PURPOSE: To evaluate the association between birth characteristics, including parental sociodemographic characteristics, and early-onset pituitary adenoma (PA) and craniopharyngioma. METHODS: Leveraging the population-based California Linkage Study of Early-onset Cancers, we identified the birth characteristics of incident cases with PA (n = 1,749) or craniopharyngioma (n = 227) who were born from 1978 to 2015 and diagnosed 1988-2015, as well as controls in a 50:1 ratio matched on birth year. Adjusted odds ratios (OR) and 95% confidence interval (CI) estimates were computed using unconditional multivariable logistic regression. RESULTS: Males had a lower risk of PA than females (OR = 0.37, 95%CI: 0.34-0.41), and Black (OR = 1.55, 95%CI: 1.30-1.84) or Hispanic (OR = 1.53, 95%CI: 1.34-1.74) individuals had a higher risk compared to non-Hispanic Whites. Older maternal age was positively associated with PA (OR = 1.09, 95%CI: 1.04-1.15 per 5 years, p < 0.01), as was higher maternal education (OR = 1.12, 95%CI: 1.04-1.20 per year, p < 0.01). There were no statistically significant associations between birthweight (OR = 1.04, 95%CI: 0.99-1.09 per 500 g, p = 0.12), birth plurality, or birth order and PA. When stratified by race and ethnicity, the significant association with maternal education was identified only for non-Hispanic White individuals. On multivariable logistic regression, no statistically significant associations were identified between birth characteristics and incidence of craniopharyngioma, except that risk was higher among Hispanic (OR = 1.45, 95%CI: 1.01-2.08) compared to non-Hispanic White individuals. CONCLUSION: In this large, population-based study, female sex, older maternal age, higher maternal education, and Hispanic ethnicity and Black race compared to non-Hispanic White race, were associated with an increased risk of PA in children and young adults.

Background

We evaluated the potential role of birth characteristics in the etiology of early-onset meningioma.

Methods

Leveraging a population-based linkage of California birth records (from 1978 to 2015) and cancer registry data (from 1988 to 2015), we identified 362 nonmalignant meningioma cases aged 0-37 years and selected 18 100 controls matched on year of birth. Cases and controls were compared with regard to birth characteristics, with adjusted odds ratios (ORs) and 95% confidence intervals (CIs) estimated from unconditional multivariable logistic regression models. We also conducted stratified analyses by race/ethnicity and age.

Results

Female sex (compared to male: OR = 1.43, 95% CI: 1.16 to 1.79; P < .01) and Black race (compared to White: OR = 1.46, 95% CI: 1.02 to 2.07; P = .04) were associated with higher risk of meningioma. Higher birth order (OR = 0.90, 95% CI: 0.81 to 0.99 per additional birth position; P = .04) was associated with a lower risk. No significant associations were observed between birthweight, gestational age, delivery mode, maternal age, or maternal education and meningioma risk. In the non-Latino White subgroup, higher birthweight was associated with a higher risk of meningioma (OR = 1.20, 95% CI: 1.02 to 1.41 per 500 grams; P = .03), but this was not recapitulated in the Latino subgroup. In age-stratified analyses, female sex was a risk factor for those diagnosed at the age of 20-37 years but not among younger individuals.

Conclusions

In this large population-based study less prone to selection and recall bias, higher birth order was associated with a reduced risk of early-onset meningioma, while female sex and Black race were linked to an increased risk. There were also indications of differential associations by race/ethnicity and age of diagnosis.

Purpose

VEGF is upregulated in glioblastoma and may contribute to immunosuppression. We performed a phase II study of pembrolizumab alone or with bevacizumab in recurrent glioblastoma.

Patients and methods

Eighty bevacizumab-naïve patients with recurrent glioblastoma were randomized to pembrolizumab with bevacizumab (cohort A, n = 50) or pembrolizumab monotherapy (cohort B, n = 30). The primary endpoint was 6-month progression-free survival (PFS-6). Assessed biomarkers included evaluation of tumor programmed death-ligand 1 expression, tumor-infiltrating lymphocyte density, immune activation gene expression signature, and plasma cytokines. The neurologic assessment in neuro-oncology (NANO) scale was used to prospectively assess neurologic function.

