BG12 A case of severe gastrointestinal bleeding while on vismodegib therapy

Abstract

We report the case of a 50-year-old woman, with a history of Gorlin syndrome on vismodegib therapy, who presented with two episodes of upper gastrointestinal bleeding (UGIB) in the absence of other risk factors. Gorlin syndrome is a rare disorder characterized by multiple basal cell carcinomas (BCCs) secondary to a mutation in PTCH1. Mutations in PTCH1 lead to dysregulation of the hedgehog signalling pathway and subsequent abnormal proliferation. Vismodegib is a systemic hedgehog inhibitor that has been shown to be effective in treating advanced BCCs and Gorlin syndrome. Our patient acquired multiple BCCs which excision, photodynamic therapy and topical chemotherapy agents failed to control. Therefore, a decision to commence vismodegib was made. During treatment with vismodegib, she had a perforated gastrointestinal ulcer and required an emergency laparotomy. Vismodegib was stopped, but over the next few years, her BCCs progressed again to an excess of 50 BCCs, including large plaques of carcinoma measuring up to 12 cm in diameter. Vismodegib was restarted with a high-dose proton–pump inhibitor cover, as recommended by the gastroenterology team, and her BCCs were largely resolved. However, a second bleed occurred approximately 1 year after restarting treatment. Gastroscopies undertaken following these episodes were largely normal, showing mild, nonerosive duodenitis only, and Helicobacter pylori testing was negative. Given the lack of pre-existing risk factors and temporal relation to vismodegib therapy, the decision was made to suspend the drug. To our knowledge, this is the first case reported in the literature of UGIB associated with vismodegib. A separate case has reported colonic mucosal changes in a patient with chronic diarrhoea on vismodegib. The hedgehog protein and RNA expression have been found to be present in the gastrointestinal endothelium and mesenchyme. Evidence suggests the hedgehog pathway activation in gastrointestinal lining is involved in the wound-healing response, endothelial turnover and activation of mesenchymal immune responses. Therefore, inhibition of the hedgehog pathway via vismodegib could potentially impair the essential maintenance of the gastrointestinal endothelium. We postulate that this mechanism could have led to the presentation in our patient, through endothelial damage exposure of vessels leading to gastrointestinal bleeding. Treatment options for BCC in our patient are now limited. Vismodegib is one of the few therapies that has been shown to induce remission of symptoms and reduce disease burden. We present this case to raise awareness of this potential adverse event.