Trametinib in Patients With NF1-, GNAQ-, or GNA11-Mutant Tumors: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocols S1 and S2.

PURPOSE: NCI-MATCH is a precision medicine trial using genomic testing to allocate patients with advanced malignancies to targeted treatment subprotocols. This report combines two subprotocols evaluating trametinib, a MEK1/2 inhibitor, in patients with Neurofibromatosis 1 (NF1[S1] or GNA11/Q [S2]) altered tumors. METHODS: Eligible patients had tumors with deleterious inactivating NF1 or GNA11/Q mutations by the customized Oncomine AmpliSeq panel. Prior MEK inhibitor treatment was excluded. Glioblastomas (GBMs) were permitted, including malignancies associated with germline NF1 mutations (S1 only). Trametinib was administered at 2 mg once daily over 28-day cycles until toxicity or disease progression. Primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS) at 6 months, PFS, and overall survival. Exploratory analyses included co-occurring genomic alterations and PTEN loss. RESULTS: Fifty patients were eligible and started therapy: 46 with NF1 mutations (S1) and four with GNA11 mutations (S2). In the NF1 cohort, nonsense single-nucleotide variants were identified in 29 and frameshift deletions in 17 tumors. All in S2 had nonuveal melanoma and GNA11 Q209L variant. Two partial responses (PR) were noted in S1, one patient each with advanced lung cancer and GBM for an ORR of 4.3% (90% CI, 0.8 to 13.1). One patient with melanoma in S2 had a PR (ORR, 25%; 90% CI, 1.3 to 75.1). Prolonged stable disease (SD) was also noted in five patients (four in S1 and one in S2) with additional rare histologies. Adverse events were as previously described with trametinib. Comutations in TP53 and PIK3CA were common. CONCLUSION: Although these subprotocols did not meet the primary end point for ORR, significant responses or prolonged SD noted in some disease subtypes warrants further investigation.

Safety and Efficacy of Mek Inhibitors in the Treatment of Plexiform Neurofibromas: A Retrospective Study.

INTRODUCTION: Plexiform neurofibromas (PN) represent the main cause of morbidity in patients affected by Neurofibromatosis Type 1 (NF1). Until recently, surgery has been the main treatment option in these patients, but it is burdened with a low efficacy rate and a high incidence of side effects as well as recurrence. In recent years, MEK inhibitors (MEKi) such as selumetinib and trametinib have shown great promise. METHODS: We retrospectively describe a single center cohort of NF1 patients affected by PN1 and treated with MEKi since 2019 to 2021. Patients recruited in the study were affected by PN that were not eligible to complete surgical excision, symptomatic or with major cosmetic deformation or functional neurological deficits. RESULTS: Most patients experienced improvement in clinical symptoms and quality of life, with reduction or stabilization of lesions. However, no complete response was achieved. The most common adverse effects involved the skin, affecting every patient. Importantly, no life-threatening adverse effects occurred. CONCLUSIONS: In our experience, MEKi treatment has been shown to be both safe and effective in improving symptomatology and quality of life.

Do hormonal contraceptives stimulate growth of neurofibromas? A survey on 59 NF1 patients.

BACKGROUND: Neurofibromas are benign tumors of the peripheral nerves and hallmark of neurofibromatosis type 1 (NF1), a tumor suppressor gene syndrome. Neurofibromas mostly start developing at puberty and can increase in size and number during pregnancy. Expression of progesterone receptors has been found in 75% of the tumors. Many female NF1 patients are thus concerned about the possibility that hormonal contraceptives may stimulate the growth of their neurofibromas. METHODS: A survey was carried out on 59 female NF1 patients who are practicing or have practiced hormonal contraception to examine the effect of the various contraceptives on the growth of neurofibromas. RESULTS: Majority (53 out of 58) of patients who received oral estrogen-progestogen or pure progestogen preparations reported no associated tumor growth. In contrast, significant tumor growth was reported by two patients who received depot contraceptive containing high dose of synthetic progesterone. CONCLUSIONS: Oral contraceptives do not seem to stimulate the growth of neurofibromas in NF1 patients. High doses of progesterone might stimulate the growth of neurofibromas and deserve more caution.

Early lesion of N-nitroso-N-ethylurea-induced hamster neurofibromatosis model.

To investigate histogenesis of neurofibroma, early lesions of N-nitroso-N-ethylurea-induced neurofibroma of Syrian golden hamsters were examined. The lesions were detectable from 8 weeks of age, and a total of 14 lesions in 9 hamsters from 8 to 12 weeks of age were observed. Most of the lesions were found in the skin; they were also observed in the trigeminal nerve, cervical plexus, and abdominal sympathetic ganglion. Histological examination revealed there were two types of early lesions such as solitary and plexiform types. The former developed in the s.c. or dermal part of the skin and showed invasive growth of the surrounding tissue, while the latter originated from the large nerves such as the trigeminal nerve or cervical plexus. Growth kinetics of the early lesions was quantitated by continuous administration of bromodeoxyuridine and double immunostaining. Using these systems we observed that various kinds of cells had already participated in early lesions and later Schwann cells became a main component of the tumor. The histogenesis of neurofibroma was considered to be complexed by proliferation of several kinds of cell types at the early stage.

