The use of vismodegib to shrink keratocystic odontogenic tumors in basal cell nevus syndrome patients

Abstract

Importance

Keratocystic odontogenic tumors of the jaw (KCOTs) affect more than 65% of patients with basal cell nevus syndrome (BCNS). Surgery frequently causes facial disfigurement and is not always curative. Most BCNS-related and some sporadic KCOTs have malignant activation of the Hedgehog (HH) signaling pathway.

Observations

We examined the effect of vismodegib (an oral HH-pathway inhibitor) on KCOT size in BCNS patients enrolled in a clinical trial testing vismodegib for BCC prevention (NCT00957229), using pre and post-treatment MRIs. Four men and 2 women had pretreatment KCOTs, mean longest diameter 2.0cm (range: 0.7–3.3cm), occurring primarily in the mandible. Subjects were treated with vismodegib (150mg/day) for a mean 18 months (SD: 4.8, range: 11–24). Four subjects experienced a size reduction and 2 had no change. Vismodegib reduced the mean longest diameter of KCOTs in all subjects by 1.0cm (95% CI: 0.03, 1.94, p= 0.02) or 50% from baseline. We observed no enlargement of existing KCOTs or new KCOT development.

Conclusions and relevance

Vismodegib shrinks some KCOTs in BCNS patients and may offer an alternative to surgical therapy. These effects were maintained for at least 9 months after drug cessation in 1 patient. Further studies assessing long-term efficacy and optimal maintenance regimens should be performed.

Introduction

Basal cell nevus (Gorlin) syndrome (BCNS) (OMIM#109400) is a rare autosomal dominant disease in which affected individuals can develop a panoply of phenotypic abnormalities, the most prominent of which are basal cell carcinomas (BCCs) of the skin and keratocystic odontogenic tumors of the jaw (KCOTs)¹. The incidence of KCOTs varies from 4%–16.5% of oral pathology specimens²; however they affect 65–100% of BCNS patients¹. Multiple KCOTs, which typically grow rapidly, are often the earliest presenting feature of BCNS. Surgery is the standard of care but it frequently causes facial disfigurement and often is not curative ^2–4. To our knowledge, there is no effective non-surgical therapy for KCOTs.

Patient with BCNS inherit one defective copy of the tumor suppressor gene PATCHED 1 (PTCH1) (OMIM#601309), which encodes a primary inhibitor of the Hedgehog (HH) signaling pathway. Functional loss of the second allele leads to activation of HH pathway signaling⁵. KCOTs in patients with BCNS and in 30% of sporadic lesions harbor somatically acquired PTCH1 mutations⁴ and increased HH target gene expression (GLI1)⁶ _ENREF_7. They have also been seen in heterozygous Ptch1 knockout mice and in K5-Gli2 transgenic mice ^6,7. This discovery highlights the possibility that the newly approved targeted HH pathway inhibitor, vismodegib (Erivedge), might be effective for KCOT treatment. We conducted a sub-study in patients enrolled in a recent clinical trial testing vismodegib for BCC prevention⁸ to determine its effect on KCOT size in patients with BCNS. This study received institutional review board approval by Children’s Hospital Oakland Research Institute, and all participants provided written consent.

Report of cases

Of 41 BCNS subjects enrolled in a clinical trial (NCT00957229) testing vismodegib 150mg daily for BCC prevention⁸, 18 participated in the KCOT sub-study and had pre-treatment (baseline) MRIs. We performed post-treatment MRIs in 8 subjects with KCOTs at baseline who had received at least 11 months vismodegib after the pre-treatment MRI (Figure 1).

Figure 1.

CONSORT diagram. A CONSORT flow diagram of patient selection highlighting reasons for exclusion from the case series, as well as, baseline and post-treatment MRI results.

We recorded reasons for not having a MRI, time interval between MRIs, treatment duration and KCOT characteristics. We calculated the percentage reduction in KCOT size (longest diameter in centimeters) from baseline and used the Wilcoxon signed rank test to compare the change in KCOT diameters pre and post-vismodegib.

