Vismodegib as First-Line Treatment of Mutated Sonic Hedgehog Pathway in Adult Medulloblastoma

INTRODUCTION

Medulloblastoma (MB) is an aggressive, primitive neuroectodermal tumor mainly affecting pediatric patients and with frequent involvement of the posterior fossa and extraneural metastasis. MB has a low incidence in adults (< 1% of adult brain tumors) and treatment protocols for adult patients have been adapted from pediatric oncology.^1,2

PTCH1³ tumor suppressor gene functions as an inhibitor of smoothened (SMO) and downstream sonic hedgehog (SHH) signaling. SHH ligand connects to the receptor on PTCH1, which results in SMO suppression (Fig 1). PTCH1 germline inactivating mutations are associated with Gorlin syndrome, which is associated with a high incidence of basal cell carcinoma (BCC) and predisposition to MB.^4-6 This association is strengthened because somatic mutations that inactivate PTCH1 are frequently found in the sporadic forms of these types of cancers. Genomic analyses of MB have identified PTCH1 a mutation incidence of 3%-7% of MB cases. On the basis of gene expression profiling, four molecular subgroups of MB have been identified: WNT, SHH, group 3, and group 4.⁷ The prognosis for patients within the SHH subgroup MB differs greatly upon TP53 mutation status, wherein patients with wild-type TP53 have a significantly better 5-year overall survival rate (76%) compared with those with TP53 mutation (41%).⁸

FIG 1.

Graphic representation of sonic hedgehog (SHH) pathway. (1) HH ligand binding to PTCH1. (2) Binding of HH to PTCH1 releases SMO. (3) Showing the inhibition of SMO by vismodegib, which leads to inhibition of the whole pathway.

Although several case reports showed promising results for molecular targeted therapy in the population of adults with MB,⁹ to our knowledge, this is the second reported case treated with target therapy as first-line treatment.¹⁰ Vismodegib is an SHH pathway inhibitor that acts as an SMO development suppressor; it has been approved for BCC treatment^4,6 but not for adult MB.

Here, we present a new approach for the treatment of adult MB based on genomic findings. A young woman without evidence of Gorlin syndrome presented with an unresectable, multifocal, and predominantly spinal form of SHH-type MB and was treated with vismodegib as first-line therapy. She showed positive and sustained response. Although this is a notoriously aggressive neoplasm, this patient is presently alive after 15 months of treatment, presenting leptomeningeal spread of the tumor. This represents a promising treatment and suggests that resistance is slow to develop, which should also spark additional investigation.

CASE REPORT

A 24-year-old woman was admitted to the hospital because of a 6-month history of unsteadiness and worsening lower-limb paresthesia. Neurologic evaluation revealed a fully conscious and oriented patient with normal cranial nerves, lower extremity dysmetria, subxiphoid paresthesia, and grade 3/5 paraparesis. Spinal computed tomography (CT) was normal. Brain and spinal magnetic resonance imaging revealed heterogeneous, nonenhancing right cerebellar and vermis lesions with multiple spinal intramedullary lesions causing significant cord compression (Fig 2). The patient underwent urgent decompressive laminectomy with maximal safe resection.

FIG 2.

Spinal magnetic resonance images. (A) Preoperative magnetic resonance imaging (MRI) scan: sagittal T2. (B) Sagittal T1 with gadolinium MRI. (C) Cross-section MRI. Blue arrows point to multiple spinal intramedullary, homogenously enhancing lesions. Orange arrow points to substantial spinal cord compression.

Histopathology showed a small, round, blue cell tumor infiltrating spinal meninges that was composed of nodular, reticulin-free zones of variable sizes and surrounded by densely packed, highly proliferative cells, occasional nuclear molding, without vascular proliferation or necrotic foci. Pathologic findings indicated metastatic desmoplastic/nodular MB, WHO grade IV. Immunohistochemistry of the internodular hypercellular areas was consistent with SHH-type MB with wild-type TP53, as described Figure 3A-3E). In addition, next-generation sequencing–based assay¹¹ (Foundation Medicine, Cambridge, MA) identified nonsense mutation in PTCH1 gene R135*. Moreover, microsatellite instability–stable, low tumor mutational burden, and variants of uncertain significance (VUS) were identified as described in Figure 3F. Positron emission tomography (PET)-CT showed postoperative spinal intramedullary hypermetabolic uptake (Fig 4A, blue arrow). Chemoradiotherapy was recommended to the patient as standard treatment. However, because of the patient's aversion to chemotherapeutic agents, she was treated only with radiotherapy. Treatment protocol consisted of 36 Gy in 20 fractions to the entire craniospinal axis, followed by a boost of 18 Gy in nine fractions to the posterior fossa and 8 Gy in four fractions to the spinal drop metastases. PET-CT scan after radiation therapy showed extraneural bilateral proximal humorous (Fig 4B, blue arrow) and a new, small, lung opacification (Fig 4B, green arrow), most probably due to radiation pneumonitis. On the basis of the patient mutational profile, vismodegib was initiated as compassionate treatment at 150 mg orally daily after local institutional review board approval. Six months later, there was no clinical or radiologic evidence of MB lesions, including complete response of extraneural lesions (Fig 4C). Currently, 15 months since starting treatment, the patient shows significant clinical symptoms improvement and is under rehabilitation treatment.

