PROPOSAL TITLE 

The UCSF Meningioma Program tumor board and multidisciplinary clinic

PROJECT LEADS

David R. Raleigh, MD, PhD, Associate Professor of Radiation Oncology, Neurological Surgery, Pathology

Nancy Ann Oberheim Bush, MD, PhD, Associate Professor of Neurology, Neuro-Oncology, Neurological Surgery

Jennifer Viner, DNP, ANP-BC, CNRN, Nurse Practitioner of Neurological Surgery and Neuro-Oncology

EXECUTIVE SPONSORS

Alan Ashworth, PhD, FRS, Professor and President of the UCSF Comprehensive Cancer Center

Edward Chang, MD, Professor and Chair of Neurological Surgery

Mitchel S. Berger, MD, Professor of Neurological Surgery and Director of the UCSF Brain Tumor Center

John de Groot, MD, Professor of Neurology and Director of Neuro-Oncology

Catherine Park, MD, Professor and Chair of Radiation Oncology

Susan Chang, MD, Professor of Neuro-Oncology

Arie Perry, MD, Professor of Pathology and Director of Neuropathology

ABSTRACT. Meningiomas are the most common primary intracranial tumors. It is estimated that that 40,000 meningiomas are diagnosed in the United States each year, and that 1% of humans will develop a meningioma in their lifetime. Nevertheless, there are no comprehensive meningioma programs in any medical centers. The objective of this proposal is to develop a comprehensive meningioma program organized around principles of clinical excellence, scientific discovery, multidisciplinary collaboration, and education. To do so, we will use translational science as an engine for clinical trials and patient recruitment to cement UCSF as the physical hub of the nation’s first meningioma program. We have a successful track record of meningioma investigation and treatment that we are poised to amplify through institutional support. Our portfolio of discoveries and innovations include predictive biomarkers and prospective registries that are already changing the standard of care for patients with meningiomas, and new small molecule, biologic, and theranostic treatments that we are testing in clinical trials. We hypothesize that development of (1) a meningioma tumor board and (2) a multidisciplinary clinic will refine postoperative treatment and imaging surveillance paradigms for patients with meningiomas, thereby reducing variation in practice and inequity, improving outcomes, reducing costs, and enriching revenue.

TEAM

Javier E. Villanueva-Meyer, MD, Associate Professor of Radiology (Neuro-Radiology)

Ramin Morshed, MD, Assistant Professor of Neurological Surgery

W. Patrick Devine, MD, PhD, Assistant Professor of Pathology and UCSF Clinical Cancer Genomics Laboratory

Kanish Mirchia, MD, Clinical Instructor of Pathology and UCSF Clinical Cancer Genomics Laboratory

William C. Chen, MD, Clinical Instructor of Radiation Oncology

Charlotte Huie, MSN, Nurse Practitioner of Neuro-Oncology and Neurological Surgery

Isha Sethi, BS, Clinical Research Coordinator of Radiation Oncology and Neurological Surgery

PROBLEM. Meningiomas comprise 40.5% of primary intracranial tumors and are the only brain tumors that are more common in women, Black, and elderly patients, who are underrepresented in brain tumor clinical trials^1,2. Meningioma treatments are largely restricted to surgery and radiotherapy, whereas systemic therapies remain ineffective or experimental^3,4. Historically, the World Health Organization (WHO) has graded meningiomas according to histological features such as mitotic count⁵. Most WHO grade 1 meningiomas can be effectively treated with surgery or radiotherapy, but many grade 2 or 3 meningiomas are resistant to treatment and cause significant neurological morbidity and mortality³. Moreover, some WHO grade 1 meningiomas develop recurrences that cannot be predicted from histological features, and some WHO grade 2 or grade 3 meningiomas are unexpectedly well controlled with surgery and radiotherapy. In recognition of the controversies surrounding meningioma risk stratification and treatment, the NRG BN-003 and EORTC 1308 Phase III clinical trials currently randomize patients with primary WHO grade 2 meningiomas to postoperative surveillance or postoperative radiotherapy after gross total resection⁶. The only multicenter prospective studies of meningiomas that have reported data are RTOG 0539 and EORTC 22042, and these Phase II clinical trials provide safety and non-randomized radiotherapy outcome data based on clinical criteria that do not predict radiotherapy responses in most retrospective series^7–10. Thus, there are urgent, unmet needs for improved risk stratification, development of medical therapies, and prediction of postoperative radiotherapy responses for patients with meningiomas.

