA

Direct human evidence linking hormonal therapies and PIK3CA-mutant meningiomas remains limited, and some of it represents hypothesis and speculation. Examples of such suggestive studies include the fact that progestin-exposed patients appear enriched for PIK3CA mutations (35% vs. 3% controls), skull-base localization, and multiplicity [31]. Case reports describe PIK3CA mutations in CPA-treated transgender patients [32], with variable tumor response post-CPA cessation, complicating mechanistic hypotheses [32, 33]. The human evidence for many of these hormonal therapies is heterogeneous and does not yet clearly reveal a mechanism or targetable therapy for patients with PIK3CA-mutant meningiomas. We can turn to studies in animal models to help uncover the evidence linking progestin intake and PIK3CA. Cômes and colleagues developed a mouse model of Pik3ca-mutant meningioma to try to answer this question [34]. The meninges in these mice had a similar PR expression to that of humans. They showed that Pik3ca mutations were sufficient to induce tumorigenesis and progression of meningiomas. When these mice were treated with CPA alone, this tumorigenic effect did not occur after an 11-month mean follow-up. Interestingly, this tumorigenic effect remained absent whether the CPA was administered alone or combined with a Pik3ca mutation after 8.6 mean month follow-up; these mice developed breast tumors instead. In other words, a synergistic progestin and Pik3ca effect was not demonstrated. The lack of tumorigenesis of CPA in separate Nf2-mutant models showed that CPA fails to promote tumor growth compared to non-CPA-treated Nf2 mice. Using an in vitro model, the lack of statistically significant meningeal cell proliferation under CPA was further confirmed (whilst Pik3ca did increase proliferation). However, CPA did increase cellular proliferation in arachnoidal cells (not dural cells), but not in a statistically significant way. A possible explanation, then, is that they do not have an oncogenic effect directly but could contribute to some architectural/microenvironment changes; the authors postulate an element of “hormone addiction”, where meningiomas that are progestin-associated (not necessarily progestin-caused), rescind their growth when the progestin compound is taken away [34]. This could explain the epidemiological evidence discussed previously, which shows meningioma growth regression after therapy cessation. However, it does not yet clearly link PIK3CA with progestin compounds.

Nonetheless, the results of hormone-related meningiomas are not always consistent, with some data that do not show high rates of PI3K pathway mutation. In an Indonesian study in 2022, consisting of 99 patients, the authors identified a strong relationship between hormonal contraceptive intake and spheno-orbital localization of meningioma [35]. Nevertheless, they did not conduct molecular profiling to confirm mechanistic links to PI3K signaling. In contrast, another study investigated 30 CPA-related meningiomas and found PIK3CA or AKT1 mutations in only 33.3% of such tumors [36]. This still implies an enrichment relative to sporadic tumors, but the enrichment was less than previously estimated. These tumours also showed chromosome stability and a low-grade, meningothelial predominant histopathology. These discrepancies may be explained by differences in the subtype of hormones, length of exposure, type of mutation detection used (exon-specific sequencing), and nature of the study population. Collectively, the current study aims to underline the complexity of hormonal-PI3KCA interplay and suggest the necessity for future, prospective, molecularly stratified investigations.

Lastly, from a mechanistic standpoint, further scholarship is needed to untangle the specific hormonal pathway(s) that affect meningioma growth, especially in patients with exposure to progestins. Future experiments should include subsequent CRISPR-mediated knockouts of PR and AR in CPA-treated human meningioma cells, in vivo lineage tracing studies of PIK3CA-mutant mice treated with hormone therapies, and single-cell RNA-seq of tumor tissue following hormonal exposure. Potentially, these studies could help advance the understanding of whether tumorigenesis in this scenario is driven by receptor agonism, antagonist intervention, or indirect regulation of the transcriptional machinery.

