Diagnosis Of Brain Metastases Research Articles

Abstract A023: Analysis of survival and prognostic factors for patients with non-small cell lung cancer and brain metastasis: 10-year experience in a single institution

Abstract The aims of the study were 1) to perform the review of non-small cell lung cancer (NSCLC) patients with brain metastasis in our institution, 2) to investigate the response and prognostic factor of brain metastasis after institution’s best treatment, and 3) to suggest the shift of treatment paradigms for brain metastasis. From Jan. 2007 to Oct. 2018, A total 214 NSCLC patients with brain metastasis were enrolled. Female to male ratio was 0.65 and median age at diagnosis of NSCLC was 64 years (range, 30-90). 54 patients had a solitary brain metastasis and 76 patients had more than 10 lesions. Supratentorial, infratentorial and both locations were 106, 17, and 91 patients, respectively. 116 patients (54%) had symptoms associated with brain metastasis at the diagnosis of brain metastasis. Radiation only, radiosurgery, craniotomy with whole brain radiotherapy (WBRT), and supportive care were given for brain metastasis in 111 (52%), 10 (5%), 13 (6%) and 61 (29%) patients, respectively. Overall survival (OS) was associated with age, treatment modality, histology, egfr mutation. Median OS of Radiation only, radiosurgery, craniotomy with WBRT, and supportive care was 13, 15, 15 and 9 months, respectively (P-value 0.044). Median OS of adenocarcinoma and squamous cell carcinoma was 15 and 4 months, respectively (P-value <0.05). Median OS of egfr mutation and wild type was 18 and 9 months, respectively (P-value 0.016). The number and location of brain metastasis, symptoms and sex were not associated with OS Serial brain imaging was performed in 99 patients. 61 out of them (62%) developed shrinkage of brain metastasis (response group). Median OS of response and non-response group were 23 and 17 months (p-value 0.618). Age is significantly associated with response of brain metastasis to the institution’s best treatment (p-value 0.047). Interestingly, 3 patients developed complete remission of brain metastasis following WBRT and chemotherapy. The response duration was 431, 390, 641 days, respectively. Our data show that the prognosis of brain metastasis primarily depends on the age of NSCLC patients rather than the number, location of brain metastasis, treatment modality. Survival of NSCLC patients with brain metastasis was about 15 months despite the institution’s best treatment. The authors suggest that we should update our institution’s treatment policy and provide the latest treatments for patients. Citation Format: Seung Ho Yang. Analysis of survival and prognostic factors for patients with non-small cell lung cancer and brain metastasis: 10-year experience in a single institution [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A023.

Real-world outcomes in non-small-cell lung cancer patients with MET Exon 14 skipping mutation and brain metastases treated with capmatinib.

Aim: To assess real-world clinical outcomes in patients with non-small-cell lung cancerwith MET exon 14 skipping mutation and brain metastases (BM) who received capmatinib, a recently approved MET inhibitor, in routine US clinical practice. Materials & methods: Patient data were collected using a retrospective medical record review, led by participating oncologists. Eligible patients initiated treatment with capmatinib in any line, after BM diagnosis, between May 2020 and June 2021. Data on real-worldoverall response rate (rwORR) and real-world progression-free survival (rwPFS) were descriptively analyzed. Results: 68 eligible patients were analyzed. In patients treated with first-line (1L) capmatinib (n=55), the rwORR was 90.9% systemically and 87.3% intracranially; median systemic rwPFS was 14.1months. Among radiation-naive patients on 1L capmatinib (n=20), rwORR was 85.0%, both systemically and intracranially; median systemic rwPFS was 14.1months. Conclusion: This study showed substantial systemic and intracranial effectiveness for capmatinib in real-world setting; findings were consistent for RT-naive patients.

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.

Natural history of lung squamous cell brain metastases in patients treated with radiosurgery: a thirty-year experience at a tertiary medical center.