In 2021, the WHO revised meningioma grading criteria to incorporate rare DNA mutations alongside traditional histological features¹¹. The WHO 2021 update reflects a growing understanding of the molecular landscape of meningiomas from diverse bioinformatic studies. DNA sequencing^12–15, copy number variant (CNV) analyses^16–18, RNA sequencing^19,20, or DNA methylation profiling^21–24 have been used to classify meningiomas based on recurring somatic short variants^12–15, chromosome gains or losses^16–18, differentially expressed genes^19,20, or DNA methylation probes²³, families²⁴, groups²², or subgroups²¹. Integrated systems have been proposed based on (1) CNVs, CDKN2A/B status, and histological features¹⁶, (2) CNVs, DNA methylation families, and histological features¹⁷, or (3) CNVs, DNA methylation profiling, RNA sequencing, and DNA sequencing which reveal biological groups and subgroups of meningiomas that are concordant with results from DNA methylation profiling or RNA sequencing alone^18,21,22. Clinical implementation of these complex biomarkers requires multidisciplinary discussion and consensus recommendations, barriers that we propose to overcome in this project through the development of (1) a specialized tumor board and (2) a multidisciplinary clinic that will refine postoperative treatment and imaging surveillance paradigms for patients with meningiomas at UCSF.

Over the past 6 years, we have used federal and philanthropic support to discover biological drivers, new targets, predictive biomarkers, and imaging features that provide a framework for redefining clinical paradigms for meningiomas (Vasudevan et al. Cell Reports 2018, Magill and Vasudevan et al. Nat Commun 2020, Choudhury et al. Nat Genet 2022, Chen et al. Nat Med 2023, Lucas et al. Nat Genet 2024). Our scientific discoveries in meningioma biology are permeating WHO and National Comprehensive Cancer Network (NCCN) guidelines and have inspired investigator-initiated and cooperative group trials (NCT04659811, NRG-BN2222). Students, residents, postdocs, and fellows are now specializing in meningioma investigation at UCSF, and patients with meningiomas are increasingly traveling to UCSF for specialized care. Nevertheless, UCSF lacks a multidisciplinary meningioma program to coordinate care across providers and departments and provide access to survivorship programs, such as is routinely available for most other tumor types. We have developed the necessary expertise and personnel to address this problem, and we have implemented prospective registries and clinical trials that we will use as catalysts for self-sustaining clinical, translational, and basic science research. 

TARGET (SMARTIE)

1. Specific: We will implement a bi-monthly meningioma tumor board that will be staffed by physicians from Radiation Oncology (Raleigh, Chen), Neuro-Oncology (Oberheim Bush), Neurological Surgery (Morshed), Neuro-Radiology (Villanueva-Meyer), and Neuropathology (Mirchia). The tumor board will meet in person from 9:30-10:30 am on Thursdays at the UCSF Parnassus Medical Center in room M380. A telehealth option will be available for providers who may intermittently be at other UCSF campuses. Biomarker and clinical data will be reviewed (anticipated 12 cases/meeting), and consensus recommendations will be conveyed through written and verbal communication from our project team to referring providers and patients. Bi-monthly multidisciplinary clinics on alternating Thursdays staffed by physicians from Radiation Oncology (Raleigh, Chen), Neuro-Oncology (Oberheim Bush), and Neurological Surgery (Morshed) will provide patient consultation, treatment, follow-up, imaging surveillance, and survivorship and caregiver support. 
2. Measurable: The primary endpoint will be refinement of postoperative treatment and imaging interval recommendations based on consideration of meningioma biomarkers alongside traditional clinical criteria. As described in the Return on Investment section, we anticipate refining recommendations for approximately 30% of patients (Chen et al. Nat Med 2023). Tumor board recommendations before and after consideration of meningioma biomarkers will be recorded by the Clinical Research Coordinator who is assigned to this project (Sethi). The secondary endpoints will be patient enrollment on clinical trials (NCT04659811, NRG-BN2222), patient referral to the UCSF Brain Tumor Center Supportive Care Services program, and patient enrollment on 2 prospective registries that we have created to more broadly track the success of our program and develop the next generation of predictive biomarkers and treatments for meningiomas. The first is the BEAM program (Biomarker Evaluation for All Meningiomas), a prospective registry that is assembling multidisciplinary clinical and molecular data for all patients with meningiomas who are evaluated at UCSF. The BEAM program allows us to incorporate new investigations of blood and cerebrospinal fluid alongside our well-established workflows for tumor tissue. The second prospective registry is the Living with Meningioma program, a once-yearly survey that is compatible with handheld and standard computing devices and is being used to track patient-reported survivorship in collaboration with the Eureka Research Platform through the UCSF Department of Epidemiology and Biostatistics.
3. Achievable: In terms of identifiable intermediate actions and milestones, we have identified two nurse practitioners who will support inpatient (Viner) and outpatient (Huie) meningioma care at UCSF. Both are experts in neuro-oncology paradigms, and both will participate in tumor boards, multidisciplinary clinics, and inpatient postoperative consultations to recruit and retain patients in the UCSF Meningioma Program. Both nurse practitioners and Dr. Bush from Neuro-Oncology have access to the broad range of supportive care services that span caregiver and survivor resources and education, including a cognitive health clinic. 
4. Relevant: All necessary medical staff, knowledge, and time are available for successful completion of the primary endpoint of this proposal, including the infrastructure that is required for meningioma biomarker evaluation, as described below in the Proposed EHR Modifications section. We request funding for SRA and CRC salary, and for online and print materials, to support and publicize this program. 
5. Timebound: We will initiate tumor board meetings and multidisciplinary clinics in July 2024. We will review our progress toward primary and secondary endpoints during once-monthly virtual meetings between the project leaders, team members, and executive sponsors on the third Friday of each month from 12-1 pm. 
6. Inclusive: Our tumor board and multidisciplinary clinic will be open to all medical professionals who are interested and able to dedicate their time and expertise to improving treatments for patients with meningiomas. Although we have assembled a team of physicians, nurse practitioners, and staff who will be essential for the success of this program, our long-term goals are to increase awareness of meningioma and drive patient volume at UCSF. To achieve these goals, we must be inclusive in our activities and decision making in a way that shares power, and we will organize yearly conferences to publicize our efforts. We will also organize meningioma support groups that will be made available to patients and caregivers. 
7. Equitable: In contrast to many other intracranial tumors, patients with meningiomas often have a protracted disease course, long lifespan, and are from demographics that face barriers to healthcare access. There has been a lack of attention and focus on meningioma survivorship in the brain tumor community, and the rates of returning to work after craniotomy and cranial radiotherapy are abysmal. We will use the Living with Meningioma program to ensure our efforts are responsive to patient- and caregiver-reported experiences, broadly generalizable, and enhance meningioma survivorship. More broadly, we will use this app to publicize and  leverage cognitive rehabilitation services focused on work accommodation and return to work efforts. 