Clinical trials examining hormonal therapies in meningioma

Given the strong association between hormonal signaling and meningioma pathogenesis [37, 38], numerous clinical trials have attempted to elucidate the role of hormonal therapies as potential therapeutic interventions for the treatment of refractory meningiomas. Early studies focused on anti-estrogen and anti-progestin agents due to the known expression of estrogen and progesterone receptors in meningiomas [39]. More recent efforts have shifted towards somatostatin receptor-targeted treatments (SSTRs) and peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs [40–42]. Despite contemporary efforts, no hormonal treatment has yet demonstrated definitive clinical efficacy, recapitulating the need for further pharmacological exploration of hormonal signaling in meningiomas, particularly in the context of molecular subtypes such as PIK3CA-mutant meningiomas, which remain largely unexplored in current clinical trials.

Completed clinical trials of hormonal therapies in meningioma

Anti-estrogen and anti-progestin therapies

One of the earliest clinical trials to date evaluating hormonal modulation in meningiomas examined tamoxifen, a selective estrogen receptor modulator (SERM) widely used in estrogen-driven malignancies such as breast cancer. The trial assessed tamoxifen in six patients with fibrous meningiomas at the skull base and parasagittal regions. The trial showed only one case of a non-specific response, two cases of stable disease, and one case of progression, indicating that estrogen receptor blockade alone is unlikely to yield meaningful therapeutic effects in meningiomas [43]. Similarly, a phase II trial was conducted in a larger cohort of 21 patients with unresectable meningiomas, reporting a 5% partial response rate, 32% stable disease rate, and 53% progression rate, confirming the lack of significant benefit from estrogen receptor antagonism [44].

Given the high expression of progesterone receptors (PR) in meningiomas, progestin-based therapies were subsequently explored. The clinical trial investigated the synthetic progestin megestrol acetate in nine patients with meningothelial, fibrous, and anaplastic meningiomas [45]. While two patients exhibited stable disease, the remaining seven showed disease progression, and three patients had to discontinue treatment due to worsening vision. The study concluded that megestrol acetate was ineffective and carried significant toxicity, particularly substantial weight gain, fluid retention, and hypertension, which were notable adverse effects.

Following these disappointing hormonal trials, clinical trial efforts shifted toward mifepristone, a progesterone receptor antagonist. One clinical trial investigated 28 patients treated with daily oral mifepristone for a median of 35 months (2–157 months) [46]. Although eight patients exhibited minor responses (improved radiographic findings or visual field improvement), 7 were either male or premenopausal women, suggesting a possible hormone-dependent effect in certain subgroups. However, three patients developed endometrial hyperplasia or polyps, raising concerns about long-term safety. Another study demonstrated a ≥ 20% tumor volume reduction in three patients with transitional meningiomas, although the sample size was small [47]. Another trial examined mifepristone in 17 patients with WHO Grade II atypical meningiomas but found no significant improvement in progression-free survival (PFS), casting further doubt on the drug’s clinical utility [48].

Somatostatin receptor-targeting therapies

Due to the lack of prevailing efficacy in estrogen and progesterone-targeted therapeutic approaches, clinical trial efforts shifted toward somatostatin receptor (SSTR)-targeting agents. SSTR2A (Somatostatin Receptor 2 A) is the most highly expressed somatostatin receptor in meningioma and downregulation or loss of SSTR2A expression is associated with higher-grade (WHO grade II/III) and significantly more aggressive meningiomas and higher rates of recurrence [49]. Chamberlain et al. conducted a phase II trial evaluating octreotide (Sandostatin LAR) in recurrent or progressive meningiomas, reporting disease stabilization exclusively in receptor-positive cases, reinforcing the need for biomarker-driven therapy selection [49]. Norden et al. later examined pasireotide (a second-generation somatostatin analog) in 34 patients with WHO Grade I, II, and III meningiomas, showing that receptor-positive cases had tumor stabilization but no significant shrinkage, suggesting the existence of additional resistance mechanisms [50]. Similarly, Hrachova et al. found that WHO Grade I meningiomas responded more favorably to octreotide therapy than higher-grade tumors, reinforcing the hypothesis that lower-grade meningiomas may be more hormonally sensitive [51].

Ongoing hormonal therapy trials for meningioma

Given the partial success of somatostatin analogs, several ongoing clinical trials are currently investigating peptide receptor radionuclide therapy (PRRT), which combines SSTR-targeting agents with radioactive isotopes to achieve more effective tumor burden control.

