Page 1 of 27 Accepted Preprint first posted on 16 July 2008 as Manuscript ERC-08-0083

Reapprasial of the role of endocrine therapy

in meningioma management

Cyrus Chargari, 1,2 Lionel Vdrine, 2 Oliver Bauduceau, 2 Sylvestre Le Moulec, 2

Bernard Ceccaldi, 2 and Nicolas Magn 1*

1
Department of radiotherapy, Intitut Gustave Roussy, Villejuif, France
2
Department of oncology and radiotherapy, Hpital du Val-de-Grce, Paris, France

* Corresponding author:

Nicolas Magn

Department of Radiotherapy,

39 rue Camille Desmoulins,

94805 Villejuif, France

Tel.: + 33 1 42 11 42.11; Fax: + 33 1 42 11 52 08

Email: nicolas.magne@igr.fr

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Abstract

Recurrent meningiomas constitute an uncommon but significant problem after standard

therapy failure. Speculation that meningiomas may be subject to endocrine influence was

supported by both immunohistochemical analyses and epidemiological data. Therefore,

alternative strategies such as endocrine therapy have been suggested. Although evidence of

consistent findings for the role of specific hormonal exposures is mounting, there are

numerous discrepancies about the mitogenic effect of hormonal manipulation on meningioma

cells. A better understanding of the molecular mechanisms involved in meningioma

pathogenesis may not only lead to the identification of novel diagnostic and prognostic

markers but may also facilitate the development of new pathogenesis-based targeted

strategies. This review of literature aims to summarize the present state-of-the-art of

endocrine therapy in management of meningiomas, in order to establish whether

hormonotherapy could be included in the therapeutic strategy for unresectable and/or

progressive tumours in previously irradiated meningioma patients.

Key words: meningioma, breast cancer, hormonotherapy, clinical trials.

Introduction

Meningiomas are common tumours of the central nervous system that originate from the

meningeal coverings of the spinal cord and the brain. Although the cell of origin has yet to be

proven, meningiomas are probably derived from arachnoidal cap cells (Riemenschneider et al.

2006). They constitute approximatively 13 to 26% of all intracranial tumors (Kleihues et al.

2002). For most of those lesions, conventional strategy combining both surgery and radiation

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therapy provides long-term effective and sufficient clinical results (Whittle et al. 2004,

McMullen & Stieber 2004). Surgery is considered as the standard first-line treatment in

meningiomas. Its primary goal is the complete removal of the meningioma. However, the

decision to operate is guided by the clinical history of the patient, symptoms, accessibility of

the tumour and estimation of the clinical benefit achievable by surgery (Bindal et al. 2003).

However, some meningiomas recur or are resected subtotally because of anatomical problems

such as their location at the skull base and are deferred to postoperative or salvage

radiotherapy. The indications for radiotherapy are atypical or anaplastic meningiomas,

recurrences or inacessible meningiomas. Postoperative radiation therapy after the first

resection of benign meningiomas is still controversial. However, it is currently used in cases

of incomplete resection or in cases of tumour progression. This unresolved issue should be

examined prospectively in a randomised study that compares a policy of watchful waiting

versus adjuvant conformal irradiation (EORTC 26021 trial). In a minority of patients,

regrowth of tumor tissue after irradiation is a major clinical problem. Supported by promising

results in breast cancer treatment (Jones & Buzdar 2004, Santen & Harvey, 1999), systemic

approaches based on hormone manipulation were tested in those patients with poor functional

prognosis, in order to improve their clinical outcome.

In the present report, the main goal was to establish whether hormonotherapy could be

included in the therapeutic strategy for unresectable and/or progressive tumours in previously

irradiated meningioma patients.

Literature review

An English-language literature search was conducted to identify all published studies

assessing hormonal influences on meningiomas, in order to highlight potential prognostical

and therapeutical value of endocrine therapy. Data for this review were identified by searches

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of Medline and Cancerlit. The search terms meningioma, hormonotherapy, breast cancer,

clinical trial were used. References identified from within retrieved articles were also used.

There was no limitation on year of publication and no abstract forms were included.