In this study we report our 30-year experience in stereotactic radiosurgery (SRS) treatment of lung squamous cell carcinoma (LUSC) brain metastases (BMs). It will serve to provide detailed longitudinal outcomes and predictors of efficacy in treating LUSC-BMs with SRS. We retrospectively reviewed 51 patients and 109 tumors treated with SRS at our center between 1993 and 2022. Patient demographics, PDL1 genotype, immunotherapy use and mortality cause were recorded. Radiological and clinical outcomes were followed at 1-3-month intervals post-SRS. Cox-regression analysis and Kaplan-Meier survival curves were performed in statistical analysis. We included 37 male and 14 female patients (median age 62.7 years at BM diagnosis). Median overall survival (OS) time was 6.9 months, 6-month OS rate was 62.1%, and Karnofsky performance scale (KPS) was the only independent predictor. Median time for local control maintenance was 7.6 months, 6-month local control rate was 69.1%, with TKI as the only independent predictor. Median time to distant failure was 5.13 months, 6-month distant failure rate was 51.1%, and factors with significant impact included gender (p = 0.002), presence of extracranial metastases (p < 0.001), use of immunotherapy(p < 0.001), PDL1 genotype (p = 0.034), and total intracranial metastases number (p = 0.008). However, no definitive benefits of immunotherapy were identified in patients with higher PDL1 mutational tumors. In this study we defined the natural history of disease progression and outcomes in SRS-treated LUSC-BM patients. We also identified predictors of OS and tumor control among these patients. The findings of this study will serve as a guide when counseling these patients for SRS.

MET-9 LEPTOMENINGEAL CARCINOMATOSIS ~ ITS' ASSOCIATION WITH MOLECULAR AND PATHOLOGICAL SUBTYPES~

Abstract Background Leptomeningeal carcinomatosis (LMC) is the most difficult condition to treat brain metastases (BM), and the presence or absence of malignant cells in the cerebrospinal fluid (CSF) is important in determining treatment strategies. Here, we defined Type I LMC (CSF cytology positive) as LMC, and compared the risk of LMC in lung cancer (LC) by subtypes. Patients and Methods In principle, at our hospital, we confirm CSF cytology when any of the following is observed: enhanced lesion in contact with the cerebrospinal fluid cavity, cranial nerve symptoms, or concurrent hydrocephalus. Of the 833 cases of BM from LC diagnosed since 2005, 794 cases, excluding 39 cases for which molecular diagnosis was not performed, were enrolled. Results There existed EGFRm: 321 cases, ALK: 19 cases, without driver mutation (w/oDM): 313 cases, small cell lung cancer (SCLC): 141 cases. 1326 CSF cytological examinations were performed in 533 patients, and 162 were diagnosed as LMC. The frequency of LMC at diagnosis of BM was EGFRm: 8.7%, ALK: 5.3%, w/oDM: 3.2%, and SCLC: 0.0% (P&amp;lt;0.0001). The time to LMC from diagnosis of LC was significantly shorter in EGFRm than ALK (H.R.:4.89, P=0.027), w/oDM (H.R.:2.96, P&amp;lt;0.0001), and SCLC (H.R.:7.23, P&amp;lt;0.0001). The use of TKIs after diagnosis of LC in EGFRm patients did not prevent LMC (HR: 0.932, P=0.493). The time to LMC from diagnosis of BM was also shorter in EGFRm in compared with ALK (H.R.: 4.89, P=0.027), w/oDM (H.R.: 3.94, P=0.057), and SCLC (H.R.: 8.94, P&amp;lt;0.0001). L858R had a higher risk of LMC than Ex19deletion (HR: 1.59, P=0.037). Neither TKI use (HR: 0.989, P=0.971) nor radiotherapy (HR: 0.846, P=0.567) prevented LMC. Conclusion EGFRm has a higher risk of developing LMC than other subtypes, and it is thought to be a factor in the high risk of central nervous system death in this subtype.

