Exploring precision medicine in primary brain tumors asco annual meeting antiemetic drugs side effects

The Education Session “Precision Medicine for Primary Central Nervous System Tumors: Are We There Yet?” on June 2* will highlight the novel, clinically actionable mutations that have been identified in gliomas, craniopharyngiomas, and meningiomas.

During the session, presenters will “summarize recent advances in our understanding of the molecular landscape of gliomas, craniopharyngiomas, and meningiomas and will discuss the diagnostic and therapeutic implications of these findings,” session Chair Priscilla Kaliopi Brastianos, MD, of Massachusetts General Hospital and Harvard Medical School, said. “We hope this will be an enriching talk for trainees, physicians, and allied health professionals who have an interest in primary brain tumors.

“The progress in primary brain tumors is exciting,” Dr.

Brastianos said. The identification of these mutations “has truly opened up new potential treatment options for patients. Based on these findings, the efficacy of new targeted agents is currently being investigated in clinical trials and, if successful, may change treatment paradigms in these tumors,” she said.

Improved sequencing techniques over the past several decades have resulted in an increased understanding of the cancer genome. The discovery of genetic driver mutations in brain tumors has subsequently been integrated into the diagnostic process and has led to implementation of targeted treatment strategies in affected patients by directing them to clinical trials. These targeted therapies can block the growth and spread of cancer by interfering with specific molecules involved in the growth, progression, and spread of cancer.

In low-grade gliomas, MGMT-promoter methylation status, IDH-mutation status, upregulation of the PI3K/AKT/mTOR-pathway, and BRAF mutations have shifted the focus of treatment toward agents that target these associated alterations. When the MGMT-promoter methylation status is considered, for example, alkylating and methylating chemotherapy can be considered targeted treatments. Targeting DNA-repair mechanisms using PARP inhibitors and agents that target the IDH-mutant enzyme and gene fusion are promising for treating patients with glioblastoma who have those genetic alterations.

Upregulation of the PI3K/mTOR pathway has been identified as playing a major role in glioblastoma, but it may also be relevant in lower-grade gliomas, according to the presenters. The discovery of IDH mutations as a key driver for a subset of gliomas has drastically altered the understanding of gliomas. After the IDH mutations were discovered in gliomas, frequent IDH mutations were identified in several other tumor types, including acute myeloid leukemia, cholangiocarcinoma, and certain sarcomas.

The presentations will look at the pathogenic role of IDH mutations, which were discovered more than a decade ago. Even though clinical progress has been disappointing, inhibitors of the IDHmt protein remain promising and warrant further study. Craniopharyngiomas and Precision Medicine

Craniopharyngiomas comprise 1% to 3% of all brain tumors in the United States. 1 These locally aggressive, low-grade epithelial neoplasms start in the suprasellar region of the brain and can result in devastating symptoms in affected patients. Not only is intervention challenging, but the clinical management of patients can be impeded by the lack of standardized clinical practice guidelines and effective systemic therapies. Speakers during the Education Session will review recent research that has identified highly recurrent driver mutations of craniopharyngiomas and the implications of this research for targeted therapy.

Promising response rates have been noted with BRAF-inhibitor therapy in patients with BRAF V600E–mutant melanomas, gangliogliomas, pleomorphic xanthoastrocytomas, and hairy cell leukemias. Because of the success in those patients, patients with papillary craniopharyngiomas may benefit from these treatment options and can be enrolled in clinical trials, according to Dr. Brastianos. Presenters will outline the “spectacular results” that have already been achieved in several published case reports, she said. Case reports 2,3 have found similar successful response rates in patients with papillary craniopharyngiomas who were treated with a combination of BRAF and MEK inhibitors, Dr. Brastianos said.

A phase II clinical trial (NCT03224767), led by Dr. Brastianos, is investigating the role of dual BRAF and MEK inhibition in patients with newly diagnosed and recurrent papillary craniopharyngiomas. Patients in the trial will be treated with vemurafenib and cobimetinib. The trial will also analyze papillary craniopharyngioma tissue pre- and post-treatment with whole-exome and RNA sequencing to identify genetic alterations that may evolve during treatment. That analysis will hopefully help refine therapeutic strategies, she explained. Meningiomas and Targeted Therapy

Most meningiomas have been treated with surgical resection, but the treatment can be challenging and is associated with high morbidity in some anatomical locations. Not all patients can be successfully treated with surgical resection alone, and the recurrence rate after 5 years can range up to 95% for World Health Organization grade 3 disease. 4,5 Systemic therapies in recurrent grade 2-3 meningiomas in recent years have led to disappointing results, Dr. Brastianos said.

Presentations will review the latest research in whole-genome and whole-exome sequencing in meningioma tissue samples. This research has found relatively simple genomes with fewer copy number alterations, translocations/rearrangements, and mutations than are usually observed in other tumors in adult patients.

A phase II trial (NCT02523014), also led by Dr. Brastianos, is analyzing the activity of SMO, AKT, and NF2 inhibitors in recurrent or progressive meningiomas that have the SMO, AKT, or NF2 mutation. Other driver mutations have also been described.

Other research has suggested that there may be a role for immunotherapy in grade 1-3 meningiomas, as PD-L1 expression was found to be increased in anaplastic meningiomas. The mechanisms that have been identified may contribute to an immunosuppressive microenvironment and to aggressive phenotype of this tumor subtype. 6 A phase II trial (NCT03279692) is now recruiting patients to look at the role of pembrolizumab in recurrent or residual high-grade meningiomas, she said.