Epidemiological background

The aetiology of primary brain tumours remains a controversial issue and the only somewhat

well-established risk factors for meningioma are ionizing radiation (Sadetzki et al. 2002,

Pettorini et al. 2008). A significant increased risk of meningioma has also been advocated in

some hereditary syndromes where the mismatch repair gene or the deletion of

neurofibromatosis type 2 gene (NF2) have been associated with the occurrence of cerebral

benign tumors (Claus et al. 2008, Louis et al. 2007). Mutations in the NF2 gene probably

account for the formation of more than half of all meningiomas (Simon et al. 2007), which are

hallmark features of this autosomal dominant disorder caused by germline mutations in the

NF2 gene on chromosome 22q12 (Baser et al. 2003).

Although a role of head injury for the induction of meningiomas has been suspected, this

question cannot be answered definitely. It was suggested that the local alteration of the blood

brain barrier might be involved by a consequent massive influx of cytokines into the

extravasal space. Moreover, it was also advocated that several genes would be upregulated

after traumatic brain injury, including genes controlling transcription regulation, signal

transduction and intercellular adhesion (Michael et al. 2005).

In adults meningiomas, epidemiological data have identified a ratio of 2:1 in female gender

(Carroll et al. 2000). Although a possible hormonal association between breast cancer and

meningiomas has not been clarified, the simultaneous occurrence of meningiomas and breast

cancer is an unusual but well-known event and several cases have been reported with or

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without brain metastasis (Brandis et al. 1993, Maiuri et al. 2002, Markopoulos et al. 1998).

According to data from the Swedish Cancer Registry and from the United Stated Surveillance,

Epidemiology and End Results (SEER) Program, (Ahsan et al. 1995, Malmer et al. 2000), the

increased risk of developing meningioma was reported to be 1.5-1.7 times after breast cancer,

with a mean time interval between the diagnosis of breast cancer and meningioma of 99.5

months.

Breast cancer and meningioma present some similar features that might account for their

association: both tumors occur most frequently in female in their fifth to seventh decades of

life, may grow during the early postpartum period and express progesterone and oestrogen

receptors on their cell membranes (Hatiboglu et al. 2008, Britt et al. 2007). Both clinical case

reports and retrospective data reported that meningioma may grow rapidly during periods of

relative hormonal excess, during the luteal phase of the menstrual cycle and in the latter

trimesters of pregnancy (Wahab et al. 2003). Furthermore, menopause and oophorectomy

have been identified as conferring protection against the risk of developing meningiomas,

while excess of adiposity is positively associated with the disease (Kanaan et al. 2003). Some

authors described growth of meningiomas after estrogen-progestin therapy (Gazzeri et al.

2007). Custer et al. investigated the association between oral contraception (OC) or hormonal

replacement therapy (HRT) and intracranial meningioma in women, using a population-based,

matched case-control study (Custer et al. 2006). Exposures for 143 cases and 286 controls

matched on age within five years were obtained by interview. Risk of meningioma appeared

modestly elevated in past OC users, and in current users. However, the confidence intervals

were wide and no significant association between meningioma risk and duration of OC use

was found. Discrepant results were recently obtained by Blitshteyn et al. (Blitshteyn et al.

2008). Authors retrospectively reviewed a total of 1390 women with a history of symptomatic

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or incidentally discovered meningiomas, 156 (11%) of whom were either current or past HRT

users. A logistic regression analysis, adjusted for age, demonstrated a significantly positive

association between a diagnosis of meningioma and HRT use. Similarly, Wigertz et al. also

found an increased relative risk of meningioma among postmenopausal women for ever use of

HRT (Wigertz et al. 2007). Further evaluation of exogenous hormone use in women with

meningioma is needed with particular attention to stratification by hormonal receptor status,

duration of and age at use as well as tumor receptor subtype (Claus et al. 2007).

Whereas alterations of the BCRA1 and BCRA2 are not common pathogenic events in the

development of meningiomas (Kirsch et al. 1997), the correlation between breast cancer and

meningioma raises the question of a common pathogenic mechanism. Several studies have

shown that hyperinsulinaemia could promote carcinogenesis in breast cancer. This mechanism

might possibly involve activity of insulin growth factor I (Stoll 1999, Hudelist et al. 2007).