One of the most promising investigational agents is Lutetium-177 DOTATATE (Lu-177 DOTATATE), an FDA-approved therapy for gastroenteropancreatic neuroendocrine tumors (GEP-NETs) currently being repurposed for meningiomas. Cordier et al. (NCT04997317) are conducting a phase 0 trial comparing the efficacy of [177Lu]Lu-DOTA-JR11 (a somatostatin receptor antagonist) versus [177Lu]Lu-DOTATOC (a somatostatin receptor agonist) in patients with progressive, therapy-resistant meningioma [52]. Initial results suggest higher tumor-absorbed doses and a favorable therapeutic index with [177Lu]Lu-DOTA-JR11, warranting further clinical and biomedical investigation.

Merrell et al. (NCT04082520) are evaluating Lutetium-177 DOTATATE in 41 patients to estimate its disease control rate and potential tumor volume reduction, particularly in patients with recurrent WHO Grade I meningiomas [53]. In a parallel effort, Salloum et al. (NCT05278208) are investigating Lutathera (Lu-177 DOTATATE) in 65 patients with recurrent and/or progressive meningiomas, using progression-free survival (PFS) as the primary outcome measure [54]. Kaley et al. (NCT03971461) are also conducting a Phase II study examining Lutetium-DOTA therapy in WHO Grade I, II, and III meningiomas, focusing on tumor response and safety [55]. Finally, Kumthekar et al. (NCT04082520) are assessing Lutetium-DOTATATE in 27 patients with WHO Grade I and II meningiomas, incorporating quality-of-life measures to determine patient-reported benefits beyond radiographic response [53].

Limitations of existing clinical trials in hormonal therapy for meningioma

Despite many decades of scholarship, the clinical efficacy of endocrine therapy in meningioma remains unestablished, primarily due to significant methodological limitations in the conducted trials. The majority of early-stage trials—most importantly trials of mifepristone, megestrol acetate, and tamoxifen—were conducted prior to the routine use of molecular or receptor characterization. The studies, therefore, failed to subgroup patients according to hormone receptor status or PIK3CA mutation status and thus obscured the possibility of treatment effects in biologically meaningful subgroups.The SWOG Phase 3 mifepristone trial was the largest prospective trial to have been conducted, but it was negative. The trial neither performed hormonal receptor testing nor assessment of downstream signal responses, and thus its capability to validate target engagement or best patient selection approach was diminished.

More recent efforts such as the Chamberlain et al. octreotide trial, despite being biomarker-selected, had only SSTR2-positive patients. While disease stabilization was reported, study design did not allow testing whether SSTR2 positivity as a predictive biomarker was authentic. The Norden et al. trial of a second-generation somatostatin analog, pasireotide, in 34 patients with no radiographic responses despite receptor positivity does, however, suggest drug limitations in efficacy or resistance pathways downstream. Retrospective series such as Hrachova et al. are beneficial practical experience, particularly in hypothesizing WHO Grade I tumors being hormonally more sensitive. However, lack of uniform imaging criteria, prospective verification, and potential selection bias temper the strength of such an observation.

Collectively, these limitations highlight the need for biomarker-based, molecularly stratified clinical trials. Future study design must incorporate receptor expression profiling, PIK3CA mutational analysis, and pharmacodynamic endpoints for determining genuine target engagement and therapeutic response. Molecular subtype and prior history of hormonal exposure will play a pivotal role in stratifying patients to the correct subgroup for revealing clinically relevant responses and avoiding false negatives within this heterogeneity of disease.

Future directions in clinical trials

As elucidated in the preceding paragraphs, current clinical trials primarily focus on somatostatin receptor (SSTR)-targeted therapy and peptide receptor radionuclide therapy (PRRT). However, given the compelling PIK3CA-hormonal signaling axis, it is imperative that future clinical trials incorporate PIK3CA mutation screening as a biomarker for patient stratification. The therapeutic landscape for hormone-dependent cancers (breast, prostate, and endometrial cancer) has already benefited from the integration of PI3K inhibitors (alpelisib, taselisib, and buparlisib) in combination with endocrine therapy [53, 56–58]. Similar combinatorial strategies should be tested in PIK3CA-mutant meningiomas, particularly those associated with hormonal therapy exposure.

