Abstract
Background
Smoothened inhibitors (SMOi) have shown activity in Sonic Hedgehog (SHH) medulloblastoma, however this therapeutic class was not developed in children due to severe effects ...reported on growth. We hereby report long-term follow-up of young patients treated with SMOi for recurrent medulloblastoma.
Methods
Clinical data on response and toxicity from patients treated with vismodegib or sonidegib from 2011 to 2019 for a SHH medulloblastoma were retrospectively reviewed. Methylation analysis and whole exome sequencing were performed whenever possible.
Results
All patients with a somatic PTCH1 mutation responded to SMOi (6/8), including 2 prolonged complete responses. One patient was free of disease 8.2 years after treatment. SMOi was challenged again for 3 patients. Two of them had a response, one with SMOi alone, the other one in combination with temozolomide despite previous progression under monotherapy. SMO resistance mutations were found in patients from biopsy at relapse. Combination with temozolomide or surgery plus radiotherapy was associated with very long disease control in 2 patients. The most severe adverse events were myalgia and growth plate fusion with metaphyseal sclerosis. Normal growth velocity was recovered for 1 patient although her final height was below estimated target height.
Conclusions
Targeting SMO in mutated PTCH1 is an interesting strategy for long-term responses. Combination of SMOi with chemotherapy or surgery and local radiotherapy is an appealing strategy to prevent early resistance and diminish SMOi exposure, especially in young patients. Inhibition of SHH pathway causes growth and development impairment but partial recovery of the growth velocity is possible.
Abstract BACKGROUND Medulloblastomas (MB) Sonic hedgehog (SHH) subtype are associated with a cancer predisposition syndrome (CPS) in about 15% of cases, the most frequent being related to ELP1 ...pathogenic variant (PV). The aim of our study is to better evaluate penetrance of this CPS and detail the characteristics of the related tumors. METHODS Twenty-nine ELP1-mutated MB identified in France were retrospectively reviewed. Molecular characteristics of the tumor and clinical features of the patients were collected; whenever possible, the germline DNA from patients and their relatives were sequenced. RESULTS All patients (sex ratio 16/13) presented with SHH-MB, mostly nodular desmoplastic (n=20/28), between 3 and 15 years of age (median 7.3). All mutations are found in the germline when a constitutional DNA sample was available (n=26). Most tumors (93%) showed a biallelic inactivation of PTCH1, other recurrent alterations concerned the TP53 pathway (including 1 somatic TP53 VP) and activation of MYCN/MYCL signaling. We observed that ELP1-mutated MB behave as sporadic cases, with similar distribution within clinical and molecular risk groups of MB, similar outcomes (5y-OS = 85%) and no unusual side effects of treatments. Three patients developed a second tumor (2 high-grade gliomas and 1 thyroid carcinoma) within the irradiation fields. All germline PV were inherited from one asymptomatic parent (11 trio). No specific morphological features were mentioned. Only two index cases from the 29 French patients had a previous familial history of MB (occurring in a cousin), with many asymptomatic carriers. Except the MB, no other cancer was significantly associated with the ELP1 PV. CONCLUSIONS the low penetrance, the ‘at risk’ age window limited to childhood and the narrow tumor spectrum, question the actual benefit of genetic screening in these patients and their family. Our results suggest restricting ELP1 germline sequencing to patients with MB, depending on the parents’ request.
Abstract
Medulloblastoma (MB), the most frequent embryonic tumor of the cerebellum is classified into four molecular subgroups (WNT group, SHH group, group 3 and group 4). Although the vast majority ...of MB are sporadic, predisposing genetic diseases have been described in rare WNT MB and more frequently in the SHH group. In a recent pediatric series of SHH-MB, germline alterations of the ELP1 gene have been described in 14% of cases, making this gene the most frequent genetic predisposition in MB. We have investigated the potential interest of ELP1 immunostaining on a large cohort of 132 MB. A complete loss of ELP1 staining was observed in 12 SHH MB (among 57 total SHH MB: 21%). The loss of ELP1 immunostaining was well correlated with the presence of a bi-allelic alteration of the gene except for one case for which the MB had a loss of ELP1 protein expression demonstrated by immunohistochemistry (IHC) and confirmed by whole proteome analysis, although no obvious genetic alteration in the coding sequence of ELP1 could be found. Molecular analysis of a large “molecular” cohort of 266 MB from French centers for which somatic ELP1 was sequenced allows to identify 12 additional MB with bi-allelic ELP1 genetic alterations. Our results demonstrate the benefit of the ELP1 IHC as an accurate and reliable tool to screen ELP1-deficient MB. This new immunohistochemical tool will now be advantageously used to screen SHH MB upfront for genetic alteration in ELP1, and will subsequently help orientating these patients towards genetic counseling.
Abstract
PURPOSE
To identify prognostic factors for overall survival (OS) after recurrence in childhood medulloblastoma (MB). PATIENTS AND
METHODS
Consecutive patients with MB treated at Gustave ...Roussy from 2007 to 2015 were retrospectively reviewed. Central histopathological review and molecular subgrouping are ongoing.
RESULTS
Among our cohort of 131 patients, recurrence occurred in 46 children (35%) at median time of 13.5 months (range, 1-88 months). The pattern of recurrence was local in 9 patients, metastatic in 21 and synchronous metastatic and local in 16 patients. One, 3 and 5-year OS from recurrence were 44.7 ± 0.75%, 30.5 ± 0.86% and 25.4 ± 0.85%, respectively. Patients with late recurrence (time from diagnosis until recurrence ≥ 12 months) had a better outcome with a median survival after recurrence of 27 months (95%-CI, 7.67-46.32) compared to those with shorter time to relapse (median of 2 months; 95%-CI, 0.57-3.42). The variables influencing survival after recurrence were time to relapse, histopathological subtype and pattern of relapse/progression. Adjusting for time to relapse, multivariate analysis showed that age at diagnosis (< or > 5 years) was not a significant predictor for OS after recurrence.