Kaplan et al. have noticed an association between meningioma and intake of saturated fat. As

gene expression of different insulin-like growth factors has also been reported in meningioma,

it is therefore of interest to delineate a possibility of hyperinsulinaemia as a triggering factor

in both meningioma and breast cancer (Kaplan et al. 1997). Other authors hypothesized that

because obesity affects male steroid hormone synthesis, male patients with meningiomas

might exhibit a high obesity rate, suggesting a hormonal influence on meningiomas in men as

well as women (Aghi et al. 2007).

Moreover, the human progesterone receptor (PgR) gene shares the same location as the

mammary oncogene int-2 in chromosomal 11q13 (Law et al. 1987). Although this proximity

may explain the role of progesterone in breast cancer, the role of oncogene int-2 in the genesis

of meningiomas is not yet known. Besides, both meningiomas and breast cancers overexpress

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the c-myc oncogene. Claus et al. measured via immunohistochemistry PgR and ER from 31

meningioma patients undergoing neurosurgical resection and compared with gene expression

profiling results (Claus et al. 2008). Genes on the long arm of chromosome 22 and near the

NF2 gene were most frequently noted to have expression variation, with significant up-

regulation in PgR+ versus PgR- lesions, suggesting a higher rate of 22q loss in PgR- lesions.

It remains difficult to interpret the results from epidemiological trials that are most often

biased and retrospectively analysed. Epidemiological reports frequently include all women

regardless of menopausal status. Moreover, effects of exogenous hormones are not the main

hypothesis examined. Another weakness of those studies is the lack of detailed information on

when in time the patients had taken hormones and what types of compounds they had used.

Epidemiological background, including female predominance in meningiomas incidence,

suggested that growth of meningiomas is hormone dependant. Growing evidence of an

hormonal association between meningiomas and breast cancer incite to focus on the

predictive value and therapeutic consequences of hormonal status in alternative strategies for

patients with unresectable and/or already irradiated progressive meningioma. However, it is

obvious that further studies remain necessary.

Hormonal receptors status and patients outcome

It has been demonstrated that most of meningiomas express hormone receptors on their cell

membranes, although to a variable extent (Marosi et al. 2008). Actually, up to 90% of

meningiomas express PgR, while fewer 30% to 48% express oestrogen receptors (ER)

(Korhonen et al. 2006). Omulecka et al. examined samples from 64 tumors and demonstrated

a positive immunoreaction for PgR in 100% meningothelial, 95% transitional, 46% fibrous

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and 78% atypical variant of meningiomas. Besides, intensity of immunoreaction was stronger

in grade I than in grade II tumors (Omulecka et al. 2006). In the past two decades, the relation

between sexual hormone receptors and meningiomas has been the subject of several studies

(Blankenstein et al. 2000, Fewings et al. 2000, Gursan et al. 2002, Markwalder et al. 1988,

Nagashima et al. 1995, Perrot-Applanat et al. 1992, Strik et al. 2002), providing sufficient

evidence that the expression of PgR by meningioma cells is a prognostically favourable sign.

In opposite, loss of this expression would be accompanied by a more aggressive tumoral

behaviour. Pravdenkova et al. advocated that the expression of the PgR alone in meningiomas

signals a favourable clinical and biological outcome. A lack of receptors or the presence of

ER correlates with an accumulation of qualitative and quantitative karyotype abnormalities, a

higher proportional involvement of chromosomes 14 and 22 in de novo tumors, and an

increasing potential for aggressive clinical behaviour, progression and recurrence of

meningiomas (Pravdenkova et al. 2006). These results seem to be consistent with those from

a long-term prospective analysis of 62 meningiomas in 53 patients. Although no association

could be demonstrated between recurrence and patient's gender, extent of resection,

histological subtype, or tumor site, there was a significant association between recurrence and

negativity for PgR status (p = 0.013), indicating that benign meningiomas that are PgR

positive are less likely to recur (Fewings et al. 2000). Roser et al. also established a

significant correlation between negative PgR expression and high tumour vascularity with

high Ki-67 labelling index (LI) (Roser et al. 2004 [b]) which combined with p53 labelling

indices would be a useful additional tool in discriminating atypical from benign or anaplastic

meningiomas, especially in histological borderline cases. Besides Ki67 is an important

predictive tool of meningioma natural history (Bruna et al. 2007, Terzi et al. 2008). However,

recent results from a retrospective analysis of 55 patients with benign meningiomas could not

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demonstrate a correlation between PgR expression and patterns of recurrence after seemingly

complete removal (Maiuri et al. 2008).

