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Purpose A phase I/II trial was performed to evaluate the safety and immunogenicity of a novel vaccination with α-type 1 polarized dendritic cells (αDC1) loaded with synthetic peptides for glioma-associated antigen (GAA) epitopes and administration of polyinosinic-polycytidylic acid [poly(I:C)] stabilized by lysine and carboxymethylcellulose (poly-ICLC) in HLA-A2+ patients with recurrent malignant gliomas. GAAs for these peptides are EphA2, interleukin (IL)-13 receptor-α2, YKL-40, and gp100. Patients and Methods Twenty-two patients (13 with glioblastoma multiforme [GBM], five with anaplastic astrocytoma [AA], three with anaplastic oligodendroglioma [AO], and one with anaplastic oligoastrocytoma [AOA]) received at least one vaccination, and 19 patients received at least four vaccinations at two αDC1 dose levels (1 × or 3 × 107/dose) at 2-week intervals intranodally. Patients also received twice weekly intramuscular injections of 20 μg/kg poly-ICLC. Patients who demonstrated positive radiologic response or stable disease without major adverse events were allowed to receive booster vaccines. T-lymphocyte responses against GAA epitopes were assessed by enzyme-linked immunosorbent spot and HLA-tetramer assays. Results The regimen was well-tolerated. The first four vaccines induced positive immune responses against at least one of the vaccination-targeted GAAs in peripheral blood mononuclear cells in 58% of patients. Peripheral blood samples demonstrated significant upregulation of type 1 cytokines and chemokines, including interferon-α and CXCL10. Nine (four GBM, two AA, two AO, and one AOA) achieved progression-free status lasting at least 12 months. One patient with recurrent GBM demonstrated sustained complete response. IL-12 production levels by αDC1 positively correlated with time to progression. Conclusion These data support safety, immunogenicity, and preliminary clinical activity of poly-ICLC-boosted αDC1-based vaccines.

Purpose O6-Methylguanine-DNA methyltransferase (MGMT) functions to counteract the cytotoxic effects of alkylating agents, such as nitrosoureas, which play a central role in the treatment of childhood malignant gliomas. Epigenetic silencing of MGMT has been associated with prolonged survival in adults with malignant gliomas, although the association between MGMT expression status and outcome in pediatric malignant gliomas has not been defined. Methods We examined the association between MGMT expression and survival duration using tumor samples from the Children's Cancer Group 945 study, the largest randomized trial for childhood malignant gliomas completed to date. All patients received alkylator-based chemotherapy as a component of adjuvant therapy. Archival histopathologic material yielded tissue of sufficient quality for immunohistochemical assessment of MGMT expression status in 109 specimens. Results Twelve of the 109 samples demonstrated overexpression of MGMT compared with normal brain. Five-year progression-free survival was 42.1% ± 5% in the 97 patients whose tumors had low levels of MGMT expression versus 8.3% ± 8% in the 12 patients whose tumors overexpressed MGMT (P = .017, exact log-rank test). The association between MGMT overexpression and adverse outcome remained significant after stratifying for institutional histologic diagnosis (eg, anaplastic astrocytoma or glioblastoma multiforme), as well as age, amount of residual tumor, and tumor location. Conclusion Overexpression of MGMT in childhood malignant gliomas is strongly associated with an adverse outcome in children treated with alkylator-based chemotherapy, independently of a variety of clinical prognostic factors.

2072 Background: Brain metastases (BM) are an increasingly common consequence of breast cancer (BC). Knowledge of the microenvironment in primary BC and its impact on prognosis is evolving. A similar understanding of the microenvironment of BC metastases is lacking, particularly for the brain, where unique immune regulation governs stroma composition. Such features of the peri-tumoral landscape, i.e. high immune infiltrate and low hemorrhage, offer prognostic value in BM from melanoma. This study reports on 4 biomarkers, gliosis (glio), immune infiltrate (immune), hemorrhage (hem) and necrosis (nec), and their prognostic significance in BCBM. Methods: A biobank of 203 patients (pts) who underwent craniotomy between 1989-2013 was created across 4 sites. Glio, immune, and hem (grouped 0 v 1-3) and nec (0-2 v 3) were scored via H&E stain (0-3). Overall survival (OS (years)) from craniotomy was estimated using the Kaplan-Meier method; log-rank tests compared OS. Cox proportional hazards regression was used to evaluate prognostic value of the 4 biomarkers. Results: Mean age at primary BC diagnosis was 48 years (range 26-77). BCBM subtype (n = 158) was 36% HER2+, 26% HR+/HER2-, 38% HR-/HER2- (TN). Across all samples, expression was 82% glio, 45% immune, 82% hem, and 13% nec. Subtype differences were seen for nec (higher in TN, p < 0.01). Across all pts, expression of glio, immune, and hem was associated with improved OS (years): 1.08 v 0.62 (p = 0.03), 1.31 v 0.93 (p = 0.03), 1.07 v 0.92 (p = 0.1), respectively. Nec was associated with inferior OS: 0.38 v 1.12 (p = 0.01). The association with improved OS was maintained for glio in TN (p = 0.02), and immune (p = 0.001) and hem (p = 0.07) in HER2+. In a multivariable model for OS, adding the 4 biomarkers to traditional clinical variables (age, race, subtype) significantly improved the model fit (p < 0.001). Conclusions: Nec is a poor prognostic finding in BCBM across all subtypes. Glio confers superior prognosis in TN, while immune and hem correlate with superior prognosis in HER2+. A deeper understanding of the rich BCBM microenvironment both refines prognostic considerations for this pt population and may lead to future investigations of targeted immunotherapies in select subtypes of BCBM.

e20033 Background: To date, little is known about how primary melanomas clonally evolve to distant metastases, including brain, and how driver mutations are selected during melanoma progression. To...

