Time Of Brain Metastasis Diagnosis Research Articles

Abstract 3785: Clinical and genomic characterization of melanoma brain metastases

Abstract Introduction: Melanoma has a high propensity for brain metastasis (BM). Although advancements in brain-penetrant treatments have resulted in improved central nervous system (CNS) disease control, BMs remain a significant cause of morbidity and mortality. The molecular features of melanoma BM are poorly defined, and there is an unmet need to identify biomarkers associated with CNS-specific outcomes. Methods: We retrospectively identified 109 patients with melanoma BM who underwent craniotomy at Memorial Sloan Kettering Cancer Center (MSK) between 01/2014 and 04/2023. BM specimens were sequenced using MSK-IMPACT, an FDA-approved next-generation sequencing assay covering 341-505 genes with 700X coverage. Clinical characteristics and CNS-specific outcomes were available from 107 patients; CNS-specific radiographic endpoints were verified through direct inspection of contrast-enhanced MRI imaging by a board-certified neuroradiologist. Clinical data included baseline characteristics, prior systemic or radiotherapy (RT), and CNS-directed follow up including recording local progression of disease (POD), regional POD, and development of leptomeningeal disease (LMD).   Results: Majority (68%,73/107) patients were male with a median age at the time of primary diagnosis of 56 (range 3-88). Forty-eight patients (45%) had advanced disease (stages III and IV) at the time of initial diagnosis. At the time of BM development, half of the patients had 2-5 intracranial tumors present (50%) with a median diameter of largest BM of 33.4mm (range .9mm-64mm). The median KPS was 80 at the time of BM diagnosis, and 79% had neurologic symptoms prior to resection. 81 patients (76%) were treatment naïve at the time of resection and 56 patients (53%) developed CNS recurrence with the majority of those having local POD (29%,16/56) followed closely by regional POD of 1 lesion (25%,14/56). The most frequent genomic alterations in the cohort were TERT (87%), CDKN2A (50%), BRAF (43%), NRAS (28%), and PTEN (25%). The median fraction genome altered was 0.3047 and the median tumor mutational burden was 13.2 muts/Mb. We compared the genomic profiles of BM tumors of patients that had no progression, local POD, regional POD, and LMD. Compared to patients with no progression, patients with local POD were more likely to have RB1 alterations (18.1% vs 2.1%, p = 0.04, q = 0.83) and patients with LMD were less likely to have TERT alterations (62.5% vs 93.8%, p = 0.03, q = 0.75). Conclusions: Our analysis between genomic markers and clinical outcomes in melanoma BM reveals genomic features which may improve prediction and treatment strategies.   Citation Format: Michel Padilla Mazzeo, Henry S. Walch, Rahul Kumar, Jordan Eichholz, Claire Cooper, Nishta Nandakumar, Junchao Shen, Ishaani Khatri, Luke Del Balzo, Anna Skakodub, Emily Miao, Daniel W. Kelly, Kenny Kwok Hei Yu, Jessica Wilcox, Brandon S. Imber, Yao Yu, Yoshiya Yamada, Harish Vasudevan, Ahmet Ilica, Nikolaus Schultz, Luke R. Pike. Clinical and genomic characterization of melanoma brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3785.

NCOG-02. MANAGEMENT OF PATIENTS WITH MELANOMA BRAIN METASTASES AND PRIOR SYSTEMIC TREATMENT EXPOSURE: A SINGLE-CENTER EXPERIENCE

Abstract Although systemic therapy (ST) for melanoma patients with untreated brain metastases (BrM) has activity, ST options for patients with melanoma BrM that develop on or after ST are limited. In this single-center retrospective study, we describe the characteristics and survival outcomes of patients aged > 18 years with metastatic melanoma and who developed BrM > 90 days after their first dose of checkpoint inhibitor (CPI) or targeted therapy (TT). Relevant clinical data and data on ST prior to and after BrM diagnosis were collected. MRIs were reviewed to assess intracranial progression-free survival (IC-PFS) as per RANO-BM criteria. The primary outcome was overall survival (OS). Cox regression model was applied to identify factors associated with OS. Between 2010 and 2019, we identified 103 patients with median age 56 (29-92) years, 69 (67%) of whom were male; 57 (55%) had BRAF V600-mutant tumors. Ninety-four (91%) had no known BrM at the time of first-line therapy. Median number of BrM was 3 (1-58), median number of prior ST was 1 (1-5), 75 (73%) had prior CPI exposure and 70 (68%) were on concurrent CPI or TT at the time of BrM diagnosis. Local treatments included SRS in 43 (42%) and WBRT in 46 (44%) patients. From BrM diagnosis, median IC-PFS and OS were 3.5 (95% CI 2.6-4.3) and 6.9 (95% CI 5.2-8.6) months, respectively. Adverse prognostic factors were: BRAF wild-type (HR 2.04, 95% CI 1.15-3.64), ECOG 2-4 (HR 3.55, 95% CI 1.93-6.53), and increasing number of prior ST (HR 1.62, 95% CI 1.23-2.13). CPI therapy that was continued, started, or restarted after BrM was associated with improved median OS compared to non-ICI therapy (9.9 vs. 3.5 months, HR 0.45, 95% CI 0.27-0.74). In conclusion, our data support development of CPI-based trials for patients who experience progression with BrM on or after modern ST.

Treatment modalities and survival outcomes in prostate cancer parenchymal brain metastasis.