Strik et al. reported the role of PgR receptor expression on relapse in the long-term clinical

course of 93 benign meningiomas. Authors assessed the expression of PgR and the

proliferation marker MIB-1 in the primary tumours of 30 cases of benign, completely

resected, recurrent meningiomas, when compared with 63 cases of meningiomas without

recurrence for 14 or more years (Strik et al. 2002). They concluded to significantly higher risk

for recurrence (odds ratio 3.53) for tumours with a low expression of PgR. These findings

support previous studies and demonstrate an association between low expression of PgR and

higher risk of recurrence. In a recent retrospective study of 31 patients with meningioma

undergoing neurosurgical resection, PgR and ER were measured via immunohistochemistry

then compared with gene expression profiling results. After examination of gene expression

for meningioma cases by hormone receptor status, Claus et al. established a stronger

association with PgR than with ER status (Claus et al. 2008). Maiuri et al. also concluded

from 50 completely resected benign (WHO I) meningiomas, that higher mitotic index, Ki-67

LI, and PgR negativity had a strong predictive value of recurrence (p < 0.0001), particularly

when Bcl-2 positivity is associated. In opposite, the ER status was not relevant (Maiuri et al.

2007). Although the role of sexual steroids hormones in genesis of meningiomas is yet no

clarified, there is growing evidence that progesterone may at least contribute to the growth of

PgR-positive meningiomas (Marosi et al. 2008). This suggests that PgR status may be a

clinical marker for genetic subgroups of meningioma and warrant further examination.

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Almost studies frequently included meningiomas with different resection grades, histological

subtypes and a substantial number of atypical meningiomas. Sexual hormone receptor status

should routinely be studied for its prognostic value especially in female patients and should be

taken into account in tumor grading. Besides, the initial receptor status of a tumor may change

in progression or recurrence of tumor, thus have some prognostic and therapeutic

implications. Moreover, there has been a long-standing debate in the literature as to whether

the PgR that are present in meningiomas are functional. In contrast to breast cancer the

PgR/ER receptors in meningiomas are probably not functional in all tumours (Speirs et al.

1997). Abnormally spliced forms of ER have been reported in human meningiomas, which do

not bind the ligand, but may constitutively induce PgR expression. The presence of ER

variants might explain the autonomous expression of PgR in meningioma (Koehorst et al.

1993). However, it was suggested that promegestone (R5020), a progesterone agonist, would

increase transcription only in meningioma cell cultures that express the PgR, supporting the

concept that progestins may play a role in meningioma growth (Carroll et al. 1995). It

remains to be elucidated if these transcripts are or will be translated to a biologically active

protein. These considerations may explain why the breast cancer drugs do not affect

meningioma growth in a desirable way.

No association between PgR status or proliferation labelling index and variables such as

tumour location, first time resection versus reoperation, and histological subtype has been

reported in the literature so far. However, significantly higher MIB-1 indices have been found

in recurrent than primary meningioma (Wolfsberger et al. 2004). As these patients represent

the best candidates for adjuvant hormonal therapy, further assessment of these potential

changes remains necessary.

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Endocrine therapy

Epidemiological and immunohistochemical data have led to some attempts of treatment with

anti-hormonal therapies for patients with PgR-positive meningioma (Strik et al. 2002). After

repeated surgery and radiotherapy, the number of patients affected by recurrent, progressive

and symptomatic meningiomas is small. However, these patients with poor prognosis

represent a major therapeutic challenge. Few data are available on benefit of hormonotherapy

in unresectable meningioma on progression. Supported by promising results in breast cancer

treatment, new chemotherapeutic approaches based on hormone manipulation were tested in

patients with meningioma, making long-term antiprogestational therapy a logical treatment

strategy. Postoperative radiation is currently used in cases of incomplete resection or in cases

of tumour progression. For that reason, reports that assessed the role of endocrine therapy in

meningioma management included patients with progressive disease after either postoperative

radiotherapy or primary radiotherapy.

Mifepristone (RU486) is an oral antiprogestational commonly used in adjuvant strategy or

metastatic treatment of ER positive breast cancer with a significant benefit in global survival.