FIG 3.

(A) Histopathologic examination of the tumor shows a biphasic, small, round, blue cell tumor with hypocellular nodules with a hypercellular internodular area. The pattern was confirmed with a reticulin stain. (hematoxylin and eosin; original magnification, ×10). (B-E) On immunostaining, the tumor cells showed strong cytoplasmic immunoreactivity, but, more importantly, negative nuclear staining with (B) β-catenin, (C) cytoplasmic staining with filamin A and (D) GAB1, and (E) cytoplasmic and nuclear staining with YAP-1. This particular combination of immunostaining patterns is consistent with SHH-type medulloblastoma, and additional immunostains with TP53 showed a wild-type immunoreactivity pattern. (F) Variants of unknown significance analyzed by next-generation sequencing.

Fig 4.

Whole-body imaging ¹⁸F-fluorodeoxyglucose positron-emission tomography–computed tomography showing (A) examination postsurgical intervention, (B) postradiation therapy (blue arrows point to extraneural metastasis; green arrow points to postradiation pneumonitis. (C) Six months after vismodegib treatment, imaging shows no evidence of metastatic disease.

DISCUSSION

We describe here a case of adult MB with mutation in the PTCH1 gene that achieved a remarkable and prolonged clinical and radiologic response to the SHH pathway inhibitor vismodegib as first-line therapy following craniospinal irradiation. Although vismodegib is not approved by the US Food and Drug Administration for this indication, the treatment was given as compassionate therapy after the molecular findings.

The identification of molecular drivers involved in MB tumorigenesis, including WNT, SHH, and groups 3 and 4, has enabled the identification of additional prognostic markers to the established histopathologic typing.¹² MB with SHH subtype is associated with desmoplastic histology in the vast majority of reported cases, including pediatric and most adult patients, and has been associated with better prognostic outcomes.¹³ Moreover, loss of heterozygosity (LOH) of PTCH1 has been associated with prolonged progression-free survival in a setting of second-line therapy with vismodegib, whereas in the same setting, mutations in the SHH pathway downstream to SMO did not respond to the treatment.¹⁴ The patient presented in this case has a nonsense mutation in position R135* of PTCH1 and mutation allele frequency of 97%, which could be an indication of LOH. Moreover, the patient has a mutation in the promoter of TERT, which has significant co-occurrence with small nuclear RNA mutations and subsequently could be indicative of PTCH1 inactivation; Figure 3F presents details about VUS mutations.¹⁵ The promising findings in this case demonstrate that vismodegib may be considered a first-line treatment in adult patients with MB with SHH-type MB with mutations upstream to SMO in the SHH pathway.

AUTHOR CONTRIBUTIONS

Conception and design: Waleed Kian, Laila C. Roisman, Nadav Wallach, Farouq Alguayn, Walid Shalata, Dina Levitas, Daniel Levin, Eyal Fenig, Konstantin Lavrenkov, Margarita Tokar, Nir Peled, Alexander Yakobson

Collection and assembly of data: Waleed Kian, Laila C. Roisman, Abed Abo-Quider, Benzion Samueli, Farouq Alguayn, Walid Shalata, Dina Levitas, Nir Peled, Alexander Yakobson

Data analysis and interpretation: Waleed Kian, Laila C. Roisman, Iris M. Goldstein, Farouq Alguayn, Walid Shalata, Dina Levitas, Olga Belochitski, Eyal Fenig, Margarita Tokar, Nir Peled, Alexander Yakobson

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.

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Laila C. Roisman

Stock and Other Ownership Interests: Teva

Honoraria: Pfizer, Roche, AstraZeneca, Takeda

Consulting or Advisory Role: AllScripts

Patents, Royalties, Other Intellectual Property: Approved interferon patents

Nir Peled

Honoraria: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, MSD Oncology, Novartis, Pfizer, Roche, Takeda

Consulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, MSD Oncology, Novartis, Pfizer, Roche

Research Funding: MSD Oncology (Inst), Roche (Inst), AstraZeneca (Inst), Takeda (Inst), Merck Serono (Inst), Novartis (Inst)

Travel, Accommodations, Expenses: Roche (Inst), MSD Oncology, AstraZeneca, Pfizer (Inst)

No other potential conflicts of interest were reported.