Prostate cancer (PCa) parenchymal brain metastases are uncommon and troubling observations in the course of the disease. Our study aims to evaluate the prevalence of brain metastases among PCa patients while reporting various therapeutic modalities, clinical features, and oncological outcomes. We retrospectively identified 34 patients with parenchymal brain metastasis out of 4575 patients using a prospectively maintained database that contains clinicopathologic characteristics of PCa patients between January 2012 and December 2021. Based on the three treatment modalities used, the patients were divided into three groups: stereotactic radiosurgery (SRS), whole brain radiotherapy (WBRT), and systemic therapy alone. The Kaplan-Meier curve was used to calculate overall survival [OS] probability and the Cox proportional hazards regression model was used to compare between groups. At the time of brain metastasis diagnosis, the median age was 66 years, the median (interquartile range [IQR]) prostate-specific antigen (PSA) was 2.2 (0.1-26.6) ng/ml and the median (IQR) months from initial PCa diagnosis to brain metastasis development was 70.8 (27.6-100.9). The median (IQR) primary Gleason score was 8 (7-9) and over a median (IQR) follow-up time of 2.2 (1.2-16.5) months, 76.5% (n = 26) of the patients died. Thirteen (38.2%) patients had solitary lesion, whereas 21 (61.8%) had ≥2 lesions. The lesions were supratentorial in 19 (55.9%) patients, infratentorial in six (17.6%), and both sides in nine (26.5%). Among all 34 patients, 10 (29.4%) were treated with SRS, seven (20.6%) with WBRT, and 17 (50%) with systemic therapy alone. OS varied greatly between the three treatment modalities (log-rank test, p = 0.049). Those who were treated with SRS and WBRT had better OS compared with patients who were treated with systemic therapy alone (hazard ratio: 0.37, 95% confidence interval: 0.16-0.86, p = 0.022). In our single-institutional study, we confirmed that PCa brain metastasis is associated with poor survival outcomes and more advanced metastatic disease. Furthermore, we found that SRS and WBRT for brain metastasis in patients with recurrent PCa appear to be associated with improved OS as compared with systemic therapy alone and are likely secondary to selection bias.

Safety and efficacy of silibinin in patients with brain metastases after stereotactc radiosurgery: SUSTAIN trial.

e14012 Background: Brain metastases (BMs) account for more than one-half of all intracranial tumors. Over the past years, stereotactic radiosurgery (SRS) has become the mainstay of BMs treatment, providing high rates of local tumor control. Nevertheless, SRS alone is associated with a 30-50% risk of distant brain failure (DBF), consequently requiring careful follow-up and possible rescue treatments. Silibinin or silybin, a natural polyphenolic flavonoid, has shown promising antitumor activity, leading to improvement of BMs in patients (pts) with progressive non-small cell lung cancer. Therefore, our exploratory study aims to evaluate whether the use of a silibinin-based nutraceutical can significantly reduce DBF rate at 6 months in pts with first-diagnosed BMs treated with SRS with or without surgery. Methods: SUSTAIN is an interventional, prospective, single arm, phase II study. A total of 80 pts treated in our center are planned to be enrolled. Pts receive 2 capsules (cps) of silibinin-based nutraceutical per day for the first month after SRS and 1 cp per day thereafter. Primary endpoints are 6-month distant brain failure (DBF) rate and safety; secondary endpoint is 6-month overall survival (OS) rate. Contrast-enhanced magnetic resonance (MRI) of the brain is performed at baseline and every 12 weeks after SRS treatment; radiological response is assessed according to RANO criteria for brain metastases (RANO-BM). Results: Thirty pts has been enrolled at the time of this primary analysis (Tab1). NSCLC and breast cancer were the prevalent histologies (14 and 10 cases respectively). Twelve pts were chemotherapy naive at the time of BMs diagnosis; 10 pts has received 1 systemic therapy line and 8 pts has received 2 lines or more. Overall, the number of treated lesions was 73, with a median of 1 lesion (range 1-9). All pts underwent SRS (Fig.1), with a median prescription dose (PD) and a median prescription isodose line (IDL) of 24 Gy and 80% respectively. After a 14-month enrollment period, with a median follow-up of 9 months, 6 pts reported distant intracranial failure according to RANO-BM criteria, with a 6-month DBF rate of 20%. Only 1 treated lesion met the criteria for progression, accounting for a 6-month local control (LC) rate of 98%. Six pts died, with a 6-month OS rate of 80%. Radiological radionecrosis was detected in 3 pts (10%), who developed G1 neurological symptoms managed with low-dose dexamethasone. Two pts discontinued silibinin-based nutraceutical assumption due to G1 nausea. No other adverse events were reported. Conclusions: At about half of our enrollment target, the results show a favorable trend towards 6-month DBF rate reduction. Toxicity proved manageable, consistent with the literature and limited to gastrointestinal effects. A larger sample and longer follow-up is needed to confirm our hypothesis.

An Efficient Approach to Mapping the Distribution of Renal Cell Carcinoma (RCC) Brain Metastases (BrM) (P10-13.003)

<h3>Objective:</h3> To assess the distribution of RCC BrM in clinical context. <h3>Background:</h3> RCC frequently presents with hemorrhagic BrMs. BrM distribution patterns and their associations with lab/clinical parameters are poorly understood. <h3>Design/Methods:</h3> We performed a retrospective analysis including RCC patients who underwent BrM resection at our institution. We reviewed gadolinium-enhanced MRI brain and CT head at the time of BrM diagnosis and assessed the presence of hemosiderin (MRI) or hemorrhage (CT) in the BrM. BrMs were marked in their corresponding anatomic location in a brain template. Public brain atlases (Faria and Liu 10.25790/bml0cm.109; Vachet, SCR_002606) were used for distribution analysis. Serum markers were correlated with imaging. <h3>Results:</h3> A total of 67 BM were analyzed from 46 patients (age 63±10years/35M), 23 synchronous BM, 9 patients had two, 6 had 3 concurrent BrMs. 97% of the lesions were spheric in shape. Mean 1D and 2D (RANO) tumor dimensions were 2.0±1.1cm and 4.7±4.9cm², respectively and correlated with neutrophil count at BrM diagnosis (r=0.3, p=0.01). Multilobar edema was seen in 36% of BrM. 82% of BrMs contained hemosiderin and 80% were hemorrhagic. Most BrMs were in the frontal (45%), parietal (21%) and occipital (18%) lobes. Posterior cerebral artery distribution contained 34% of BrM despite it supplying only 16% of brain volume. Higher platelet counts were associated with BrMs in the posterior circulation territories (p=0.05). BrM hemosiderin was associated with larger tumors (p=0.04), lower platelet counts (p=0.01) and higher hemoglobin (p=0.08). Renal vein thrombosis (RVT) at primary diagnosis was associated both BrM hemosiderin (p=0.05) and hemorrhage (p=0.03). CNS progression-free survival was shorter in those who had RVT (p=0.04), or had BrM hemosiderin (p=0.04). <h3>Conclusions:</h3> The presented mapping method offers an objective and efficient way to assess lesion distribution that reveals clinically relevant patterns. BrM hemosiderin deposits are linked to lower platelet counts and may provide prognostic information. Further analyses are underway. <b>Disclosure:</b> The institution of Dr. Kamson has received research support from Maryland Cigarette Restitution Fund. Mr. Feinaj has nothing to disclose. Dr. Elias has nothing to disclose. Mr. Yerrapragada has nothing to disclose. Dr. Bettegowda has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bionaut Labs. Dr. Bettegowda has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Rodey, Dickason, Sloan, Akin &amp; Robb, P.A.. Dr. Bettegowda has stock in OrisDx. The institution of Dr. Bettegowda has received research support from NIH. Dr. Bettegowda has received intellectual property interests from a discovery or technology relating to health care. Mr. Singla has nothing to disclose. Yasser Ged has nothing to disclose.