GAPS. Limited understanding of meningioma biology and the misconception that all meningiomas are “benign” has encumbered medical and scientific advances for patients. Despite these misconceptions, meningioma recurrence is the leading cause of death in patients with meningiomas that are resistant to standard interventions²⁵. We will establish UCSF as the global destination for meningioma patients and the premier center to train the next generation of leaders in meningioma treatment and investigation. Using translational science as an engine for clinical trials that incorporate predictive biomarkers, novel medical therapies, and patient- and caregiver-reported outcomes, this program will further distinguish UCSF from other regional medical centers and increase our market share of patients with the most common primary intracranial tumor. In doing so, we will minimize loss-to-follow for the at-risk patient population who is most likely to develop meningioma. No comprehensive meningioma programs exist at any other medical centers, but the scientific and clinical expertise necessary to develop this program are present at UCSF.

INTERVENTION. We hypothesize that development of (1) a meningioma tumor board and (2) a multidisciplinary meningioma clinic will refine postoperative treatment and imaging surveillance paradigms for patients with meningiomas at UCSF, thereby reducing variation in practice and inequity, improving patient outcomes, reducing costs, and enriching revenue to the healthcare system. We will integrate predictive biomarkers for meningioma outcomes (Choudhury et al. Nat Genet 2022, Chen et al. Nat Med 2023, see supporting files) with traditional clinical criteria to offer the highest level of multidisciplinary care to all patients regardless of barriers to healthcare access. This is a collaborative project between the UCSF Comprehensive Cancer Center, the UCSF Clinical Cancer Genomics Laboratory, the UCSF Departments of Neurological Surgery, Radiation Oncology, Radiology, and Pathology, and the UCSF Division of Neuro-Oncology. The multidisciplinary team we have assembled for this proposal is comprised of existing UCSF faculty and staff with expertise and interest in meningioma treatment and investigation. To overcome potential barriers to implementation, we have recruited a multidisciplinary team of executive sponsorswho are responsible for implementing and overseeing meningioma investigation and treatment. We do not anticipate adverse outcomes to reducing variation of practice, but to ensure a culture of continuous improvement we will discuss patient- and provider-reported concerns during meetings between project leaders, team members, and executive sponsors on the third Friday of each month from 12-1 pm.