Mifepristone inhibits the transcriptional activity of PgR by complex mechanisms at

concentration much lower than progestins (Edwards et al. 2000). The use of progesterone

antagonists in the palliation of meningioma has been discussed repeatedly for more than 10

years (Markwalder et al. 1985, Haak et al. 1990, Lamberts et al. 1992, Strik et al. 2002).

Olson et al. assessed hormonotherapy in specimens from 3 convexity meningiomas.

Mifepristone caused inhibition of cell growth in all three tumors, ranging from 18% to 36%.

These data were the first to suggest that selected meningiomas are subject to hormonal

influence in vitro and encouraged further development of alternative modes of therapy for

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recurrent and unresectable meningiomas (Olson et al. 1986). Later, the effect of

medroxyprogesterone acetate (MPA) on growth fractions of ex vivo meningiomas was

demonstrated in using the Ki-67 monoclonal antibody (Markwalder et al. 1988). Growth

fractions in samples from 5 meningioma patients not treated with MPA were determined for

comparison. The percentage of Ki-67-positive cells in meningioma tissue was lower by a

factor of 6, 5, and 3, respectively, after MPA therapy. In meningioma specimens from patients

receiving no MPA therapy, Ki-67-positive cells were present in 1.02 +/- 0.48%, whereas the

percentage of Ki-67-positive cells was 0.41 +/- 0.40 in samples from MPA-treated tumors (p

< 0.02). Authors concluded that MPA reduced the growth fractions of most meningiomas and

would be suitable for adjuvant hormonotherapy. However, further reports were more

disappointing. Lamberts et al. reported the results of mifepristone delivered to 10 patients

treated with 12 recurrent or primary inoperable meningiomas, all of whom had shown recent

neuroradiological and/or ophthalmological evidence of tumor growth (Lamberts et al. 1992).

They received 200 mg mifepristone daily for 12 months. Most patients initially had

complaints such as nausea, vomiting and asthenia. In 4 patients, prednisone (7.5 mg/day) was

given, after which these side effects subsided. Mifepristone treatment resulted in control of

tumor growth in 6 out of 10 patients with recent evidence of tumor growth. Among them, 3

presented consistent tumor shrinkage. In 2006, Grunberg et al. assessed the feasibility of

hormonotherapy in 28 patients with unresectable meningioma, treated with oral mifepristone

200 mg/day and oral dexamethasone 1 mg/day for the first 14 days. With a median duration of

therapy of 35 months (range 2-157 months), repeated oral administration was feasible and

well tolerated with mild fatigue (22 patients), hot flashes (13 patients), and

gynecomastia/breast tenderness (6 patients) being the most common side effects. However,

endometrial hyperplasia was noted in several patients (n=3) and one patient developed

peritoneal adenocarcinoma after 9 years of therapy. Minor responses (improved automated

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visual field examination or improved CT or MRI scan) were noted in 8 patients, 7 of whom

were male or premenopausal female, that can result in significant clinical benefit is this

subgroup of patients (Grunberg et al. 2006). The only prospective study on this topic was

conducted on 160 patients. Eighty patients were treated with mifepristone 200mg and 80

patients were treated with placebo for a median duration of 10 months. Grade IV toxicities

were experienced by 6 patients in the mifepristone arm, whereas one patient had grade IV

toxicity in the placebo arm. Grade III toxicities were seen in 30 patients in the mifepristone

arm and in 24 patients in the placebo arm. Most of reported toxicities were fatigue (72%

versus 54%), headache (44% versus 41%), and hot flushes (38% versus 26%). Besides,

several female patients developed endometrial hyperplasia. This trial was prematurely closed

and is yet to be published. Neither trend nor difference was observed between the 2 arms in

terms of time to progression: 55% of patients had stable disease, 1% of patients had partial

response and no patient could achieve complete response (Newfield et al. 2001).

Tamoxifen is an orally active selective ER modulator which competitively binds to ER,

producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects.