Long-term survival of breast cancer patients with brain metastases: subanalysis of the BMBC registry

Up to 30% of metastatic breast cancer (BC) patients develop brain metastases (BM). Prognosis of patients with BM is poor and long-term survival is rare. Identification of factors associated with long-term survival is important for improving treatment modalities. A total of 2889 patients of the national registry for BM in BC (BMBC) were available for this analysis. Long-term survival was defined as overall survival (OS) in the upper third of the failure curve resulting in a cut-off of 15 months. A total of 887 patients were categorized as long-term survivors. Long-term survivors compared to other patients were younger at BC and BM diagnosis (median 48 versus 54 years and 53 versus 59 years), more often had HER2-positive tumors (59.1% versus 36.3%), less frequently luminal-like (29.1% versus 35.7%) or triple-negative breast cancer (TNBC) (11.9% versus 28.1%), showed better Eastern Cooperative Oncology Group (ECOG) performance status (PS) at the time of BM diagnosis (ECOG 0-1, 76.9% versus 51.0%), higher pathological complete remission rates after neoadjuvant chemotherapy (21.6% versus 13.7%) and lower number of BM (n= 1, BM 40.9% versus 25.4%; n= 2-3, BM 26.5% versus 26.7%; n ≥4, BM 32.6% versus 47.9%) (P < 0.001). Long-term survivors had leptomeningeal metastases (10.4% versus 17.5%) and extracranial metastases (ECM, 73.6% versus 82.5%) less frequently, and asymptomatic BM more often at the time of BM diagnosis (26.5% versus 20.1%), (P < 0.001). Median OS in long-term survivors was about two times higher than the cut-off of 15 months: 30.9 months [interquartile range (IQR) 30.3] overall, 33.9 months (IQR 37.1) in HER2-positive, 26.9 months (IQR 22.0) in luminal-like and 26.5 months (IQR 18.2) in TNBC patients. In our analysis, long-term survival of BC patients with BM was associated with better ECOG PS, younger age, HER2-positive subtype, lower number of BM and less extended visceral metastases. Patients with these clinical features might be more eligible for extended local brain and systemic treatment.

Abstract 4483: Distinct spatial distribution patterns of ALK-inhibitor naïve versus ALK-inhibitor treated ALK-positive NSCLC brain metastases

Abstract Background: Non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase rearrangement (ALK+) has a high affinity to form brain metastases (BrM). The cumulative incidence of BrMs in ALK+ lung cancer is over 50%, despite highly effective ALK tyrosine kinase inhibitors (TKIs) with CNS activity. Pharmacokinetic (PK) data from other CNS-active lung cancer TKIs (e.g., osimertinib) have revealed major brain white vs. gray matter drug concentration differences, raising the possibility of a PK-driven effect on BrM formation and response. This study aims to compare the size and distribution of ALK+ NSCLC BrMs at diagnosis in a TKI-naïve and TKI-exposed cohort. Methods: We retrospectively reviewed brain MRIs from the date of BrM diagnosis for patients with ALK+ NSCLC at Johns Hopkins. Demographic and clinical information were collected by chart review. Each tumor was marked in a standard space brain model in the corresponding anatomic location represented by a sphere of corresponding diameter using 3D Slicer 4.11. FreeSurfer white-gray matter atlases were used to assess BrM distribution. The data for patients who were on TKI vs TKI-naïve at the time of BrM diagnosis were then analyzed separately. T-tests were used to compare the metastatic burden (sum of BrM diameters), mean BrM diameter per patient, number of BM per patient, per individual mean of white matter exclusive (defined as no overlap with gray matter) and deep white matter (≥5mm away from gray matter) BrMs between patient groups. Results: 429 BrMs were identified in 39 patients, with 25 patients being TKI-naïve at the time of BrM diagnosis while 14 patients were on TKI therapy. TKI-exposed patients had significantly smaller BrM diameters than those in the TKI-naïve group (6.1±3.8 vs 10.2±5.5mm, p=0.02). While metastatic burden was very similar between the groups, the mean number of BrM per patient was numerically higher in the TKI-exposed group (10.6±11.9 vs 6.2±9.5; p=0.22). Notably, patients in the TKI-exposed group also had higher numbers of white matter exclusive (3.5±4.4 vs 1.4±2.0, p=0.05) and deep white matter metastases (3.2±4.3 vs 1.3±2.0, p=0.06) than those who were TKI-naïve. Conclusion: Our data highlight the differences in BrM characteristics among ALK+ NSCLC exposed to ALK TKI. TKI therapy was associated with similar BrM burden but smaller individual lesions that were more likely to be exclusive to the white matter where drug concentrations might be significantly lower. These findings suggest that suboptimal drug CNS distribution in the white matter may underly brain progression of ALK+ NSCLC despite TKI therapy. Spatial analyses evaluating ALK TKIs of varying CNS penetrance and later disease time points in more granular anatomic regions are ongoing. Citation Format: Tia Cheunkarndee, Paola Ganem, Kristen A. Marrone, Joseph C. Murray, Josephine L. Feliciano, Christine L. Hann, Susan C. Scott, David Ettinger, Valsamo Anagnostou, Patrick M. Forde, Julie R. Brahmer, Benjamin P. Levy, Vincent Lam, David O. Kamson. Distinct spatial distribution patterns of ALK-inhibitor naïve versus ALK-inhibitor treated ALK-positive NSCLC brain metastases. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4483.