Retrospective analyses of hormonal therapy trials in meningioma should also assess whether PIK3CA-mutant tumors display differential responses to anti-progestin (mifepristone) or SSTR-targeted therapies (octreotide, Lutathera). The observed lack of response to mifepristone in prior trials may reflect inadequate molecular stratification, as PIK3CA-mutant tumors may possess alternative resistance mechanisms requiring dual inhibition of hormonal and PI3K signaling pathways. The clinical relevance of PIK3CA mutations in meningiomas extends beyond mere classification; it represents a critical intersection between hormonal therapy, tumor growth, and treatment resistance. The parallels with hormone-dependent malignancies in breast and prostate cancer [59, 60] suggest that targeting PI3K signaling alongside hormonal modulation may overcome resistance mechanisms and provide durable therapeutic responses. As meningioma clinical trials evolve, integrating PI3K-AKT-mTOR inhibitors into stratified, biomarker-driven therapeutic approaches will be crucial in optimizing patient outcomes.

PIK3CA in other body systems

PI3KCA gene mutations have been identified across various cancer types, with increased focus on hormone-dependent tumors such as breast and prostate cancer, where hormonal regulation and PI3K pathway interactions are well-studied. Although meningiomas manifest with distinct clinical and biological behavior, particularly in higher-grade subtypes and their intracranial localization, findings from hormone-dependent cancer models may still offer valuable conceptual and translational insights. Specifically, key insights into hormonal resistance mechanisms and combined hormone receptor/PI3K pathway targeting strategies can be derived from these other cancer models that may help generate novel hypotheses for investigation in meningioma, a tumor type also known to be highly regulated by hormonal signaling. In what follows, we emphasize key points from breast and prostate cancers that may inform future studies in select subtypes of meningioma, such as hormone receptor-positive or clinically aggressive.

Breast cancer: leveraging PI3K Inhibition to enhance hormonal therapy

Although breast cancer differs from meningioma in tissue origin, tumor microenvironment, and treatment responsiveness, it nonetheless serves as a well-established model of the PI3K-hormonal signaling axis. The current study made such parallels not to draw a comparison between their therapeutic benefits, but to offer a perspective based on the mechanistic understanding from hormone-driven malignancies (with focus on PIK3CA-mutant-affected therapy resistance) and how this may guide future trial design and biomarker choice for meningiomas.

The PI3K/AKT/mTOR pathway is overactivated in approximately 70% of breast cancer patients [61]. PIK3CA gene alteration is most prevalent, implicated in over a third of cases [62]. As a hormone-dependent malignancy, breast cancer is significantly regulated by sex hormones. It has been reported that over 75% of breast cancers express the estrogen receptor (ER) and progesterone receptor (PR), making them valuable prognostic and predictive markers for hormonal therapy [63].

Despite advances in breast cancer prognosis, nearly half of patients develop endocrine resistance to therapy, which relies on inhibiting hormone production that keeps the cancer growing [64]. Notably, only 20–40% of advanced breast cancer (ER+) patients respond favorably to endocrine treatment, with a median response duration of 8–14 months [65]. Emerging evidence suggests that treatment resistance may include aberrant ER co-activator regulation, truncated isoforms or post-translationally modified ER expression, and enhanced growth factor receptor signaling [62].

Recent studies have described PI3K pathway activation as a key mediator of resistance in HER2 + and ER + breast cancer undergoing hormonal treatment [66]. PIK3CA mutations have been reported in approximately 25% of HER2-positive breast cancer cases and nearly half of ER + patients, with over 80% clustering in the helical or kinase domains of p110α [66–68].