Markwalder et al. reported 6 patients with meningiomas treated with tamoxifen and found no

significant change in tumour growth with drug treatment (Markwalder et al. 1985). In this

small study, survival at 72 months was 72%, whereas it has been reported to be 71% with

subtotal resection alone. In a phase II evaluation of an hormonotherapy by tamoxifen given 40

mg/m b.i.d. for 4 days, then 10 mg b.i.d. thereafter in unresectable or refractory

meningiomas, Goodwin et al. observed only one patient (5%) achieving a partial response

while 2 had a minor response measured on computed TDM which was of short duration (4

and 20 months). Six patients (32%) remained stable for a median duration of more than 31

months while 10 (53%) demonstrated progression. Whereas 22 % reported subjective

improvement, this did not correlate with objective improvement in all cases, and a definite

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recommendation for the use of tamoxifen in refractory meningiomas could not be made

(Goodwin et al. 1993). Published data on meningiomas endocrine therapy in preclinical and

clinical settings are reported in Table 1.

From clinical results to molecular pathways

Steroid hormone receptors belong to a large superfamily of nuclear receptors that bind DNA

at specific sites to control gene transcription (Savouret et al. 1991). However, the mechanisms

by which steroid receptors modulate the transcription of target genes remains under

investigation. The existence of interactions between steroid hormones and peptide growth

factors has also been reported (Murphy et al. 1986). After interaction with ligand, the

receptors undergo conformational changes. Consequently, dimmers of receptors recognize

specific regulatory DNA sequences upstream of several target genes. Activated receptors

direct the assembly and the stabilization of a preinitiation complex that might conduct

transcription of these genes (Carroll et al. 2000). Several coactivators that are associated in a

ligand-dependent manner have been identified, enhancing trans-activation of target genes

(Horwitz et al. 1996). It was demonstrated the expression of the steroid coactivators steroid

receptor cofactor (SRC-1), amplified breast cancer protein (AIB1), and transcriptional

intermediary factor 2 (TIF2) in most of meningiomas (Carroll et al. 2000). Better

characterization of coregulators would be necessary and may partially explain the wide

heterogeneity in response to endocrine therapy. The complex process of transcriptional

activation of the steroid hormone receptors may be influenced by the relative amount of these

components. Modulation in expression of patterns of the concerned genes suggests that their

expression may be tissue dependent. If hormonal therapy has a direct action on the PgR, these

patients should respond best to anti-progesterone treatment. A major obstacle in

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understanding the molecular changes that lead to meningioma formation and progression is

the lack of appropriate in vitro and in vivo model systems. It was suggested that the relative

expression of coactivators in meningiomas may contribute to heterogeneity of hormonal

responses and to discrepancies about the mitogenic effect of steroids on meningiomas in both

in vitro and in vivo models.

Another explanation would be that the postulated antiproliferative effect of hormonal

modulation may appear only in patients with highly differentiated tumors, probably not in

patients with multiple recurrences or with atypical or anaplastic meningioma on progression

after aggressive conventional therapies. PgR-positive cells in all histological grades are

distributed heterogeneously throughout the tumour and it is still unclear whether areas of PgR

positivity in meningiomas reflect the status of the whole tumour (Brandis et al. 1993).

Because of modern microsurgical techniques, where only tumour parts are deferred to the

pathologist, there is a subsequent risk of over- or underestimation of focal accumulation of

biological activity within the meningioma. As PgR index is variable in meningioma,

depending on clinical parameters and histopathological features, stratification on the basis of

PgR index should be considered for further anti-progesterone therapy trials (Wolfsberger et

al. 2004).

At least two PgR isoforms have been found, PgR-B and PgR-A, each of which are likely to

have different biological functions. While both isoforms have similar DNA and ligand

binding affinities (Lessey et al. 1983, Graham et al. 1996), they exhibit different regulating

properties. PgR-A is considered to be a dominant negative transrepressor whereas PgR-B is a

strong transactivator (Wen et al. 1994). It was demonstrated that meningiomas contain both

isoforms in variable ratios, but most of meningiomas express more PgR-A than PgR-B. This

variability may have some biological significance. It was assumed that progesterone

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responsiveness could be based on transrepression rather than on transactivation of target

genes. Progesterone blockade may only be effective in certain subsets of meningiomas

(Verheijen et al. 2001).

Rubinstein et al. compared hormone receptors in initially excised versus recurrent intracranial

meningiomas. Although minor changes in the PgR status induced by radiotherapy should not

be excluded, authors demonstrated that these receptors persisted in recurrent meningiomas

and even significantly increased (p<0.02) (Rubinstein et al. 1994). In MCF7 breast cancer cell

lines, Paulsen et al. demonstrated that a radiation dose of 6 Gy reduced the ER content in

cytosol, but brought no alterations to the PgR content (Paulsen et al. 1996). These results

support hormone treatment for nonresectable meningiomas, especially at recurrence.