Impact of prior systemic therapy on lymphocytic infiltration in surgically resected breast cancer brain metastases.

Tumor-infiltrating lymphocytes (TILs) have been positively correlated with response to systemic therapy for triple-negative and HER2 + subtypes and improved clinical outcomes in early breast cancer (BC). Less is known about TILs in metastatic sites, particularly brain metastases (BM), where unique immune regulation governs stromal composition. Reactive glial cells actively participate in cytokine-mediated T cell stimulation. The impact of prior medical therapy (chemotherapy, endocrine, and HER2-targeted therapy) on the presence of TILs and gliosis in human breast cancer brain metastases (BCBM) has not been previously reported. We examined prior treatment data for 133 patients who underwent craniotomy for resection of BMs from the electronic medical record. The primary endpoint was overall survival (OS) from the time of BM diagnosis. We examined the relationship between prior systemic therapy exposure and the histologic features of gliosis, necrosis, hemorrhage, and lymphocyte infiltration (LI) in BCBMs resected at subsequent craniotomy in univariate analyses. Complete treatment data were available for 123 patients. BCBM LI was identified in 35 of 116 (30%) patients who had received prior systemic treatment versus 5 of 7 (71.4%) who had not {significant by Fisher's exact test p = 0.045}. There were no statistically significant relationships between prior systemic therapy and the three other histologic variables examined. This observation suggests that systemic therapy may interfere with the immune response to BCBMs and cause exhaustion of anti-tumor immunity. This motivates clinical investigation of strategies to enhance LI for therapeutic benefit to improve outcomes for patients with BCBMs.

Abstract OT3-19-01: Phase II Study of Screening Brain MRIs in Stage IV Breast Cancer

Abstract Background: As systemic therapy improves, there has been an increasing number of breast cancer patients who develop brain metastasis. Screening of asymptomatic stage IV breast cancer patients with brain MRIs is not currently recommended by the National Comprehensive Cancer Network (NCCN) Guidelines. Retrospective reports suggest breast cancer patients are more likely to present with more advanced central nervous system disease at the time of brain metastasis diagnosis compared to melanoma and non-small cell lung cancer (NSCLC) patients. This may be in part due to routine screening recommendations in melanoma and NSCLC. Early detection and treatment of brain metastases may improve outcomes for breast cancer patients. Trial Design: The study is designed as a single arm, nonrandomized phase II study, with the goal of investigating the role of screening brain MRIs in neurologically asymptomatic patients with metastatic breast cancer. Breast cancer patients will be allocated based on receptor subtypes into triple negative (TN), HER2+, and hormone receptor (HR)+/HER2- breast cancer. Following study enrollment, patients will undergo a screening brain MRI. Patients will undergo a second brain MRI at first systemic progression or at 6 months whichever event occurs sooner. Eligibility: Asymptomatic, stage IV breast cancer patients that have progressed past first line therapy in the metastatic setting with an ECOG/= 6 months are eligible. Specific Aims: The primary objective is to determine the incidence of asymptomatic brain metastasis in metastatic breast cancer by subtype. Secondary objectives include determining the incidence of asymptomatic leptomeningeal disease, the number and size of brain metastases at diagnosis, the number of patients requiring whole brain radiation therapy vs. stereotactic radiation following diagnosis and overall survival and brain metastasis specific survival following brain metastasis diagnosis in metastatic breast cancer by subtype. Statistical Methods: A total of 30, 30, and 40 TN, HER2+, and HR+/HER2-, breast cancer patients will be enrolled, respectively. Using an incidence rate of 17%, the 95% CI by subtype will be (0.06,0.351), (0.06,0.351), and (0.07,0.322). Patient Accrual: This study is open with 30 patients enrolled at the time of submission. A total of 100 patients will be enrolled. Contact Information: Kamran A. Ahmed MD, Moffitt Cancer Center, email: kamran.ahmed@moffitt.org, Clinical trial information: NCT05115474. Funding: Florida Breast Cancer Foundation. Citation Format: Kamran A. Ahmed, Youngchul Kim, Avan Armaghani, John Arrington, Ricardo Costa, Brian J. Czerniecki, Roberto Diaz, Peter A. Forsyth, Hung Khong, Kimberley Lee, Loretta Loftus, Marilin Rosa, Hatem H. Soliman, Iman Washington, Aixa Soyano, Hyo S. Han. Phase II Study of Screening Brain MRIs in Stage IV Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-19-01.

Mapping distribution of brain metastases in renal cell carcinoma (RCC) and association with clinical features.