Results

Pembrolizumab alone or with bevacizumab was well tolerated but of limited benefit. For cohort A, PFS-6 was 26.0% [95% confidence interval (CI), 16.3-41.5], median overall survival (OS) was 8.8 months (95% CI, 7.7-14.2), objective response rate (ORR) was 20%, and median duration of response was 48 weeks. For cohort B, PFS-6 was 6.7% (95% CI, 1.7-25.4), median OS was 10.3 months (95% CI, 8.5-12.5), and ORR was 0%. Tumor immune markers were not associated with OS, but worsened OS correlated with baseline dexamethasone use and increased posttherapy plasma VEGF (cohort A) and mutant IDH1, unmethylated MGMT, and increased baseline PlGF and sVEGFR1 levels (cohort B). The NANO scale contributed to overall outcome assessment.

Conclusions

Pembrolizumab was ineffective as monotherapy and with bevacizumab for recurrent glioblastoma. The infrequent radiographic responses to combinatorial therapy were durable. Tumor immune biomarkers did not predict outcome. Baseline dexamethasone use and tumor MGMT warrant further study as potential biomarkers in glioblastoma immunotherapy trials.

Abstract

PURPOSE

Vascular endothelial growth factor (VEGF) is upregulated in glioblastoma and may contribute to immunosuppression. We performed a phase 2 study of pembrolizumab, a programmed death-1 (PD-1) blocking antibody alone or with the anti-VEGF antibody bevacizumab in recurrent glioblastoma with detailed analyses of biomarkers and patient neurologic function.

METHODS

Eighty bevacizumab-naive, recurrent glioblastoma patients were randomized to receive pembrolizumab with bevacizumab (cohort A, n=50) or pembrolizumab monotherapy (cohort B, n=30). The primary endpoint was six-month progression-free survival (PFS-6). Exploratory endpoints included evaluation of tumor PD-L1 expression, TIL density, immune activation gene expression signature and plasma cytokines with outcome. Changes in neurologic function were prospectively assessed using the Neurologic Assessment in Neuro-Oncology (NANO) scale.

RESULTS

Pembrolizumab alone or with bevacizumab was well tolerated but of limited benefit. For cohort A, PFS-6 was 26.0% (95% CI: 16.3, 41.5), median OS was 8.8 months (95% CI: 7.7, 14.2), ORR was 20% and median duration of response was 48 weeks. For cohort B, PFS-6 was 6.7% (95% CI: 1.7, 25.4), median OS was 10.3 months (95% CI: 8.5, 12.5) and ORR was 0%. Factors associated with worsened OS included baseline dexamethasone use and increased post-therapy plasma VEGF (cohort A) and wild-type IDH1, unmethylated MGMT and increased baseline PlGF and sVEGFR1 levels (cohort B), but tumor immune markers were not informative. The NANO scale effectively predicted neurologic function.

CONCLUSIONS

Although well tolerated, pembrolizumab was ineffective both as monotherapy and with bevacizumab for recurrent glioblastoma. Nonetheless, radiographic responses to combinatorial therapy were durable. Baseline dexamethasone use and plasma cytokines but not tumor immunologic biomarkers were associated with outcome. Neurologic function evaluated by the NANO scale contributed to outcome assessment.

Abstract

PURPOSE

The neurologic assessment in neuro-oncology (NANO) scale was developed as a standardized metric to objectively measure neurologic function in brain tumor patients to complement radiographic assessment in defining overall outcome. A multicenter, phase 2 study of pembrolizumab with or without bevacizumab in patients with recurrent glioblastoma incorporated the NANO scale as an exploratory endpoint.

METHODS

Neurologic examination was evaluated at baseline and MRI assessments using the NANO scale until patients came off study. Statistical descriptive data analysis was performed using R (version 3.4.3). Correlation analysis utilized Fisher’s exact test.

RESULTS

NANO compliance rate was 94% in 80 patients accrued on the study. Of the 80 patients, 7 were missing NANO at baseline visit and were excluded from analysis for NANO response criteria. Fifteen patients did not have end of treatment NANO evaluation. Of 73 patients, 35 (48%) had a normal neurologic examination at baseline by NANO. Strength and language accounted for the majority of changes in neurologic function over the course of study treatment. Eighteen patients (25%) had neurologic progression by NANO, of whom 2 did not have concurrent radiographic progression. Three patients (pembrolizumab plus bevacizumab cohort) had a neurologic response associated with stable disease on MRI. NANO assessment prior to initiation of cycle 3 correlated with RANO response (p=0.011), change in KPS (p=0.002) and dexamethasone requirement (p=0.007) while those with NANO progression at this assessment had worse overall survival (291 vs 324 days), but this trend did not achieve statistical significance (p=0.2).

CONCLUSIONS

Evaluation of neurologic function by NANO scale was feasible in a multicenter prospective study in patients with GBM with a high compliance rate. The NANO scale objectively tracked stable neurologic function in most patients throughout the trial period and was associated with a trend for survival.