MET-5 OUTCOME OF MULTIDISCIPLINARY TREATMENT FOR BRAIN METASTASES IN PATIENTS WITH MELANOMA IN THE ERA OF MODERN SYSTEMIC THERAPY

Abstract Objective Recently modern systemic therapy and stereotactic irradiation have been developed. We reviewed the therapeutic outcome of brain metastases (BM) in patients with melanoma. Methods Data of patients with melanoma BM were retrospectively analyzed. Patients underwent multidisciplinary treatment, whole brain radiotherapy, stereotactic irradiation, immune check point inhibitor (ICI) and/or BRAF inhibitor, therapeutic indication was discussed at cancer board. If they had 3cm over diameter, surgical resection for BM was performed, when systemic life expectancy longer than three months after control of their BM and controlled extra-CNS metastases. Radiotherapy of BM was selected with number, size and location. Overall survival was analysis with Kaplan-Meier survival curves. Results Eighty-four patients were treated melanoma BM between November 2004 and December 2021 at our institution. Median age was 61 years, and 54% male. Sixty-seven patients were treated BM, but 17 were selected best supportive care from progressive systemic disease. After radiotherapy, 18 patients were administrated ICI, and BRAF inhibitor 10, both ICI and BRAF inhibitor 5, cytotoxic chemotherapy 13. Median overall survival (mOS) of treatment group was 132 days (95%CI: 90-230) from the diagnosis of brain metastases, and 35 days for BSC. MOS in patients both local (radiotherapy and/or surgery for BM) and systemic therapy was longer than that of local alone (209, 64 days, p&amp;lt;0.0001). MOS of surgery group (n=10) was superior longer than the others (420, 92 days, p&amp;lt;0.0001). For treatment period, patients diagnosed BM after 2014 longer than that before 2013 (175, 117 days, p&amp;lt;0.0001), when ICI was started to use for melanoma in Japan. Conclusion Stereotactic irradiation and/or surgery supported with modern systemic therapy may be effective strategy in patients with melanoma BM. Further clinical investigations with larger cohort are needed to clarify appropriate assessments for patients with melanoma BM.

HER2-Positive Gastroesophageal Cancers Are Associated with a Higher Risk of Brain Metastasis.

Brain metastasis from gastroesophageal adenocarcinomas (GOCs) is a rare but a devastating diagnosis. Human epidermal growth factor receptor 2 (HER2) is a prognostic and predictive biomarker in GOCs. The association of HER2 with GOC brain metastasis is not known. We performed a retrospective analysis of patients with GOCs with known HER2 status between January 2015 and November 2021. HER2 was assessed on either the primary tumour or metastasis by immunohistochemistry or in situ hybridization. The diagnosis of brain metastasis was made on standard imaging techniques in patients with symptoms or signs. HER2 results were available for 201 patients, with 34 patients (16.9%) HER2 positive. A total of 12 patients developed symptomatic brain metastasis from GOCs, of which 7 (58.3%) were HER2 positive. The development of symptomatic brain metastasis was significantly higher in the HER2-positive GOCs (OR8.26, 95%CI 2.09-35.60; p = 0.0009). There was no significant association of HER2 status and overall survival in patients with brain metastasis. Although the rate of brain metastasis remains low in GOCs, the incidence of symptomatic brain metastasis was significantly higher in patients with HER2-positive tumours.

DISP-01. IMMUNOTHERAPY ADMINISTRATION RATES IN PATIENTS WITH BRAIN METASTASES: IMPACT OF END STAGE RENAL DISEASE AND DIALYSIS

Abstract INTRODUCTION Comorbid conditions such as end-stage renal disease (ESRD) are common in patients with a diagnosis of brain metastasis (BM). Renal replacement therapy for ESRD patients typically includes hemodialysis or peritoneal dialysis. However, the efficacy of immunotherapy (IT) delivery in dialyzed patients is not well understood. Therefore, treatment modalities for BM and ESRD must be considered during clinical decision-making. This study aimed to determine the rate of IT administration in ESRD patients on dialysis using a network of real-world data. METHODS Data were collected from TriNetX (TriNetX, Inc., Cambridge, MA), a research network that provides clinical data access from 92 healthcare organizations globally. The independent variables included ‘secondary malignant neoplasm of brain’, ‘introduction of antineoplastic, monoclonal antibody’, ‘pembrolizumab’, ‘nivolumab’, ‘ipilimumab’, ‘ESRD’, ‘dependence on renal dialysis’ and ‘dialysis services and procedures’. Dialyzed patients were identified as having received dialysis within 3 months before to 5 years after their brain metastases diagnoses. Rates of immunotherapy administration were measured from BM diagnosis and concomitant dialysis use, or the lack thereof. RESULTS Two patient cohorts with malignant neoplasms of the brain were identified: a dialyzed cohort of 3,593 patients and a non-dialyzed cohort of 525,831 patients. The dialyzed cohorts’ mean age at index was 64.7 years; 43% were female. Of those, 81 patients received concomitant IT (2.25%). The non-dialyzed cohorts’ mean age at index was 60.7 years; 52% were female. From this cohort, 19,347 patients with BM received IT (3.68%). Patients with BM on dialysis were less likely to receive IT than those not on dialysis (odds ratio: 0.604, 95% confidence interval: 0.484-0.753, P &amp;lt; 0.0001). CONCLUSION Patients on dialysis may be selected against as candidates for IT. Given the relative scarcity of patient size and the potential implications of dialysis, prospective studies will be vital to improving IT efficacy in patients with BM.

