Shi, Diana D.

Abstract Background IDH-mutant astrocytomas are classified as WHO grade 4 in the presence of conventional high-grade histologic features and/or homozygous CDKN2A/B deletion in the 5th edition of the WHO Classification of Central Nervous System Tumour guidelines. However, work over the past decade has indicated a number of other molecular alterations that warrant consideration as potential prognostic markers. Methods We used univariate Kaplan-Meier and multivariate Cox proportional hazards regression analysis to evaluate the prognostic effects of homozygous CDKN2A/B deletion, CDK4 amplification, CCND2 amplification, PDGFRA amplification/mutation, PIK3R1 mutation, PIK3CA mutation, MYCN amplification, EGFR amplification/mutation, TERT promoter mutation, and grade 4 histologic features in two independent cohorts of WHO grade 2-4 IDH-mutant astrocytoma (n = 840 and n = 367). Results The presence of CDK4 amplification, CCND2 amplification, PDGFRA alteration, PIK3R1 mutation, MYCN amplification, and EGFR alteration were each associated with reduced overall survival compared to WHO grade 2/3 astrocytomas without these molecular features. 17.7% (148/837) of otherwise grade 2/3 astrocytomas had one or more of these molecular criteria, with resulting intermediate clinical outcome in terms of overall survival (median survival of 67.3-82.0 months) compared to grade 2/3 astrocytomas without these molecular features (median survival of 135.0-140.7 months) and grade 4 astrocytomas (median survival of 35.3-45.0 months). Conclusions The presence of CDK4, CCND2, PDGFRA, PIK3R1, MYCN, and EGFR alterations result in an intermediate patient survival in IDH-mutant astrocytoma. Adding these molecular alterations should be considered in future diagnostic classification systems to improve stratification of high-risk patients.

Importance Brain metastases are common in patients with cancer, and radiation is often used for management. Among patients with more than 4 brain metastases, the effects of stereotactic radiation targeting only individual tumors, compared with whole brain radiation with hippocampal avoidance, which radiates both tumors and normal brain, remain unknown. Objective To determine whether stereotactic radiation improves symptom severity and interference with daily functioning, compared with whole brain radiation with hippocampal avoidance. Design, Setting, and Participants Phase 3, open-label, randomized clinical trial conducted at 4 United States–based centers. Eligible patients had 5 to 20 brain metastases and no prior brain-directed radiation. Enrollment occurred between April 11, 2017, and May 17, 2024 (final follow-up, March 18, 2025). Intervention Stereotactic radiation, compared with whole brain radiation with hippocampal avoidance. Main Outcomes and Measures Mean weighted patient-reported symptom severity and interference score change over 6 months postbaseline relative to baseline using the MD Anderson Symptom Inventory–Brain Tumor instrument (scale, 0-10; score change range, −10 to 10; −10 = best). A clinically meaningful Δ was defined as 0.98. Results Of 196 randomized patients (mean age, 61 years; 129 [66%] female; 176 [90%] White; median number of brain metastases, 14 [IQR, 11-18]; 49 [25%] with prior neurosurgical resection), 83 (42%) completed the 6-month assessment. For the primary outcome, between baseline and postbaseline assessments through the 6-month follow-up, stereotactic radiation changed the weighted composite MD Anderson Symptom Inventory–Brain Tumor score from 2.69 to 2.37 (mean change, −0.32) and hippocampal-avoidance whole brain radiation changed the score from 2.29 to 3.03 (mean change, 0.74) (mean difference, −1.06 [95% CI, −1.54 to −0.58]; P < .001). Related grade 3-5 adverse events occurred in 12 patients (12%) in the stereotactic radiation group and 13 patients (13%) in the hippocampal-avoidance whole brain radiation group; grade 1-3 fatigue was most frequent (27 [28%] vs 43 [44%], respectively). Conclusions and Relevance In patients with 5 to 20 brain metastases, these findings support stereotactic radiation over hippocampal-avoidance whole brain radiation to improve symptoms and interference with daily functioning, key components of quality of life. Trial Registration ClinicalTrials.gov Identifier: NCT03075072

PURPOSE Stereotactic radiation (SRS/SRT) as opposed to whole-brain radiation (WBRT) represents the standard of care for patients with a limited number of brain metastases given the relatively favorable toxicity profile associated with stereotactic treatment. However, in patients with small cell lung cancer (SCLC), WBRT remains standard because of a lack of prospective data supporting SRS/SRT and concerns related to intracranial progression and neurologic death when WBRT is omitted. We conducted a single-arm, multicenter, phase II trial of SRS/SRT in patients with SCLC and 1-10 brain metastases to assess neurologic death rates relative to historical controls managed with WBRT (ClinicalTrials.gov identifier: NCT03391362 ). METHODS Patients were eligible if they had SCLC or an extrathoracic small cell primary and 1-10 brain metastases. Previous brain-directed radiation including prophylactic cranial irradiation was not permitted. Neurologic death was defined as marked, progressive, radiographic brain progression accompanied by corresponding neurologic symptomatology without systemic disease progression or systemic symptoms of a life-threatening nature. Close imaging-based surveillance of the brain post-SRS/SRT was used. RESULTS Between February 2018 and April 2023, 100 patients were enrolled. The median number of brain metastases was 2 (IQR, 1-4; range, 1-10). The median overall survival was 10.2 months; only 22% of patients required salvage WBRT. In total, 20 neurologic deaths were observed, relative to 64 non-neurologic deaths. The neurologic death rate at 1 year was 11.0% (95% CI, 5.8 to 18.1); the historical rate in patients managed with WBRT was 17.5%. CONCLUSION Our prospective, multi-institutional study demonstrated low rates of neurologic death when SRS/SRT as opposed to WBRT is used in patients with SCLC and 1-10 brain metastases who are surveilled closely post-treatment, supporting the utility of stereotactic approaches in this population.

