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ICAR SINONASAL TUMORS

therapy to the forefront of locally advanced and metastatic cutaneous melanoma. 1527–1531 Although BRAF inhibitor therapy has been instrumen tal in improving survival in cutaneous melanoma, similar advances in SNMM have proven to be elusive. Across numerous studies, BRAF mutation rates in SNMM have been 0%–8% of cases. 1476,1496,1520,1532,1533 In light of this, BRAF inhibitor therapy has a limited role in the current treatment of the majority of SNMM patients. In contrast to BRAF mutations, it appears that NRAS mutations are the most identified genetic mutation in SNMM patients in 14%–30% of patients. 123,124,1476,1520,1534 NRAS mutations also stimulate the MAPK pathway by activating MEK followed by ERK , thus mediating cell proliferation. 1534–1536 NRAS mutations may also occur more commonly when the primary tumor is located in the paranasal sinuses compared to the nasal cavity. 124 As opposed to BRAF mutations where specific targeted agents are available, no such specific agent exists for NRAS mutations. However, there are several agents in clinical trials that target downstream NRAS-dependent signaling cascades, most notably MEK. 1534 Several MEK inhibitors have been studied in clinical trials includ ing binimetinib and pimasertib. 1537 Although some early data demonstrated improved survival in NRAS-mutated melanomas compared to standard-of-care chemotherapy regimens, these results were not felt to be clinically sig nificant and MEK inhibitors are not currently approved in NRAS-mutated melanomas. 1538,1539 5 Impact of PD-L1 and immunotherapy Host immune systems have the ability to selectively recog nize and destroy pathogens or unhealthy cells, including cancer cells. Immune checkpoints are present to prevent T-cells from inadvertently destroying healthy cells, as may occur in autoimmune diseases. In select cases, cancer cells can exploit these naturally occurring immune checkpoints to prevent the host immune system from recognizing them and thus triggering them for destruction, often referred to as “immune evasion.” 118 One such immune evasion mechanism that is highly prevalent across several malignancies, includ ing melanoma, involves the programmed death-1 receptor (PD-1) and PD-L1. PD-1 is a receptor that is expressed on the surface of activated cytotoxic T-cells. PD-1 acts as an immune checkpoint by stimulating apoptosis of cytotoxic T-cells and reducing apoptosis of suppressive regulatory T-cells. PD-L1 is the ligand that binds PD-1 and activates it, thus causing downstream immunosup pressive effects. 1540,1541 PD-L1 is also highly expressed in many mucosal melanomas. 1541,1542 PD-L1 expression

Cost

Cost comparison analyses have not been undertaken. Preponderance of benefits over harms.

Benefits–harm assessment

Value

Surgical resection with negative margins is beneficial to improve OS.

judgments

Policy level Recommendation. Intervention Surgical resection is the first-line therapy for

SNMM when resection with negative margins can be achieved; when feasible, endoscopic resection should be considered. In cases of locally advanced or metastatic SNMM, the morbidity of radical surgical resection should be weighed against the poor survivability of this tumor; nonsurgical options may be considered in these cases.

4 Impact of cutaneous melanoma markers and genetic mutations Although UV-light exposure is the most well-known pre disposing factor for cutaneous melanoma, risk factors for SNMM are much less well defined (Table XXIV.D.2). SNMM patients tend to present later in life and do not have a specific sex predilection or association with alco hol or tobacco consumption. 1519,1520 When SNMM tumors have been assessed for genetic mutations, only about 40% of tumors have identifiable recognized mutations. 1476,1520 Moreover, the tumor mutation burden of SNMM is not high compared to other malignancies and is not predictive tumor immunogenicity as measured by lymphocyte and T-cell infiltrate into tumor tissue. 1521 The mitogen-activated protein kinase ( MAPK ) path way is a key component of cutaneous melanoma devel opment. Dysregulation of this pathway occurs due to activation of BRAF or RAS genes, leading to increased cellular proliferation. 1522–1525 In cutaneous melanomas, BRAF mutations are the most identified mutations and are present in 50%–70% of cases. 1525 Thus, in cases of advanced cutaneous melanoma, BRAF inhibitor therapies such as vemurafenib have proven to be viable treatment options. In a landmark phase III clinical trial, patients with pre viously untreated metastatic cutaneous melanoma with BRAF V600E mutations were randomly assigned to receive vemurafenib or standard-of-care chemotherapy (dacar bazine). At 6 months, the OS was 84% in the vemurafenib group and 64% in the dacarbazine group. Vemurafenib was associated with a relative reduction of 63% in risk of death and of 74% in the risk of disease progression ( p < 0.001 for both comparisons). 1526 These data, along with addi tional subsequent studies, have pushed BRAF inhibitor