CONCLUSION
This study confirmed poor survival of patients with recurrent MB, particularly for those who relapse within 12 months after diagnosis. Yet patients with recurrence beyond 1 year have better outcome and may benefit from new therapies.
Patients with brain tumours have a high risk of water and electrolyte disorders (WED). Postsurgery diabetes insipidus (DI) may be transient or permanent, the syndrome of inappropriate antidiuretic ...hormone secretion (SIADH) and cerebral salt-wasting syndrome (CSWS) are usually transient.
Retrospective study, including patients with suprasellar tumours, treated at Hôpital Necker, Institut Gustave-Roussy or Institut Curie, in Île-de-France, between 2007 and 2011. WED were noted if they persisted >1 month after surgery.
159 patients were included, 54.1% girls, 43.9% boys. Tumour types were: glioma (43.4%), craniopharyngioma (43.4%), germinoma (11.3%), others (1.9%). Age at diagnosis was 7.1 ± 4.6 years. The median time from end of treatment was 1.9 (0-7.8) years. DI was the most frequent disorder after tumour treatment (50.3%) and was significantly associated with surgery (p < 0.001). Persistent CSWS was present in 3.6%, persistent SIADH in 1.3%. Two cases of hypernatraemia were due to adipsia. Thyrotropin deficiency after treatment was noted in 68.9% of patients tested, adrenocorticotropin deficiency in 66.2%.
Patients with suprasellar tumours have a high incidence of long-term WED, mainly DI. Assessment of thyrotroph and corticotroph function, and thirst sensation, is necessary to diagnose and manage these disorders correctly. CSWS may be persistent in few patients and requires special attention to prescribe the appropriate care.
Abstract
PURPOSE
Constitutional Mismatch Repair Deficiency (CMMRD) is a cancer predisposition due to bi-allelic mutations in one of the four main mismatch repair (MMR) genes (PMS2, MSH2, MSH6 or ...MLH1) associated with early onset of cancers, especially glioblastomas (GBM). Our aim was to decipher the molecular specificities of gliomas occurring in this context.
METHODS
A comprehensive analysis of clinical, histopathological and genomic data (whole exome sequencing) was performed for 12 children with a CMMRD for which we had available frozen brain tumor material (10 GBM and 2 anaplastic astrocytomas).
RESULTS
Eight patients harbored an ultra-mutated phenotype with more than 100 somatic non synonymous (NS) SNV/Mb. No correlation was observed between the number of mutation and sex, age, overall survival or mutated MMR gene. POLE and POLD1 exonuclease domain driver somatic mutations were described for eight and one patients respectively. The 4/12 tumors without POLE somatic mutation did not show the classical ultra-hypermutation pattern. All patients with POLE mutation had already more than 20 NS SNV/Mb (median 40NS SNV/Mb, range 23-114) suggesting that the hypermutation phenomenon started before the appearance of the somatic POLE mutation. The mutational signatures of the tumors, dominated by the MMR signatures, were not modified after the onset of the POLE mutation when analyzing the different mutation bursts. Specific recurrent somatic mutations were observed in SETD2 (9/12), TP53 (9/12), NF1 (9/12), EPHB2 (8/12), and DICER1 (7/12). Only half of the tumors overexpressed PDL1 by immunohistochemistry and this overexpression was not associated with a higher tumor mutation burden.
CONCLUSION
CMMRD-associated gliomas have a specific oncogenesis that does not trigger usual pathways and mutations seen in sporadic pediatric or adult GBM. Frequent alterations in other pathways (e.g. MAPK or DNA-PK pathway) may suggests the use of other targeted therapies aside from PD1 inhibitors.
Abstract
BACKGROUND
Previous pilot studies have shown the feasibility of preoperative chemotherapy in patients with medulloblastoma, but benefits and risks compared with initial surgery have not been ...assessed.
METHODS
Two therapeutic strategies were retrospectively compared in 92 patients with metastatic medulloblastoma treated at Gustave Roussy, France, between 2002 and 2015: surgery at diagnosis (n=54; group A) and surgery delayed after carboplatin and etoposide-based preoperative therapy (n=38; group B). Treatment strategies were similar in both groups.
RESULTS
The rate of complete tumor excision was significantly higher in group B than in group A (93.3% versus 57.4%, p=0.0013). Post-operative complications, chemotherapy-associated side effects and local progressions were not increased in group B. Preoperative chemotherapy led to a decrease in the primary tumor size in all patients, 4/38 patients experiencing meanwhile a distant progression. The histological review of 19 matched tumor pairs (before and after chemotherapy) showed that proliferation was reduced and histological diagnosis feasible and accurate even after preoperative chemotherapy. The 5-year progression-free and overall survival rates were comparable between groups. Comparison of the longitudinal neuropsychological data showed that intellectual outcome tended to be better in group B (the mean predicted intellectual quotient value was 6 points higher throughout the follow-up).
CONCLUSION
Preoperative chemotherapy is a safe and efficient strategy for metastatic medulloblastoma. It increases the rate of complete tumor excision and may improve the neuropsychological outcome without jeopardizing survival.
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