Furthurmore, there is a strong link between PI3K pathway activation (PIK3CA mutations or PTEN expression loss) and resistance to standard therapy, which includes endocrine therapy, chemotherapy, HER-2 targeted treatments, PARP inhibitors, and immunotherapy [66, 69]. However, the prevalence of PIK3CA mutations in endocrine-resistant breast cancer patients is not fully characterized and requires further validation [70].

Aberrant PI3KCA expression leads to overactivation of the PI3K/AKT/mTOR pathway, promoting oncogenesis. Evidence suggests that PI3K pathway amplification enables breast tumors to adapt to estrogen deprivation, thereby conferring hormonal therapy resistance [71]. Emerging evidence shows that endocrine-resistant breast tumors exhibit significant sensitivity upon PI3K overactivation and potentially exhibit marked sensitivity upon its inhibition [71]. Intriguingly, another study demonstrated that PIK3CA mutations play a controversial role in breast cancer, being associated with better prognostic features in the early stages of disease (e.g., histological grading) but also with increased endocrine resistance over time [69]. Although preliminary, these findings emphasize the significant regulatory role of PI3KCA in breast cancer growth and response to treatment.

Reflecting their therapeutic potential, PI3K inhibitors have emerged as promising adjuvant treatments for breast cancer. Alpelisib, an FDA-approved α-specific PI3K inhibitor, is prescribed to HR+/HER2—advanced or metastatic breast cancer patients harboring a PI3KCA mutation [72]. Breast cancer patients receiving both alpelisib and fulvestrant had improved progression-free survival (PFS) compared to patients treated with fulvestrant monotherapy [56].These findings show that targeting PIK3CA represents a promising approach to restoring endocrine sensitivity and controlling abnormal cellular function and proliferation in breast cancer. This study highlights that PI3K inhibition can enhance the effectiveness of hormonal blockade.

Prostate cancer: PI3K and hormonal pathways in therapeutic resistance

Prostate cancer is one of the leading malignancies in the United States and is associated with a poor prognosis [73]. In advanced prostate cancer, 70 − 100% of cases show dysregulation in the PI3K pathway [73]. Recent evidence links several tumor suppressor proteins to the PI3K-Akt pathway in prostate cancer. As demonstrated in a major study, SMARCC1, SIRT5, and GATA5 are PI3K-AKT protein pathway suppressors, and their downregulation drives tumorigenesis. Restoring their normal level expression also demonstrated tumor-suppressing effects in preclinical models [74]. Similar to breast cancer, prostate cancer highlights the potential cooperation between androgen receptor signaling and PI3K-AKT-mTOR dysregulation in the development of hormone therapy resistance. Although meningioma has not shown the same therapeutic liabilities, exploring these analogous signaling cascades in prostate cancer may reveal druggable intersections in meningioma that are high for both AR expression and PI3K pathway activation.

One major contributor to prostate cancer treatment resistance is androgen receptor (AR) alterations [73, 74].Similarly, the PI3K pathway closely interacts with the AR signaling axis, significantly contributing to castration resistance prostate cancer (CRPC) [59, 75]. PIK3CA mutations are often associated with the loss of phosphatase and tensin homolog (PTEN) in prostate cancer [75]. PTEN is an onco-suppressor gene that negatively regulates the PI3K-AKT pathway, and its loss contributes to treatment resistance in CRPC. PIK3CA mutations further enhance PI3K lipid kinase activity, whereas PTEN loss eliminates an essential brake on the pathway, resulting in sustained activation of the AKT-mTORC1/2 pathway [75, 76]. Additionally, androgen treatment resistance could be explained by the crosstalk between PI3K-AKT and androgen receptor (AR) signaling [59, 75]. Akt can directly interact with AR activity or phosphorylate AR co-regulators, contributing to persistent AR signaling despite androgen deprivation therapy (ADT) [76]. In line with these findings in breast cancer, preclinical models have shown that combining AR antagonists with PI3K inhibitors is a promising therapeutic approach in mouse models of CRPC [75, 77]. Notably, PIK3CA mutations drive distinct molecular behavior in tumors and serve as a strong independent prognostic biomarker in prostate cancer, even without PTEN loss [78].