We excluded subjects without paired MRIs from analysis. We examined face/neck MRI (1.5 or 3.0 T) with coronal, sagittal, and axial T1 fast spin-echo, and multiplanar T2 to demonstrate the intrinsic high T2 signal of KCOTs. A single study radiologist (T.J.) compared all paired MRI images and or/reports.

Results

Of the 41 subjects enrolled in the original clinical trial⁸ we obtained baseline MRIs in 18, 9 of whom (50%) had KCOTs. Twenty-three subjects refused to participate in the MRI-KCOT study because they had no history of tumors or had negative recent dental imaging, were unable to fit into the MRI scanner, or perceived having an MRI scan as an inconvenience (Figure 1).

We excluded from our analysis, 3 of the 9 subjects with KCOTs diagnosed on baseline MRI, due to tumor removal (N=2) or movement artifact on post-treatment MRI precluding exact measurement (N=1). We performed post-treatment MRIs in 2 subjects with no KCOTs at baseline due to new jaw pain to assess for new growth of KCOTs while receiving vismodegib. Thus a total of 6 subjects with paired KCOT MRIs are included in the final analysis (Table 1, Figure 1).

Table 1.

Percentage change in cyst size from baseline to post-treatment MRI.

Subject	Age/Sex	KCOT Location	Total months on drug by post- treatment MRI*	Months between MRI’s	Baseline KCOT size (longest diameter, cm)	Post-treatment KCOT size (longest diameter, cm)	% Change in cyst size
1	53/F	R maxilla L mandible	18	13	3.1 0.7	0 0	−100 −100
2	59/M	Midline mandible	24	23	0.7	0.7	0
3	51/M	R mandibular ramus	20#	23	2.3	2.3	0
4Ŧ	48/M	L maxilla L mandible	11#	22	3.2 0.9	0 0.8	−100 − 12
5	37/M	L maxilla R mandible	21	19	3.3 2.0	2.5 1.4	−25 −30
6	57/F	Right mandible	14#	17	1.3	1.2	−8
Mean ±SD	51±8		18.0 ± 4.8	19.5 ± 4.0	2.0 ± 1.0	1.0 ± 0.9	−50 ± 45

^*Accounting for drug breaks (i.e. a brief period off vismodegib treatment).

^#Subjects 3, 4 and 6 took 3 months of drug breaks between MRI’s.

^ŦSecond post-treatment MRI 9 months off vismodegib: L maxilla KCOT = 0cm, L mandible KCOT = 0.7cm

Study participants included 4 men and 2 women, with a mean age of 51 years (range 37–59) (Table 1). All subjects had prior removal of KCOTs, most having had at least 2 procedures.

In 6 subjects with a total of 9 documented KCOTs we obtained post-treatment MRIs within an average of 19.5 months (SD: 4.0, range 13–23) after baseline imaging. During this interval we treated these subjects with vismodegib for an average of 18.0 months (SD: 4.8, range: 11–24); 3 subjects took drug breaks (i.e. a brief period off vismodegib treatment) (Table 1). The baseline MRI of one of the 6 subjects was performed 5 months after starting vismodegib and two KCOTs were seen. The mean longest diameter of baseline KCOTs was 2.0 cm (range: 0.7–3.3 cm). KCOTs occurred primarily in the mandible (6/9). Of the 6 subjects with tumors, 4 experienced a reduction in KCOT size and 2 experienced no change. Vismodegib reduced the longest diameter of all monitored KCOTs by an average of 1.0cm (95% CI: 0.03, 1.94, p= 0.016), i.e. by 50% from baseline. No enlargement or new KCOTs occurred in any case, including the 2 subjects without KCOTs at baseline. In one subject with100% resolution of one KCOT with vismodegib, there was no recurrence 9 months after drug cessation (Figure 2). All subjects experienced mild side effects (grade 1) of taste loss, muscle cramps and hair loss as previously reported⁸. Three subjects experienced Grade 2 muscle cramps and GI disturbance necessitating brief drug breaks.

Figure 2.

MRI images of subject 4. Serial sagittal T2 weighted MRI images demonstrating the size change in the left maxillary KCOT (red arrows) from A) baseline B) after 11 months of vismodegib and C) 9 months after drug discontinuation.