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.

NCOG-01. CLINICAL DETERMINANTS IMPACTING OVERALL SURVIVAL OF PATIENTS WITH OPERABLE BRAIN METASTASES FROM NON-SMALL CELL LUNG CANCER

Abstract The incidence of brain metastases (BM) in non-small cell lung cancer (NSCLC) patients is continuously increasing. The recent improvements of systemic treatment in NSCLC necessitate continuous updates on prognostic subgroups and factors determining overall survival. In order to improve clinical decision-making, we investigated the clinical determinants affecting survival in patients with resectable NSCLC BM. A retrospective analysis was conducted of NSCLC patients with surgically resectable BM treated in our institution between 01/2015 and 12/2020. Relevant clinical factors affecting survival identified by univariate analysis where included in a multivariate logistic regression model. Overall, 264 patients were identified, with a mean age of 62.39 ± 9.98 years at initial diagnosis of NSCLC BM and overall survival (OS) of 23.22 ± 1.71 months. Factors that significantly affected overall survival from time of primary tumor diagnosis included the systemic metastatic load (mean: 45.9 ± 9.7 vs. 58.9 ± 9.4 months, p = 0.021) as well as a number of BM &amp;lt; 2 (mean: 25.5 ± 4.4 vs. 57.4 ± 7.8 months, p = 0.014). When adjusted for survival time after neurosurgical intervention, a significant survival benefit was found in patients &amp;lt; 60 years (32.5 ± 4.3 vs. 28.5 ± 5.2 months, p = 0.036) and patients without any concurrent systemic metastases at time of NSCLC BM diagnosis (mean 32.4 vs. 34.1, p = 0.032). Our data shows that the number of BM (singular/solitary), gender and age, but not localization (infra-/supratentorial), mass-edema index or time to BM occurrence impact overall survival in NSCLC BM patients.Additionally, our study shows that patients in prognostically favorable clinical subgroups have an overall survival, which differs significantly from current statements in literature. The described clinically relevant factors may improve the understanding of the risks and the course of this disease and aid future clinical decision making in tumor boards.

DISP-03. FEMALE-SPECIFIC CANCER METASTASES TO THE BRAIN: OUTCOMES IN A MEDICALLY UNDERSERVED AREA

Abstract INTRODUCTION Cancer care in medically underserved areas (MUA) is challenging and not widely reported. This report seeks to characterize the outcomes of female patients with brain metastases from breast, ovarian, cervical, and endometrial cancer who underwent surgical resection in an MUA. METHODS Our institution’s electronic medical record was queried for patients who underwent a craniotomy from 2013-2022. All female patients with brain metastasis from breast, ovarian, cervical, or endometrial cancer were included. The following variables were collected: alive or deceased, survival time, demographics, past medical history, metastasis location and number, extent of resection, time to metastasis, and time to recurrence. MUA was defined by the Health Resources &amp; Services Administration’s database (data.hrsa.gov). RESULTS Nine patients had metastases from breast, four from endometrial, one from ovarian, and one from cervical cancers. Metastases were most commonly located in the posterior fossa. The median age at surgery was 65 years. The median time from primary cancer diagnosis to brain metastasis diagnosis was 2.1 years. Gross total resection (GTR) was achieved in 15/21 metastases. Recurrence occurred in 7/15 patients after a median of 10 months. At the conclusion of the study, eight patients were deceased (53%), two patients were alive with no known new metastases (13%), four were alive with new metastases (27%), and one (6.7%) was lost to follow-up. In patients who died during the study, the median survival was 9.4 months, the median age at death was 65.7 years, and 7/8 had GTR of the metastasis(es). CONCLUSION To our knowledge, this is the first report of female-specific cancer brain metastases in an MUA. The median survival time was approximately nine months, which is similar to survival reported in multi-center studies. Further studies are recommended to identify and manage cancer care disparities in MUAs.