PROPOSED EHR MODIFICATIONS. As part of routine clinical practice at UCSF, all meningiomas undergo reflexive genomic testing with the UCSF500 next-generation targeted DNA sequencing assay for detection of short somatic variants and CNVs, and RNA sequencing for gene fusion detection and gene expression profiling (Chen et al. Nat Med 2023, see supporting files). Members of our team (Devine, Mirchia) are also members of the UCSF Clinical Cancer Genomics Laboratory (CCGL) where these tests are performed, and the CCGL will soon offer DNA methylation profiling (Choudhury et al. Nat Genet 2022, see supporting files). Thus, we will use pre-existing workflows to populate our tumor board and multidisciplinary clinic with patients whose meningiomas have completed genomic analyses. These workflows will allow us to identify patients (1) who may benefit from individualized postoperative surveillance, radiotherapy, or medical therapy, (2) who may be candidates for enrollment in the prospective BEAM registry or the prospective Living with Meningioma program, or (3) who may benefit from support through Neuro-Oncology (https://braintumorcenter.ucsf.edu/supportive-care). As part of this process, we request development of a meningioma order set through Apex that will be comprised of referrals to neurological surgery, neuro-oncology, radiation oncology, integrative medicine, social work, and brain imaging. 

RETURN ON INVESTMENT (ROI). By implementing biomarkers that predict meningioma responses to radiotherapy (Chen et al. Nat Med 2023) or to medical therapy (Choudhury et al. Nat Genet 2022) in our tumor board and multidisciplinary clinic (stating July 2024), this project will enhance revenue into the health care system and reduce costs without transferring those costs onto patients or insurers. We showed that predictive biomarkers can be used to refine postoperative management for approximately 30% of patients with meningiomas (Chen et al. Nat Med 2023), including identification of clinically low-risk but molecularly high-risk meningiomas that benefit from early postoperative radiotherapy (19.7%) and identification of clinically high-risk but molecularly low-risk meningiomas where radiotherapy may be safely omitted in favor of imaging surveillance (10.1%). By refining postoperative management recommendations and reducing variation in practice, we will (1) improve patient outcomes through early identification of meningiomas that benefit the most from postoperative radiotherapy, and (2) reduce costs by sparing patients with molecularly low-risk tumors from unnecessary postoperative radiotherapy and frequent imaging surveillance. The cost of meningioma radiotherapy ranges from $50,000 to $250,000 per patient. Over the last 10 years, an average of 142 meningioma resections/year (range: 118-155) and 102 meningioma radiotherapy treatments/year (range: 83-117) were performed at UCSF. By refining postoperative radiotherapy recommendations for 29.8% of 102 patients (~30 patients, net anticipated increase in radiotherapy for 10 patients), we anticipate the ROI for FY2025 of this project will be at least $500,000-$2,500,000 (by July 2025), not accounting for reduced healthcare costs by reducing toxicity in patients where postoperative radiotherapy may be omitted. These ROI calculations also do not include additional anticipated benefits from refined surveillance imaging (with fewer MRIs for patients with molecularly low-risk tumors, which cost $1100/MRI), removal of equity gaps for the underrepresented patient population that is most likely to develop meningiomas, increased meningioma patient volume at UCSF, and the benefit of experimental therapies that we are currently testing in clinical trials. Most importantly, this wholistic and comprehensive program will enhance the quality of life of patients. 

SUSTAINABILITY. Our team has a successful track record of R01 and philanthropic support for meningioma research (Raleigh) and contains leaders in the UCSF Comprehensive Cancer Center (Ashworth), Neurological Surgery (E. Chang, Berger), Radiation Oncology (Park), Neuro-Oncology (de Groot, S. Chang), and Neuropathology (Perry). Thus, the process owners who are responsible for implementing and overseeing meningioma treatment at UCSF are already committed to the success of this program, and we have initiated discussions to budget operational funds to continue this program beyond FY2025. Moreover, multiple federal grants to support this program have already been written and submitted, and more will be written and submitted over the course of FY2025 (Raleigh, Oberheim Bush, Villaneuva-Meyer, Morshed, Devine, Chen, Mirchia). Most recently, a P01 entitled Imaging and genomic signatures of brain tumor heterogeneity and evolution to optimize patient management that incorporates meningioma investigation in 3 of 4 projects received a fundable score and a NOA is anticipated in May 2024 (S. Chang, Raleigh, Oberheim Bush, Villaneuva-Meyer, Chen, Mirchia). 

BUDGET (Total $50,000)

Website and social media promotion of the UCSF Meningioma Program and associated trials/registries  $2,000

Patient brochure development to outline the UCSF Meningioma Program and tumor board/clinic             $5,000

SRA salary support for increased meningioma genomic testing in the UCSF CCGL                                 $18,000

CRC salary support for patient enrollment on trials/registries and database development/maintenance  $25,000

REFERENCES

See supporting files