727 Background: Brain metastases (BM) are frequently observed in metastatic RCC (mRCC) with a tendency to present with hemorrhagic BM. Distribution patterns of BM in RCC and associations with clinical outcomes are not well understood. Here we present a detailed distribution analysis in a surgically resected BM RCC cohort with a focus on clinically relevant associations. Methods: A retrospective analysis was performed on patients (pts) with mRCC who underwent craniotomy for BM at our institution. We reviewed gadolinium-enhanced MRI brain and CT head (if available) at the time of BM diagnosis. We assessed the presence of hemosiderin on MRI or hemorrhage on CT in the BM lesion and marked each at their corresponding anatomic location. Public brain atlases were used for distribution analysis. Overall survival (OS) from the date of BM diagnosis and CNS progression free survival (CNS-PFS) from the date of craniotomy were calculated. Results: A total of 67 BM were analyzed from 46 pts. 23 with synchronous BM, 9 with two and 6 with 3 concurrent BM. Most patients were male (n=35, 76%) with a median age at diagnosis of 63 years. Primary histology was clear cell in 42 pts (91%) and 10 pts (22%) had renal vein thrombosis (RVT) at primary diagnosis. IMDC scores at time of BM diagnosis were favorable in 20%, intermediate in 60% and poor in 20%. Hemosiderin (MRI) or hemorrhage (CT) was seen in 82% and 80% of BM, respectively. 55% of lesions were left sided, 45% frontal, 21% parietal, 18% occipital, 7% temporal and 6% cerebellar. Posterior circulation and posterior cerebral artery territories contained 42% and 34% of BM despite supplying only 30% and 16% of the brain volume, respectively. Patients with solitary BM had higher Karnofsky performance status (p=0.006) and lower disease burden (p=0.004) than those with multiple BM. Shorter CNS-PFS was seen in association with hemosiderin on MRI (log-rank p=0.04) and RVT in primary specimen (log-rank p=0.002). IMDC risk scores (log-rank p&lt;0.001) predicted OS. On multivariable OS analysis, BM lateralized to the right (HR 2.6, p=0.06), hemosiderin in BM (HR 6.5, p=0.02) and IMDC risk groups (intermediate HR 2.9, poor risk HR 25.6, p&lt;0.04) were independent prognostic factors for shorter OS. Conclusions: The above-presented lesion mapping method shows clinically relevant findings in RCC BM. Tumoral hemosiderin deposits appear a potential parameter to predict outcomes in RCC BM which deserve further study and validation.

Survival after resection of brain metastasis: impact of synchronous versus metachronous metastatic disease

PurposePatients with brain metastasis (BM) from solid tumors are in an advanced stage of cancer. BM may occur during a known oncological disease (metachronous BM) or be the primary manifestation of previously unknown cancer (synchronous BM). The time of diagnosis might decisively impact patient prognosis and further treatment stratification. In the present study, we analyzed the prognostic impact of synchronous versus (vs.) metachronous BM occurrence following resection of BM.MethodsBetween 2013 and 2018, 353 patients had undergone surgical therapy for BM at the authors’ neuro-oncological center. Survival stratification calculated from the day of neurosurgical resection was performed for synchronous vs. metachronous BM diagnosis.ResultsNon-small-cell lung carcinoma (NSCLC) was the most common tumor entity of primary site (43%) followed by gastrointestinal cancer (14%) and breast cancer (13%). Synchronous BM occurrence was present in 116 of 353 patients (33%), metachronous BM occurrence was present in 237 of 353 patients (67%). NSCLC was significantly more often diagnosed via resection of the BM (56% synchronous vs. 44% metachronous situation, p = 0.0001). The median overall survival for patients with synchronous BM diagnosis was 12 months (95% confidence interval (CI) 7.5–16.5) compared to 13 months (95% CI 9.6–16.4) for patients with metachronous BM diagnosis (p = 0.97).ConclusionsThe present study indicates that time of BM diagnosis (synchronous vs. metachronous) does not significantly impact patient survival following surgical therapy of BM. These results suggest that the indication for neurosurgical BM resection should be made regardless of a synchronous or a metachronous time of BM occurrence.

Intracranial Metastasis of Extracranial Chondrosarcoma: Systematic Review With Illustrative Case.

Cerebral chondrosarcoma metastases are rare and aggressive neoplasms. The rarity of presentation has precluded rigorous analysis of diagnosis, risk factors, treatment, and survival. We analyzed every reported case through exhaustive literature review. We further present the first case with Maffucci syndrome. Three databases, PubMed, Embase, and Google Scholar, and crossed references were queried for cerebral chondrosarcoma metastases. Extracted variables included demographics, risk factors, tumor characteristics, interventions, and outcomes. Univariate and multivariate analyses were performed. Fifty-six patients were included from 1,489 literature results. The average age at brain metastasis was 46.6±17.6 years and occurred at a median of 24±2.8 months from primary diagnosis. Primary tumor histology (dedifferentiated 5.0±1.5 months, mesenchymal 24±3.0 months, conventional 41±7.4 months, p<0.05) and grade (low grade 54±16.7 months vs. high-grade 10±6.4 months, p<0.001) correlated with time interval until brain metastasis. A multiple enchondromatosis syndrome occurred in 13.2% of cases. At time of brain metastases diagnosis, extracranial metastases were identified in 76.2% of cases. Median survival after the development of brain metastasis was 2.0±0.78 months with a 1-year survival of 10.0%. On regression analysis, surgery reduced brain metastasis mortality risk and radiation trended towards reduced mortality risk (surgery: hazard ratio [HR] 0.22, 95% confidence interval [CI] 0.064-0.763, p=0.017; radiation: HR 0.31, 95% CI 0.091-1.072, p=0.064). We present a systematic review of cerebral chondrosarcoma metastases. Primary tumor histology and grade correlate with time until cerebral metastasis. Following cerebral metastasis, these tumors have poor prognosis and modestly benefit from surgery.

Evaluating the impact of early identification of asymptomatic brain metastases in metastatic renal cell carcinoma.

Brain metastases (BM) in metastatic renal cell carcinoma (mRCC) have been reported to be present in up to 25% of patients diagnosed with mRCC. There is limited published literature evaluating the role of routine intra-cranial imaging for the screening of asymptomatic BM in mRCC. To evaluate the potential utility of routine intra-cranial imaging, a retrospective cohort study was conducted to characterize the outcomes of mRCC patients who presented with asymptomatic BM, as compared to symptomatic BM. The Canadian Kidney Cancer Information System (CKCis) database was used to identify mRCC patients diagnosed with BM. This cohort was divided into two groups based on the presence or absence of BM symptoms. Details regarding patient demographics, disease characteristics, systemic treatments, BM characteristics and survival outcomes were extracted. Statistical analysis was through chi-square tests, analysis of variance, and Kaplan-Meier method to characterize survival outcomes. A p-value of <0.05 was considered statistically significant for all analyses. A total of 267 mRCC patients with BM were identified of which 106 (40%) presented with asymptomatic disease. The majority of patients presented with multiple (i.e., >1) BM (75%) with no significant differences noted in number of BM or BM-directed therapy received in symptomatic, as compared to asymptomatic BM patients. Median [95% confidence interval (CI)] overall survival (OS) from mRCC diagnosis was 42 months (95% CI: 32-62) for patients with asymptomatic BM, and 39 months (95% CI: 29-48) with symptomatic BM (p=0.10). OS from time of BM diagnosis was 28 months (95% CI: 18-42) for the asymptomatic BM group, as compared to 13 months (95% CI: 10-21) in the symptomatic BM group (p=0.04). Given a substantial proportion of patients may present with asymptomatic BM, limiting intra-cranial imaging to patients with symptomatic BM, may be associated with a missed opportunity for timely diagnosis and treatment. The utility of routine intra-cranial imaging in patients with renal cell carcinoma, warrants further prospective evaluation.