Transplacental induction of peripheral nervous tumor in the Syrian golden hamster by N-nitroso-N-ethylurea. A new animal model for von Recklinghausen's neurofibromatosis.

Multiple peripheral nervous tumors were induced in 45 of 60 (75.0%) Syrian golden hamsters by transplacental administration of N-ethyl-N-nitro-sourea. Moreover, melanomas, pheochromocytomas, and Wilms' tumors developed in six (10.0%), three (5.0%), and 13 (21.7%) animals, respectively. The histologic, immunohistochemical, and electron microscopic findings of the peripheral nervous tumors were similar to those of human neurofibroma, and their growth pattern and distribution resembled those of human von Recklinghausen's neurofibromatosis (VRNF). The occurrence of melanoma, pheochromocytoma, and proliferative foci of melanin-containing cells in neurofibroma suggests that the targets of ENU in hamsters are the neural crest-derived cells. With its high incidence of Wilms' tumor, the hamster with ENU-induced tumors is considered to be a good animal model for human neurocristopathy, including VRNF.

Experimental model of tumors associated with neurofibromatosis.

Four groups of animals, each composed of 22 pregnant Wistar rats, were used in this study. Single intraperitoneal (IP) injections of ethylnitrosourea (ENU) at a dose of 15 mg/kg body weight (BW) were given to the animals of two groups on days 15 and 21 of pregnancy, respectively. The progeny of a third group received by subcutaneous injection (SC) the same dose of ENU, 15 mg/kg BW, on day 1 postnatally. The descendants of the fourth group served as untreated controls. The most striking findings were observed in the progeny of the mothers treated on day 15 of pregnancy, in which group 64 of 180 descendants developed peripheral nervous system (PNS) tumors, 30% of which had plexiform pattern. One hundred fifteen of the 180 descendants developed central nervous system (CNS) gliomas, mainly oligodendrogliomas, and five animals presented with Wilms' tumors. No tumors of these types were observed in the untreated controls. Although descendants of mothers treated on day 21 of pregnancy had the highest number of PNS tumors (130 of 172 animals), only 21% of these tumors were plexiform; CNS gliomas were observed in 78 animals and Wilm's tumors in one animal. The lowest percentage of PNS tumors with plexiform pattern (16%) was found in the group of 157 descendants treated postnatally on day 1, in which 88 animals developed PNS tumors, 76 developed CNS gliomas, and no animals developed Wilms' tumors. The higher percentage of plexiform PNS tumors found in the descendants treated prenatally on day 15 of pregnancy was statistically significant (P less than 0.05) when compared with the percentage found in the group treated postnatally. This significance was also valid for the plexiform tumors that developed selectively from branches of the trigeminal nerves (of the PNS tumors from this location, 48% showed a plexiform pattern), but only in the progeny exposed to ENU on day 15 of pregnancy. This same progeny also had the highest numbers of CNS and Wilms' tumors. Because in humans, plexiform neurofibromas are considered to be the neoplastic markers of neurofibromatosis, and CNS gliomas as well as Wilms' tumors are associated with this disease, it is suggested that exposure to ENU on day 15 of pregnancy, under the experimental conditions described here, may offer a model for investigating tumors associated with neurofibromatosis, as well as aspects of the spontaneous, noninherited forms of this disease.

Nerve growth factor modification of the ethylnitrosourea model for multiple schwannomas.

The administration of ethylnitrosourea (ENU) to pregnant rats late in gestation or to neonatal rats results in the induction of Schwann cell tumors in a high percentage of perinatally exposed animals. Exogenous administration of nerve growth factor (NGF) significantly reduces the number of Schwann cell tumors and other neurogenic tumors developing in ENU-treated rats. Administration of antibodies directed against NGF prior to neonatal ENU exposure results in a substantial increase in the incidence of Schwann cell tumors, particularly in the trigeminal nerves of both rats and mice. Transplacental ENU treatment causes early neoplastic proliferation (ENP) at 90 days of age in the Schwann cell population of trigeminal nerves in nearly all exposed rats. A variety of NGF treatment protocols (single or multiple inoculations or microinfusion prior to or following ENU exposure) resulted in a significant reduction in ENU-induced ENP in trigeminal nerves. These results indicate that NGF may convey protection either directly or indirectly, by an unknown mechanism, to Schwann cells and other supportive neural cells by reducing their sensitivity to ENU-induced neoplastic transformation.