2011 Background: Radiation therapy forms the mainstay of management for patients with brain metastases. Published randomized trials have found improved quality of life with stereotactic radiation (SRS/SRT) over whole brain radiation (WBRT) in patients with ≤ 4 brain metastases; comparative trials in patients with >4 brain metastases are lacking. In addition, prior randomized trials have demonstrated the superiority of hippocampal avoidance WBRT (HA-WBRT) over traditional WBRT, but no study has compared SRS/SRT to HA-WBRT. Accordingly, we conducted a multicenter, phase 3 randomized trial comparing SRS/SRT to HA-WBRT in patients with 5-20 brain metastases. Methods: Eligible patients were age 18-80 with 5-20 brain metastases secondary to a solid primary other than small cell lung cancer, were naïve to prior brain-directed radiation, and lacked leptomeningeal disease. The primary endpoint was the average of patient-reported symptom severity and interference over the first six months post-baseline relative to baseline, using the MD Anderson Symptom Inventory–Brain Tumor (MDASI-BT) module, a validated instrument assessing 22 symptoms and 6 interference measures integral to quality of life, each scored 0-10 with higher scores indicating greater symptomatology/interference in function. The target effect size was a symptom severity of 0.70, corresponding to 50% of the observed difference between patients with a good (90-100) versus poor (≤80) Karnofsky performance status; with 80% power and a two-sided alpha of 0.05, 196 patients were required. Results: Between 4/2017-5/2024, 196 patients enrolled, 98 in each arm. The median number of brain metastases was 14 (IQR 11-18); 25% of patients underwent prior neurosurgical resection. Baseline mean MDASI-BT symptom severity scores were 2.2 (SRS/SRT arm) and 1.9 (HA-WBRT arm), p=0.20; respective interference scores were 3.5 and 3.2 (p=0.40). The average of weighted post-baseline severity and interference scores relative to baseline indicated lower symptomatology/inference in the SRS/SRT arm, meeting the primary endpoint of the study (difference between SRS/SRT and HA-WBRT: -1.06, p<0.001). Averaged post-baseline symptom severity scores minus baseline were -0.03 and 0.59 in the SRS/SRT and HA-WBRT arms, respectively (difference -0.62, with lower symptom severity in the SRS/SRT arm, p<0.001); respective interference estimates were -0.62 and 0.89 (difference -1.50, with lower interference in the SRS/SRT arm, p<0.001). Median survival was 8.3 and 8.5 months in the SRS/SRT and HA-WBRT arms, respectively (p=0.30). Conclusions: This phase 3 randomized trial indicates that patients with 5-20 brain metastases experience fewer symptoms and less interference in function after SRS/SRT as opposed to HA-WBRT, without compromise of survival, supporting SRS/SRT as the standard of care in this population. Clinical trial information: NCT03075072 .

Abstract DNA damage response (DDR) mechanisms are critical to maintenance of overall genomic stability, and their dysfunction can contribute to oncogenesis. Significant advances in our understanding of DDR pathways have raised the possibility of developing therapies that exploit these processes. In this expert-driven consensus review, we examine mechanisms of response to DNA damage, progress in development of DDR inhibitors in IDH-wild-type glioblastoma and IDH-mutant gliomas, and other important considerations such as biomarker development, preclinical models, combination therapies, mechanisms of resistance and clinical trial design considerations.

Abstract Isocitrate dehydrogenase (IDH) mutant gliomas are the most common adult, malignant primary brain tumors diagnosed in patients younger than 50, constituting an important cause of morbidity and mortality. In recent years, there has been significant progress in understanding the molecular pathogenesis and biology of these tumors, sparking multiple efforts to improve their diagnosis and treatment. In this consensus review from the Society for Neuro-Oncology (SNO), the current diagnosis and management of IDH-mutant gliomas will be discussed. In addition, novel therapies, such as targeted molecular therapies and immunotherapies, will be reviewed. Current challenges and future directions for research will be discussed.