BIOM-02. MUTATIONAL ANALYSIS AND SINGLE CELL SEQUENCING OF MELANOMA BRAIN METASTASES REVEALS BRAF STATUS CORRELATES WITH CLINICAL OUTCOME AND DIFFERENTIAL IMMUNE POPULATIONS

Abstract Understanding the molecular landscape and microenvironment of melanoma brain metastases is critical to devise improved treatments. Here, we perform bulk and single cell genomic analysis of melanoma brain metastases to identify molecular correlates of clinical outcome. 84 consecutive patients who underwent surgical resection at a single institution with a histo-pathologically confirmed diagnosis of melanoma brain metastasis were retrospectively identified. In 60 patients (71%) with sufficient brain metastasis tissue for targeted next generation sequencing, DNA mutations were assessed with a CLIA certified sequencing assay. Single nuclear RNA sequencing using the 10x platform was performed on n=6 samples from treatment naïve patients. Overall survival (OS) and CNS progression free survival (CNS PFS) from time of brain metastasis diagnosis were estimated using the Kaplan-Meier method. The median patient age was 62 years old (range: 25-78 years), and the median clinical follow up was 17 months. A total of 33 patients (39%) had BRAFV600E melanoma brain metastases. Multivariate analysis incorporating age, performance status, and extracranial disease revealed BRAF status was an independent prognostic factor for OS (p&amp;lt; 0.05). In patients undergoing targeted next generation sequencing, the most common pathogenic variant was TERT promoter mutation (n=44; 73%). With regard to TCGA molecular melanoma subgroups, NRAS mutant (n=22; 37%) brain metastases were most common followed by BRAF mutant (n=20; 33%), NF1 mutant (n=11; 18%), and triple wildtype (n=7; 12%). Evaluation of clinical outcomes in the context of next generation sequencing results revealed no differences by TERT status but demonstrated worse overall survival in the BRAF mutant molecular group (p&amp;lt; 0.01, log-rank test). Single nuclear sequencing of 36,115 nuclei across 6 samples revealed BRAF wildtype tumors exhibit greater infiltrating immune cell populations including microglia and T cell subtypes. Future work will require integration of these findings with different systemic therapy regimens and across larger, prospective, multi-institutional cohorts.

Impact of Hormone Receptor Status on Development of Brain Metastases from HER2+ Breast Cancer

<h3>Purpose/Objective(s)</h3> Patients with HER2+ breast cancer (BC) are at high risk of developing and dying from brain metastases (BM) compared to patients who have HER2- disease. Some studies have suggested hormone receptor (HR) positivity can delay the development of BM possibly due to endocrine therapies controlling extracranial disease. However, the impact of HR positivity on the time to development of BM in HER2+ disease is not well understood. <h3>Materials/Methods</h3> We retrospectively reviewed data on patients with BM from BC from a single academic institution from 2005–2020, during which time trastuzumab was included in the standard of care. Patients with HER2+ BC and BM were stratified into groups based on HR status, i.e., ER+ and/or PR+. Overall survival (OS) data was analyzed using the Kaplan-Meier method with differences compared by the log-rank test. HR status and time to development of BM were compared using a two-tailed Student's t-test. <h3>Results</h3> Of 363 BC patients with BM, 67 patients (18.5%) were identified as HER2+ (median age 48; range 26–80). 63 (94%) of the 67 patients received trastuzumab. 39 (58.2%) of the 67 patients had HR+ disease (ER+ and/or PR+ disease) and 28 (41.8%) had HR- disease. 30 (76.9%) of 39 patients with HR+ disease received endocrine therapy. In HR+ patients, the median time to the diagnosis of BM was 48.4 mos (SD=57.9 mos), while in patients with HR- disease the median time to the diagnosis of BM was shorter at 29.0 mos (SD=49.1 mos) (p<0.02). The median OS after initial diagnosis of BM for patients with HR+ disease was 27.6 mos, and 9.8 mos for patients with HR- disease (p<0.46). Of the 67 patients, 20 (29.9%) patients presented with one BM, 23 (34.3%) with 2–9 BM, 17 (25.4%) patients with ≥10 BM, and 7 (10.4%) with unknown number of BM. The median number of BM in HR+ patients was 2.0 (SD=2.8), and the median number of BM in HR- patients was 1.0 (SD=3.2) (p<0.43). The median diameter of the dominant BM in HR+ patients was 2.5 cm (SD=1.4 cm; range=0.05–5.4 cm), and the median diameter of the dominant BM in HR- patients was 2.1 cm (SD=1.2 cm; range=0.2–4.4 cm) (p<0.14). Brain imaging was obtained for neurological symptoms in 45 (67.2%) patients; 5 (7.5%) were asymptomatic; and 17 (22.4%) had unknown indication for imaging. 30 patients (44.8%) had extracranial metastases at the initial time of HER2+ BC diagnosis, and their median time to the development of BM was 26.4 mos (SD=25.2 mos). In contrast, 34 patients (50.7%) had no extracranial or BM at BC diagnosis and had longer median interval time to BM development at 53.8 mos (SD=67.5 mos) (p<0.002). <h3>Conclusion</h3> The majority of patients with HER2+ BM were symptomatic at time of BM diagnosis. The most salient factors associated with a decreased time interval to development of BM included HR- status and presence of extracranial metastases at the time of initial HER2+ BC diagnosis.

