Trial of Temozolomide in BAP1 Mutated Patients With Advanced or Metastatic Cutaneous Melanoma

Cutaneous Melanoma

BAP1, or BRCA1-associated protein 1, is a gene involved in DNA repair via homologous recombination and is considered a tumor suppressor gene. It is lost or inactivated in a large number of tumors, and the presence of germline BAP1 mutations is associated with a syndrome of tumor predisposition. Following our team's observation of two exceptional responses to temozolomide in patients who had reached a therapeutic impasse-one of which lasted 11 months and involved both intracerebral and extracerebral tumors-we hypothesize that this mutation may lead to increased susceptibility to chemotherapy.

Although the therapeutic management of melanoma has undergone a revolution over the past decade with the advent of immune checkpoint inhibitors on the one hand, and BRAF- and MEK-targeted therapies in patients harboring a BRAF V600 mutation on the other hand, half of patients do not achieve a durable response to these strategies. In light of these major advances, chemotherapy has gradually been abandoned, even in patients with limited therapeutic options, because of its very low response rate. BAP1, or BRCA1-associated protein 1, is involved in DNA repair through homologous recombination and is considered a tumor suppressor gene. It is lost or inactivated in a wide range of tumors, and the presence of germline BAP1 mutations is associated with a tumor predisposition syndrome (BAP1 tumor predisposition syndrome, BAP1-TPDS). Following the observation by our team of two exceptional responses, both intracranial and extracranial, lasting more than six months, in two young patients with metastatic melanoma harboring a constitutional BAP1 mutation, treated in the third and eighth lines of therapy, respectively, we hypothesize that this mutation may confer increased susceptibility to chemotherapy, as has been reported in pleural mesothelioma. This increased susceptibility could help guide the therapeutic strategy for affected patients, who account for approximately 1% of cutaneous melanomas in the germline setting and 5-17% of cutaneous melanomas when somatic mutations are considered. As it remains unclear whether this effect is restricted to germline BAP1 mutations, we chose to include both germline and somatic BAP1 mutations in this study. This is particularly relevant because, in routine clinical practice, the germline or somatic nature of a BAP1 mutation is often determined at a later stage. Somatic mutation testing is frequently performed only as part of a molecular biology panel before predictive medicine strategies are considered, guided by molecular tumor boards, in patients with limited therapeutic options. Validation of this hypothesis could make it possible to identify patients who may benefit from this readily available and inexpensive treatment.

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