PURPOSE Conventional wisdom has rendered patients with brain metastases ineligible for clinical trials for fear that poor survival could mask the benefit of otherwise promising treatments. Our group previously published the diagnosis-specific Graded Prognostic Assessment (GPA). Updates with larger contemporary cohorts using molecular markers and newly identified prognostic factors have been published. The purposes of this work are to present all the updated indices in a single report to guide treatment choice, stratify research, and define an eligibility quotient to expand eligibility. METHODS A multi-institutional database of 6,984 patients with newly diagnosed brain metastases underwent multivariable analyses of prognostic factors and treatments associated with survival for each primary site. Significant factors were used to define the updated GPA. GPAs of 4.0 and 0.0 correlate with the best and worst prognoses, respectively. RESULTS Significant prognostic factors varied by diagnosis and new prognostic factors were identified. Those factors were incorporated into the updated GPA with robust separation ( P < .01) between subgroups. Survival has improved, but varies widely by GPA for patients with non–small-cell lung, breast, melanoma, GI, and renal cancer with brain metastases from 7-47 months, 3-36 months, 5-34 months, 3-17 months, and 4-35 months, respectively. CONCLUSION Median survival varies widely and our ability to estimate survival for patients with brain metastases has improved. The updated GPA (available free at brainmetgpa.com) provides an accurate tool with which to estimate survival, individualize treatment, and stratify clinical trials. Instead of excluding patients with brain metastases, enrollment should be encouraged and those trials should be stratified by the GPA to ensure those trials make appropriate comparisons. Furthermore, we recommend the expansion of eligibility to allow for the enrollment of patients with previously treated brain metastases who have a 50% or greater probability of an additional year of survival (eligibility quotient > 0.50).

Abstract Background Breast cancer treatment is based on estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2). At the time of metastasis, receptor status can be discordant from that at initial diagnosis. The purpose of this study was to determine the incidence of discordance and its effect on survival and subsequent treatment in patients with breast cancer brain metastases (BCBM). Methods A retrospective database of 316 patients who underwent craniotomy for BCBM between 2006 and 2017 was created. Discordance was considered present if the ER, PR, or HER2 status differed between the primary tumor and the BCBM. Results The overall receptor discordance rate was 132/316 (42%), and the subtype discordance rate was 100/316 (32%). Hormone receptors (HR, either ER or PR) were gained in 40/160 (25%) patients with HR-negative primary tumors. HER2 was gained in 22/173 (13%) patients with HER2-negative primary tumors. Subsequent treatment was not adjusted for most patients who gained receptors—nonetheless, median survival (MS) improved but did not reach statistical significance (HR, 17–28 mo, P = 0.12; HER2, 15–19 mo, P = 0.39). MS for patients who lost receptors was worse (HR, 27–18 mo, P = 0.02; HER2, 30–18 mo, P = 0.08). Conclusions Receptor discordance between primary tumor and BCBM is common, adversely affects survival if receptors are lost, and represents a missed opportunity for use of effective treatments if receptors are gained. Receptor analysis of BCBM is indicated when clinically appropriate. Treatment should be adjusted accordingly. Key Points 1. Receptor discordance alters subtype in 32% of BCBM patients. 2. The frequency of receptor gain for HR and HER2 was 25% and 13%, respectively. 3. If receptors are lost, survival suffers. If receptors are gained, consider targeted treatment.

1079 Background: Brain metastases (BM) are a common and fatal complication of breast cancer but survival varies widely based on various prognostic factors (PF). Hence, patient counseling and therapeutic decisions should be individualized. We previously published a prognostic index (Breast GPA) based on cohort A (1985-2007, n = 642), updated it with tumor subtype in cohort B (1993-2010, n = 400) and are now updating it with a larger contemporary cohort (C). Methods: A multi-institutional (19) multi-national (3) retrospective database of 2473 breast cancer patients with BM diagnosed from 1/1/2006-12/31/2017 was created and compared to our prior cohorts. Demographic, clinical, molecular factors, tumor subtype and treatment were correlated with survival. Kaplan-Meier survival estimates were calculated and compared with log-rank tests. Results: The median survival (MS) for cohorts A, B and C improved over time [12, 14 and 16 mo, respectively ( < 0.01)] despite the subtype distribution becoming less favorable: Luminal B (ER/PR/HER2+) decreased from 26% to 21%; HER2 (HER2+/ER/PR-) decreased from 31% to 17%, Luminal A (ER/PR+/HER2-) increased from 20% to 31%; Basal (ER/PR/HER2-) was unchanged at 24%.MS by subtype improved from 21 to 27 mo in Luminal B, 18 to 25 mo in HER2, 10 to 14 mo in Luminal A and 6 to 9 mo in Basal tumors. The number of BM was 1 in 35%, ≤4 in 67% and > 10 in 18%. PF significant for survival were tumor subtype, age, KPS, number of BM and extracranial metastases (ECM) (all < 0.01). Surprisingly, Hispanic women (7%) showed improved survival (p < 0.01). BRCA1 was mutated in 57/533 (11%) and those patients showed a trend (0.16) toward improved survival. Treatment patterns have changed: the use of whole brain radiation therapy decreased from 71% to 67% to 47% in cohorts A, B and C, respectively. Conclusions: Despite the shift to less favorable tumor subtypes, MS has improvedbut varies widely by diagnosis-specific PF. Compared to prior cohorts, number of BM and ECM were identified as new PF. Ethnic, genetic and treatment differences between the eras are apparent. The updated Breast GPA, based on these data, and the correlation between BRCA1 and tumor subtype will be presented.