Discussion

We found that vismodegib can shrink some KCOTs in patients with BCNS, with a mean size reduction of 50% in our study. Two subjects had complete resolution of one or more KCOTs, with no enlargement of existing tumors or development of new lesions in any case. We found no KCOT relapse after 9-months of drug discontinuation in one subject, who also had minimal BCC recurrence at that time.

Vismodegib is an oral HH pathway inhibitor approved for the indefinite treatment of locally advanced/metastatic BCCs. In one case report, Goldberg et al³ incidentally noted resolution of KCOTs in one BCNS patient treated with vismodegib (270mg/day) for 2 years. This dose was used in phase 1-studies before the data demonstrated 150mg/day to be the most efficacious.

It is unclear why vismodegib was effective in some, but not all of our subjects. The three patients with multiple KCOTs in our study appeared to have had the best response, regardless of size, months of treatment or drug holidays. This may reflect the increased proliferative activity associated with multiple tumors, a finding that has been associated with protein truncating PTCH1 mutations in both sporadic and syndrome-related KCOTs⁹. Another hypothesis is that higher doses of vismodegib are required to induce shrinkage. Indeed, the dose used in our study was almost half of that used in Goldberg et al’s case report³ and, cyclopamine (another HH pathway inhibitor) has been found to significantly arrest the growth of KCOT cells in a dose-dependent manner in vitro¹⁰. However, since all our patients received the same FDA-approved dose of vismodegib, we were not able to assess any dose-dependent response.

In one subject, there was no KCOT recurrence 9 months after drug cessation. In fact, there was further size reduction, albeit minimal, of the mandibular tumor. Interestingly, this subject had recurrence of only 1 BCC in the same time period, a much lower recurrence rate than previously reported⁸. The incidence of KCOT recurrence in reported series varies from 0%- 62%, with a higher recurrence rate in BCNS-related tumors (over 80%) as compared to sporadic tumors¹¹. This variability could relate to the diverse nature of the cases reported, the different treatment protocols used and variations in post-treatment monitoring. The management of KCOTs remains controversial. Conservative therapy, such as simple enucleation or marsupialization has a recurrence rate of 50% compared to a lower rate following aggressive complete resection¹². Recurrence, which typically develops within 5 years of treatment, is thought to occur due to incomplete removal of the original cysts, the presence of microscopic satellite cysts or new cyst development in adjacent areas¹³. Relapse has been reported even after 41 years¹⁴, necessitating long-term follow-up, particularly as these tumors have locally aggressive behavior and, rarely, malignant potential (primary intraosseous squamous cell carcinoma)⁴.

Limitations of this study include possible selection bias as only a subset of subjects elected to undergo imaging, selecting for patients with recent/symptomatic KCOTs. Most of the 41 clinical trial subjects reported previous surgical treatment for KCOTs. We studied only patients with BCNS, thus limiting the generalizability of the results to syndrome-related KCOTs. However, since 30% of sporadic KCOTs harbor PTCH1 mutation⁴, vismodegib could be effective for a significant percentage of sporadic tumors. In addition, analysis of KCOT tissue to assess for PTCH1 mutations could explain some of the variability in response. Strengths include the availability of pre and post-treatment MRI images for KCOT size analysis, as well as the largest number to date of patients with KCOTs treated with vismodegib. We chose to image with MRI instead of dental radiographs in order to improve KCOT measurement and to avoid exposure to ionizing radiation, which can induce BCCs in BCNS patients¹⁵.

In conclusion, our findings confirm functional involvement of the HH pathway in KCOTs and illustrate the usefulness of treatment with molecularly targeted drugs like vismodegib. This is particularly important for patients with multiple KCOTs, who can be left with facial disfigurement and speech impediment following multiple surgical procedures ³. Vismodegib offers a non-surgical treatment option, potentially revolutionizing management of KCOTs in BCNS. It is difficult to predict which patients develop KCOTs due to variable expression in BCNS; however, MRI may be used for screening during the initial diagnostic work-up and for those with jaw symptoms. Further studies into optimal maintenance regimes of vismodegib for KCOT treatment are required. An ongoing clinical trial (NCT01556009) assessing its use as maintenance therapy for BCCs may yield more information.