Association of Baseline Symptom Burden and Survival among Patients with Brain Metastases at a Tertiary Cancer Center

<h3>Purpose/Objective(s)</h3> Brain metastases (BrM) commonly affect patients with solid malignancies and often correlate with significant symptomatology that profoundly impacts patients' quality of life (QOL). As systemic therapies increasingly improve extracranial disease control but lag in intracranial efficacy, a rising incidence of BrM persists. Thus, an urgent need exists to characterize the most common symptoms associated with BrM and to correlate these symptoms with survival. <h3>Materials/Methods</h3> We identified patients who received radiation therapy (RT) within 30 days of BrM diagnosis at a tertiary cancer center between 2017-2020 who prospectively completed the MD Anderson Symptom Instrument-Brain Tumor questionnaire (a validated instrument among patients with BrM for evaluation of 22 symptoms and 6 interference measures linked to daily functioning). Symptom severity score (range 0-10, with higher scores indicating more severe symptomatology) and interference score (range 0-10, with higher scores indicating greater compromise of activity-related/affective function), were compared via t-test or ANOVA by: age (>65 vs. ≤65), sex, Karnofsky performance status (KPS) (high, 90-100 vs. low, <90), Charlson co-morbidity index (CCI) (high, >2 vs. low, 0-2), primary tumor type (lung, breast, melanoma, other), and initial intracranial treatment strategy (surgical resection, stereotactic RT, or whole brain RT). Overall survival (OS) was assessed via Cox regression with the above co-variates; symptom severity and interference were evaluated in separate Cox models. <h3>Results</h3> A total of 101 patients were identified (median age=67 years, female=60%, primary lung cancer=45%). Mean symptom severity and interference scores at time of BrM diagnosis were 2.4 and 3.4, respectively. The most common severe (defined as a score >4) symptoms were: fatigue (47%), distress (40%), sleep disturbances (37%), drowsiness (35%), and sadness (32%). The most common high (score>4) interference measures were: enjoyment of life (47%), ability to work (44%), and walking (35%). Higher symptom severity was more common among females than males (2.8 vs 1.8, respectively; p=0.01); there were no significant differences in mean symptom severity or interference scores by age, KPS, CCI, or initial BrM treatment strategy. On Cox regression, higher symptom severity and higher interference scores were associated with worse OS (HR 1.30 per 1-point increase [95% CI, 1.11-1.51], p<0.001; and HR 1.18 per 1-point increase [95% CI 1.07-1.30], p=0.001, respectively); age, KPS, CCI, and other co-variates were not significantly associated with OS. <h3>Conclusion</h3> High symptom and interference burden is common among patients with BrM and associated with worse survival. Further work should investigate how improving symptoms, such as through palliative care interventions, may impact QOL trajectories and survival among the BrM patient population.

Mutational Analysis and Single Cell Sequencing of Melanoma Brain Metastases

<h3>Purpose/Objective(s)</h3> Melanoma brain metastases are a significant source of morbidity and mortality. While radiosurgery and (CNS) penetrant therapies have improved clinical outcomes, understanding the molecular landscape and microenvironment of brain metastases is critical to devise improved treatments for patients. Here, we perform bulk and single cell genomic analysis of melanoma brain metastases to identify molecular mechanisms underlying therapeutic response. <h3>Materials/Methods</h3> 50 consecutive patients who underwent surgical resection with histo-pathologically confirmed melanoma brain metastases and known BRAF^V600E status treated at a single institution were retrospectively identified. In 25 patients (50%) with sufficient brain metastasis tissue for targeted next generation sequencing, DNA mutations were assessed with a CLIA certified sequencing assay spanning over 500 cancer genes. Single cell RNA sequencing was performed on n=5 samples with sufficient frozen tissue. Overall survival (OS) and CNS progression free survival (CNS PFS) were estimated using the Kaplan-Meier method from time of brain metastasis diagnosis. Single cell analysis was performed using the 10x platform and Seurat R package. <h3>Results</h3> The median patient age was 64 years old (27 – 78 years), and the median clinical follow up was 17 months. 21 patients (42%) had BRAF^V600E melanoma brain metastases. BRAF^V600E mutation was associated with worse CNS PFS (p=0.04, log-rank test) and OS (p=0.03, log-rank test). Multivariate analysis incorporating age, Karnofsky performance score, and presence of extracranial disease supports <i>BRAF</i> status as an independent prognostic factor for OS (p<0.05). In patients undergoing targeted next generation sequencing, the most common pathogenic variant was <i>TERT</i> promoter mutation (n=19; 76%) followed by <i>TP53</i> mutation (n=9; 36%). The four TCGA molecular melanoma subgroups were equally represented: <i>NRAS</i> mutant (n=8; 32%), <i>NF1</i> mutant (n=6; 24%), <i>BRAF</i> mutant (n=6; 24%) or triple wildtype (n=5; 20%) Evaluation of clinical outcomes in the context of next generation sequencing results revealed no differences by <i>TERT</i> status but demonstrated worse overall survival in <i>BRAF</i> mutant tumors (median OS: 11 months; p=0.01, log-rank test). Single cell sequencing of 31,219 nuclei across 5 samples revealed distinct subpopulations between <i>BRAF</i> mutant and <i>BRAF</i> wildtype tumors in both the tumor and the brain microenvironment, with increased immune infiltration in <i>BRAF</i> wildtype tumors and greater neuronal subpopulations in <i>BRAF</i> mutant lesions. <h3>Conclusion</h3> Our data suggest <i>BRAF</i> may be useful as a prognostic biomarker and <i>TERT</i> promoter mutations as a recurrent intracranial molecular alteration in melanoma. Single cell analysis shows brain metastases exhibit distinct neuronal and immune populations. Future work will require integration of molecular status with treatment to help guide therapy and interrogation of larger, prospective, multi-institutional cohorts to validate these observations.

Characterizing metastatic uveal melanoma patients who develop symptomatic brain metastases.