Four hotspot PIK3CA mutations, H1047L, H1047R, E545K, and E542K, account for nearly 90% of all PIK3CA alterations in human metastatic tumors. These mutations constitutively activate PI3K signaling, promoting cancer growth and therapeutic resistance [78]. Their role highlights the signaling complexity in hormone-dependent tumors and the necessity of simultaneously targeting multiple oncogenic pathways to optimize therapeutic outcomes.

Future directions: therapeutic insights for meningioma

Prostate and breast cancers, as hormone-driven malignancies, provide therapeutic insights for meningioma management. Given that PI3K inhibition enhances the efficacy of hormonal therapy in these cancers, and considering meningiomas’ hormone receptor expression and potential PI3K pathway involvement, similar approaches may be applicable. Considering the significant molecular diversity of meningiomas, particularly among atypical and anaplastic subtypes, these cancers may demonstrate reduced responsiveness to hormonal therapies compared to breast and prostate cancers. Nevertheless, resistance mechanisms driven by PI3K activation in hormone-dependent tumors may point to potential analogous pathways in meningiomas. Hence, further investigation is needed to determine whether PI3K pathway activation contributes to limited efficacy or resistance to hormonal treatments or drives tumor progression in specific molecular meningioma subtypes. Future clinical trials should consider stratifying meningioma patients based on PIK3CA mutation status and hormone receptor expression. This approach may help determine whether combining PI3K inhibitors with hormonal therapies can offer therapeutic benefit by overcoming PI3K meditated resistance mechanisms. Evaluating PIK3CA mutations may establish an essential biomarker for precision treatments, particularly in subtypes such as skull-base or high-grade meningiomas. This approach may ultimately guide tailored clinical approaches that address distinct molecular drivers and reflect the diverse biological landscape within tumors.

Importantly, a major ongoing trial, Alliance A071401 (NCT02523014), represents the first genomically stratified, multi-arm phase II effort targeting progressive meningiomas based on actionable pathway alterations. Patients are randomly allocated to arms according to molecular analysis, such as AKT1, PIK3CA, and PTEN mutations (the AKT inhibitor capivasertib), NF2 (GSK2256098 FAK inhibitor), SMO/PTCH1 (vismodegib), or CDK pathway dysregulation (abemaciclib). For the AKT1/PIK3CA/PTEN subset, most relevant to hormone-driven, skull-base, non-NF2 tumors, the trial evaluates progression-free survival at 6 months (PFS6) and radiologic response rate as major endpoints. Initial results of the NF2 arm, reported recently in JCO, demonstrated promising PFS6 rates (83% in grade I and 33% in grade II/III meningiomas), confirming the validity of targeted inhibition on the basis of genomic subclassification [79]. Final results for the AKT1/PIK3CA arm will be available by 2026 and have the potential to redefine therapeutic paradigms for PI3K-pathway-altered patients [80]. This trial demonstrates the necessity of incorporating molecular stratification, such as PIK3CA mutation status and hormone receptor expression, into future therapeutic trials in meningioma.

Lastly, the success of PI3K inhibitors in breast and prostate cancers became apparent after decades of numerous clinical trials had previously failed in the same indication due to underpowered molecular stratification. The scholarship in these fields emphasize the importance of stratification of meningioma trials based on both PIK3CA mutation status and hormone receptor status for planned future therapeutic development.

Author contributions

All authors contributed to the study conception and design. Michael Lim, Daniel Fountain and Sanjeeva Jeyaretna aided the conception, design and supervision. Material preparation, and analysis were performed by Matthew Abikenari. The first draft of the manuscript was written by Matthew Abikenari, Amit Regev, Vratko Himic and John Choi, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

Michael Lim (Funding from Arbor Pharmaceuticals, Accuray, BMS, Novartis; Consultant: BMS, Merck, SQZ Biotechnologies, Tocagen, VBI; Patents: Combining Focused Radiation and Immunotherapy, Combining Local Chemotherapy and Immunotherapy; Shareholder: Egret Therapeutics). Michael Lim is also a member of the editorial board for the current Journal (JNO). All other authors have no conflict to declare.