554 Background: Mutations in ESR1 (ESR1-mut) are a potential resistance mechanism to endocrine therapy, especially aromatase inhibitors (AI). Although these mutations are rare in untreated patients...

2027 Background: Brain metastases (BM) are a devastating consequence of advanced breast cancer (BC). Little is known about the clinical significance of histopathological features associated with BM...

TPS9112 Background: Dabrafenib (D) has clinical activity in patients (pts) with BRAF V600E/K mutation–positive melanoma brain metastases (MBM). The combination of D and trametinib (T) has increased...

9038 Background: We have previously shown that presence of intratumoral hemorrhage and absence of immune infiltrates in craniotomy specimens of MBM are associated with shorter overall survival (OS)...

10538 Background: Chordoma is a primary bone cancer of the axial skeleton with predilection for local invasion. Primary treatment modalities consist of surgery and radiation therapy with limited role for chemotherapy. Because patients with chordoma exhibit heterogeneous clinical history and response to therapy, we investigated potential markers predictive of clinical behavior. Methods: This study analyzed 35 clival chordoma specimens with documented immunohistochemistry (IHC) staining for Ki-67 proliferation index from 29 patients. Detailed additional pathologic studies were performed prospectively on 12 consecutive patients. This consisted of the following: IHC for brachyury, cytokeratin, p53, and epidermal growth factor receptor (EGFR); fluorescent in situ hybridization (FISH) analysis for EGFR amplification and presence of 1p36, 9p21, and 19q13 loci; polymerase chain reaction based loss of heterozygosity analysis (LOH) of 1p, 9p, 10q, 17p, and 19p loci. Results: All confirmed chordoma specimens were positive for brachyury and negative for amplification of EGFR. Increase in Ki-67 index was associated with recurrence in 5 of 6 cases. Out of the 12 patients with detailed molecular pathologic studies, 5 had loss of 1p, 2 had deletion of 9p21 (p16), and 2 had loss of 10q (PTEN). The loss of 1p and 9p were detected via both FISH and LOH analyses. 3 of the 12 patients’ tumor specimens showed a Ki-67 index of greater than 10%; the remaining specimens were less than 5%. All 3 patients with high Ki-67 index had loss of either 9p (p16) or 10q (PTEN). The tumor specimen from these 3 patients also exhibited enhanced in vitro propagation. Conclusions: Subtyping of clival chordomas based on molecular phenotype may provide prognostic information. The prospective nature of this study in concert with assessment of residual disease after surgery may allow for identification of distinct subpopulations of patients at greater risk of disease recurrence for consideration of adjuvant therapy. The correlative in vitro study will provide an opportunity to evaluate targeted therapies customized to individual molecular subgroups. No significant financial relationships to disclose.

2026 Background: Glioblastoma multiforme is the most common and malignant primary brain tumor in adults. Despite aggressive surgery, radiation, and chemotherapy, average survival time after diagnosis is about 1 year. This may be partly due to development of resistance to adjuvant therapies. While the molecular alterations in pretreated glioblastomas have been the subject of much research in recent years, changes in their genetic profile after adjuvant therapy are largely unknown. Methods: Herein we describe a cohort of over 40 glioblastomas with characterization of key genetic loci (EGFR, p53, 1p, 19q, 9p, 10q, 17p) using fluorescence in situ hybridization, PCR-based loss of heterozygosity (LOH) analysis, and immunohistochemistry on formalin-fixed, paraffin-embedded tissues. Analyses were performed on tumor tissue obtained at initial diagnosis and at first recurrence. Treatment regimen during the interval consisted of external beam radiation therapy and temozolomide, an alkylating chemotherapeutic agent. Results: About 50% showed large increases or decreases in hyperploidy of chromosomes 1, 7, 9, and/or 19 after therapy. Over 70% showed changes in LOH patterns on 1p, 19q, 9p, 10q, and/or 17p. 24% of previously non-EGFR-amplified tumors acquired low-grade amplification (less than 10 copies/chromosome 7 CEP signal) after treatment, and 16% of EGFR-amplified tumors lost amplification after treatment. Conclusions: Our results suggest that the molecular profile of these tumors is dynamic and that certain key alterations, including acquisition of low-level EGFR amplification in previously EGFR-negative tumors, occurs in a subset of cases. Such alterations may contribute to therapy resistance as the glioma evolves in a changing microenvironment. No significant financial relationships to disclose.