Metastatic uveal melanoma (mUM) is an advanced ocular malignancy characterized by a hepatotropic pattern of spread. As the incidence of brain metastases (BM) in mUM patients has been thought to be low, routine CNS surveillance has not been recommended. Notably, no formal assessment of BM incidence in mUM has to date been published to support this clinical practice. We aimed to determine the true rate of BM in mUM and to clarify the clinical and genomic risk factors associated with BM patients through a collaborative multicenter, retrospective research effort. Data collected from 1,845 mUM patients in databases across four NCI-designated comprehensive cancer centers from 2006-2021 were retrospectively analyzed to identify patients with BM. Brain imaging in most cases were performed due to onset of neurological symptoms and not for routine surveillance. An analysis of demographics, therapies, gene expression profile, tumor next generation sequencing (NGS) data, time to metastasis (brain or other), and survival in the BM cohort was completed. 116/1,845 (6.3%) mUM patients were identified with BM. The median age at time of UM diagnosis was 54 years old (range: 18-77). The median time to any metastasis was 4.2 years (range: 0-30.8). The most common initial metastatic site was the liver (75.9%). 15/116 (12.9%) BM patients presented with BM at the time of initial metastatic diagnosis. Median survival after a diagnosis of BM was 7.6 months (range: 0.4-73.9). The median number of organs involved at time of BM diagnosis was 3 (range: 1-9). DecisionDX-UM profiling was completed on 13 patients: 10-Class 2, 2-Class 1B, and 1-Class 1A. NGS and cytogenetic data were available for 34 and 21 patients, respectively. BM was identified in 6.3% of mUM cases and was associated with high disease burden and a median survival of under 8 months once diagnosed. Since most patients in this cohort were symptomatic, the incidence of asymptomatic BM remains unknown. These data suggest the use of routine brain imaging in all mUM patients at risk for developing BM for early detection.

P11.35.B The clinical course of long-term survivors after the diagnosis of brain metastasis

Abstract Background To asses demographic and clinical parameters, treatment, and course of disease in patients surviving longer ≥ 5 years after the diagnosis of brain metastasis (BM). Material and Methods We retrospectively identified patients who were treated for BM and survived ≥ 5 years after initial BM diagnosis. We analysed and described clinical and treatment related parameters with respect to histology, time to occurrence and systemic/ BM-specific treatment. Results We included 48 patients with a mean age of 55 years (range 33-81, SD 12) at diagnosis of primary tumor and 58 (range 41-84, SD 20) at initial BM diagnosis. Histology was non-small-cell lung cancer in 18 (37.5%), melanoma in 14 (29.2%), breast cancer in 11 (22.9%), renal carcinoma in 2 (4.2%), and small-cell lung cancer, cancer of unknown primary and gastrointestinal cancer in one case each (2.1%). Treatment for primary tumor included resection (83.3%), chemotherapy (43.8%), radiation (33.3%), interferon therapy (18.8%), and immuno-/targeted therapy (25%). Most patients received a combination of latter. The mean interval between primary tumor and BM diagnosis was 36 months (range -2 to 277; SD 57). At the time of BM diagnosis, 50% of patients presented with systemically stable disease, 66.7% showed BM related symptoms, 92% showed a KPS ≥70. Most patients had 1 BM (72.9%), while 20.9% had 2-3 and 6.3% &amp;gt;3. Initial treatment for BM comprised resection (60.4%), stereotactic radiosurgery (27.2%), whole-brain-radiation therapy (8.4%), and interstitial brachytherapy (4.2%). Approximately half of the patients (52.1%) suffered from ≥1 BM relapse at initial treatment site. At the time of the analysis, 13 (27.1%) patients had died; cause of death was mostly unknown, in two patients each, systemic/cerebral cause was confirmed. The mean overall survival (OS) was 131 months (range 64-344, SD 68) and 95 (range 60-246, SD 36) after diagnosis of primary tumor and BM, respectively. All patients suffering from melanoma who had received interferon therapy (n=8) survived. Neither systemic status at BM diagnosis nor the administration of novel treatment agents or chemotherapy after BM diagnosis showed an impact on OS (p=0.642, p=0.177 and p=0.628, respectively). Further survival analysis was omitted due to subgroup sizes. Conclusion Despite the usually fatal course after BM development, some patients show long-term survival. Whether specific genetic parameters have a particular impact in this subgroup of patients, warrants further investigation.

P11.23.B Neurological symptoms independently associate with overall survival in patients with melanoma brain metastases

Abstract Background Based on the the rising detection of asymptomatic brain metastases (BM) and the remarkable intracranial responses of targeted- and immunotherapy in specific subgroups of asymptomatic BM patients, we aimed to evaluate the clinical characteristics and prognostic value of neurological symptoms in BM from melanoma. Material and Methods 670 patients with newly diagnosed melanoma BM were identified from the Vienna Brain Metastasis Registry. We performed retrospective chart review and statistical outcome analyses. Results 370/670 (55.2%) patients presented with neurological symptoms including neurological deficits (316/370; 85.4%), signs of increased intracranial pressure (126/370; 34.1%) and epileptic seizures (53/370; 14.3%). 57.6% (80/139) of patients with BRAF mutated melanoma presented with asymptomatic BM at diagnosis. Absence of neurological symptoms at BM diagnosis was associated with a longer median overall survival after time of BM diagnosis (7 vs. 5 months; p&amp;lt; 0.001; log-rank test). In multivariate analysis with the diagnosis-specific graded prognostic assessment (DS-GPA: HR:1.4; 95% CI, 1.25-1.48; p&amp;lt;0.001) and the graded prognostic assessment for melanoma using molecular markers (Melanoma-molGPA: HR:0.8; 95% CI, 0.66 -0.92; p&amp;lt;0.001), the presence of neurological symptoms (HR 0.8; 95% CI, 0.69 -0.96; p=0.003/ HR:0.6; 95% CI, 0.59-0.72; p&amp;lt;0.001) was found to be independently associated with survival prognosis from time of BM diagnosis respectively. Conclusion: Neurological symptoms at the time of BM diagnosis are an independent and strong prognostic factor in melanoma BM patients. Our results argue for the integration of neurological symptoms into the prognostic assessment of patients with BM from melanoma.