Nevoid Basal Cell Carcinoma Syndrome: Report from the Zurich Nevoid Basal Cell Carcinoma Syndrome Cohort.

BACKGROUND: Nevoid basal cell carcinoma syndrome (NBCCS, Gorlin-Goltz syndrome) presents various symptoms and can disfigure patients. The estimated prevalence is around 1:100,000. OBJECTIVE: To systematically investigate the clinical manifestations of NBCCS patients of the Zurich register and compare them with those described in 4 epidemiological studies performed in other countries. METHODS: We analyzed patient characteristics and clinical manifestations in a register of 30 NBCCS patients in Zurich, Switzerland. We compared our findings to the results of 4 epidemiological studies performed in America, Australia, Japan and the UK. RESULTS: We obtained information concerning basal cell carcinomas (BCCs) and jaw cysts from 28 patients out of our population of 30 NBCCS patients. The mean age at onset of the first BCC was 24 years, and the mean age at diagnosis of the first jaw cyst was 15.6 years. The average number of jaw cysts was 8.4; the average number of BCCs was 207. 72.5% of the examined BCCs showed a nodular histology, but we also found scirrhous and superficial types. CONCLUSION: The disease burden associated with NBCCS diagnosed in Swiss patients is significant and comparable to that of other countries. Regular skin examination and oromaxillary examinations should be performed early in diagnosis, and patients should undergo early UV protection. Nodular BCC is the most common BCC subtype in this patient population.

Hedgehog pathway inhibitors promote adaptive immune responses in basal cell carcinoma.

PURPOSE: Basal cell carcinomas (BCCs) are tumors ignored by immune surveillance. Activated Hedgehog (Hh) signaling within primary cilia is a key driver in the pathogenesis of BCCs. We examined immune alterations during treatment with systemic Hh inhibitors. EXPERIMENTAL DESIGN: We investigated biopsies from patients with BCC before (23 patients) and after 4 weeks of treatment (5 patients) with Hh signaling inhibitor. Ber-Ep4, BCL-2, Ki-67, CD4, CD8, MHC class I, HLA-DR-class II, and SOX9 were analyzed by immunohistochemistry. Primary cilia were analyzed by double immunofluorescence of acetylated tubulin and SOX9. Differential gene expression for 84 cytokines and chemokines was analyzed in 3 patients. RESULTS: After 4 weeks of treatment, we found reduction of Ki-67, SOX9, Ber-EP4, and BCL-2 expression in tumors associated with morphologic signs of squamous differentiation. In addition, the number of cilia-positive BCC cells was significantly decreased. An upregulation of MHC I expression on the cell membranes of residual tumor cells and an influx of CD4(+), HLA-DR-class II(+), and CD8(+) cells with invasion into the tumor cell nests were found. Finally, qPCR arrays showed the differential expression of genes involved in modulating immune responses. CONCLUSIONS: We show that Hh pathway inhibitor-induced tumor regression is accompanied by a dynamic change of the microenvironment with a disruption of immune privilege involving an influx of cytotoxic T cells, activation of the adaptive immune functions, and a profound alteration of the local chemokine/cytokine network.

Emerging drugs and combination strategies for basal cell carcinoma.

INTRODUCTION: Basal cell carcinoma (BCC) is a malignancy that is driven by an activated Hedgehog (Hh) pathway. Smoothened inhibitors are a new promising treatment option for patients with locally advanced or metastatic BCC or basal cell nevus syndrome. But long-term data are still limited, the optimal treatment duration is not yet defined and there are already documented cases with acquired resistance. AREAS COVERED: Treatment modalities with Hh inhibitors, side effects and potential pharmacological combination options are discussed. The current literature, including PubMed, Cochrane database and registered trials on ClinicalTrials.gov, was searched. EXPERT OPINION: BCCs typically regress during therapy with Hh inhibitors. Muscle toxicity, dysgeusia and hair loss can be considered as on target adverse reactions. Muscle toxicity is the dose-limiting toxicity of sonidegib. It was not seen with vismodegib because of its high binding to plasma protein α-1-acid glycoprotein. Sonidegib is different and shows a clear dose-toxicity relationship, which allows to address the question of whether there is a dose dependency of regression rate, cure rate and progression-free survival. In addition, basic research has offered strategies to enhance efficacy by the combination with other molecules, such as EGFR inhibitors, MEK inhibitors or immunotherapy.

Vemurafenib in patients with BRAF(V600) mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study.

BACKGROUND & AIM: Brain metastases are frequent in patients with metastatic melanoma, indicating poor prognosis. We investigated the BRAF kinase inhibitor vemurafenib in patients with advanced melanoma with symptomatic brain metastases. METHODS: This open-label trial assessed vemurafenib (960mg twice a day) in patients with BRAF(V600) mutation-positive metastatic melanoma with non-resectable, previously treated brain metastases. The primary end-point was safety. Secondary end-points included best overall response rate, and progression-free and overall survival. RESULTS: Twenty-four patients received vemurafenib for a median treatment duration of 3.8 (0.1-11.3) months. The majority of discontinuations were due to disease progression (n=22). Twenty-three of 24 patients reported at least one adverse event (AE). Grade 3 AEs were reported in four (17%; 95% confidence interval [CI], 4.7-37.4%) patients and included cutaneous squamous cell carcinoma in four patients. Median progression-free survival was 3.9 (95% CI, 3.0-5.5) months, and median survival was 5.3 (95% CI, 3.9-6.6) months. An overall partial response (PR) at both intracranial and extracranial sites was achieved in 10 of 24 (42%; 95% CI, 22.1-63.4) evaluable patients, with stable disease in nine (38%; 95% CI, 18.8-59.4) patients. Of 19 patients with measurable intracranial disease, seven (37%) achieved >30% intracranial tumour regression, and three (16%; 95% CI, 3.4-39.6%) achieved a confirmed PR. Other signs of improvement included reduced need for corticosteroids and enhanced performance status. CONCLUSIONS: Vemurafenib can be safely used in patients with advanced symptomatic melanoma that has metastasised to the brain and can result in meaningful tumour regression.

Basal cell carcinoma: a paradigm for targeted therapies.

INTRODUCTION: Basal cell carcinoma (BCC) is the most frequent cancer with increasing incidence over the last decades. Standard of care is surgical excision, upon which complete tumour clearance is achieved in most cases. However, a small subgroup of patients will have remnants of disease post-excision and require further treatment options. Over 90% of all BCCs carry a mutation in PTCH 1 or SMO, two conducting proteins of the Hedgehog pathway (Hh). Therefore, inhibition of the Hh pathway is a promising option for systemic first-line therapy. Vismodegib was the first developed of these small molecules, which was approved by the FDA in January 2012. AREAS COVERED: The authors review current treatment modalities for BCC and discuss current developments in pharmacological therapy. The current literature including meta-analyses, the Cochrane database and registered as well as completed randomized controlled trials. EXPERT OPINION: Hh inhibitors are a new promising treatment option for patients with advanced or metastatic BCC. Phase I and II clinical trials with the Hh inhibitor, vismodegib, showed a significant reduction in tumour size and appearance of new tumours with relatively good tolerability. Nevertheless, further investigation on new molecules and the effectiveness of an intermittent dosing regimen is necessary.