However, it should not be excluded that functional changes in molecular mechanisms may

affect a possible hormonotherapy. This should be further assessed, in order to better

understand the reason for such discrepancies in clinical trials, most of them including patients

previously irradiated.

Conclusion

The place of hormonotherapy in meningioma remains unclear. Results from the present

analysis of literature are that the PgR status combined with the routine pathological

investigation can provide more insight in the behaviour of meningioma, particularly in

histopathological borderline cases (Roser et al. 2004 [a]). However, the PgR status alone

cannot be used to predict behaviour in benign meningiomas and should not influence the

decision about follow up intervals and therapeutic strategies. In the specific case of

unresectable meningioma residue in progression after ionizing radiation, clinical chronology

and data of literature incite to propose inclusion into a therapeutic trial. Understanding of

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pathways of steroid-mediated transactivation should allow new approaches in treatment of

meningiomas in order to improve the patients outcome (Whittle et al. 2004). Together with

routine histological evaluation, hormonal status should help to describe the biological

behaviour of meningiomas. Combination of both clinical and biological features will help to

devise more effective follow up strategies.

Although the underlying genetic causes are unknown, meningiomas growth is sustained by

the dysregulated expression of steroid hormones, growth factors, their receptors, and

activation of signal transduction cascades. Multiple new targeted agents, such as

antiangiogenic therapies, will be investigated in early phase trials for patients with recurrent

or progressive disease after standard therapy has failed. However, hormonotherapy has

probably been to early classified as out of date. Wide heterogeneity in terms of clinical

outcome and response to targeted treatment exists. Thus, further works should be focused on

the identification of better biologic and clinical factors that may serve as prognostic and

predictive markers. Moreover, future advances in basic research and genomics should

improve our understanding of the biologic basis of the meningioma development and

progression (Lusis et al. 2005, Loussouarn et al. 2006). Use of array-based approaches of

global genomic and gene expression analyses and new in vitro and in vivo models may

contribute to further development of new targeted therapies, particularly for patients for

whom surgical and radiation options have been exhausted.

Conflict of interest statement

None declared

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Table 1: Effects of endocrine therapy on growth of meningiomas

n Material Endocrine TD Results

agent (m)

Olson et al. 1986 in vitro 3 tumors (A, B, C) in TAM NA - Growth stimulation by 35% (A), transient stimulation (B) or no effect (C)
experimental media RU486 NA - Growth inhibition in all 3 tumors from 18% to 36%
17 -E2 + PG NA - Growth stimulation by 21% (A) and 36% (B)

Markwalder et al. 1985 6 Inoperable/recurrent TAM 8-12 - No benefit in 2-year PFS

tumors - 1 case of tumor response at 4 months

Lamberts et al. 1992 12 Inoperable/recurrent RU486 12 - Toxicity: nausea, vomiting and/or tiredness, 2 deaths during treatment
with evidence of 200mg/m period from unrelated causes
recent tumour growth - Efficacy: progression: n=5, stable disease: n=3, regression: n=4

Goodwin et al. 1993 19 Inoperable refractory TAM UP - One patient with partial response
meningiomas - Two patients with minor response of short duration (4 and 20 months)
- Six stable diseases for a duration of more than 31 months
- Ten patients (53%) in progression

Newfield et al. 2001 160 Randomized trial of RU486 10 - Toxicity: Grade IV toxicities in 6 patients (versus 1 in placebo group),
unresectable/progresive versus increased endometrial hyperplasia
meningiomas placebo - Efficacy: no difference in efficacy between the two arms

Grunberg et al. 2006 28 Inoperable meningiomas RU486 35 - Toxicity: mild fatigue (n=22), hot flashes (n=13), gynecomastia (n=6),
endometrial polyps (n=3) peritoneal adenocarcinoma (n=1).
- Efficacy: minor responses in 8 patients

TD: treatment duration; P: prospective; NA: not applicable; m: months; TAM: tamoxifen, PG: progesterone; 17 -E2: 17 beta-estradiol; UP: until progression; RU486: mifepristone;
PFS: progression free survival.

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