SURG-03. SURGICAL MANAGEMENT OF BRAIN METASTASIS FROM OVARIAN CANCER: A SYSTEMATIC REVIEW AND CASE SERIES

Abstract INTRODUCTION Ovarian cancer is a rare cause of brain metastasis requiring neurosurgical intervention. Management strategies vary and prognostic factors are not well known. OBJECTIVE We aim to systematically review the literature on management and outcomes of ovarian cancer brain metastasis and compare it with our experience. METHODS Systematic review was performed using PRISMA guidelines. Databases were sourced from inception to April 2022. Study selection was based on predetermined inclusion/exclusion criteria. A simultaneous retrospective analysis was performed on patients from our institution who underwent evaluation and treatment for metastatic intracranial lesions of ovarian origin. RESULTS Literature search generated 214 articles. Twelve were ultimately selected, representing 428 brain metastasis (BM) patients from ovarian cancer. Patients age from 27-80 years. The interval from cancer diagnosis to BM ranged from 0 – 226.2 months. Surgical resection (SR), stereotactic radiosurgery (SRS), and whole-brain radiotherapy were the most frequently used treatment modalities. Individual patients’ overall survival following BM diagnosis ranged from 0 – 173 months. For our institutional analysis, 9 patients were included with median age of 56 years. Median interval from diagnosis to BM was 51 months. Four patients were treated with SR and adjuvant SRS. Two patients had SR and SRS with additional extraventricular drain placement. Two patients had SR only, and one received only SRS. Median radiation dose received was 20 Gy. For those who experienced progression, median progression-free survival was 14 months. One patient exhibited no progression at the time of analysis. Three patients were alive at the time of analysis with two others lost to follow-up. CONCLUSION brain metastases following ovarian cancer are a rare outcome carrying a poor prognosis. Multimodal therapies, specifically SR and SRS, correlate with increased survival. Further study is needed to better guide optimal management, with particular attention to the benefits of resection with targeted adjuvant radiation.

Brain Metastases in Adults: A Five-Year Observational Study From King Abdulaziz Medical City.

Background As a well-documented fact, metastatic brain tumors are the most common cause of brain tumors in adults, with an incidence of 9-17%, based on various studies, although it was thought to be higher. The aim of this study was to describe recorded cases of metastatic brain tumors in the adult population of a tertiary care and oncology center in Jeddah, Saudi Arabia. Methods This study was conducted at King Abdulaziz Medical City (KAMC) at King Khalid Hospital in Jeddah, Saudi Arabia, including records from January 2016 to December 2020. The study implemented a retrospective cohort design to fulfill its aim. A data collection sheet containing demographic data such as age and gender, and information pertaining to the primary pathology, multiplicity, and survival outcome was used. Results A total number of 213 patients were enrolled in this study. Overall, 68.1% of the sample comprised of females. Approximately two-thirds (61.9%) of the patients' imaging results revealed multiplicity, whereas the remaining third (38.1%) had solitary lesions. The estimated overall survival median after the diagnosis of brain metastasis was six months (95% CI: 5.5-6.5). Conclusion We recommend conducting a nationwide study to better understand the incidence in accordance to geographical and gender differences. We can further expand our research to include other institutes in Saudi Arabia, and include important predictors such as time from the diagnosis of primary pathology to brain metastasis, disease progression cost, and disease progression in the months prior to the patients' death.

Clinical outcomes of non-small cell lung cancer brain metastases treated with stereotactic radiosurgery and immune checkpoint inhibitors, EGFR tyrosine kinase inhibitors, chemotherapy and immune checkpoint inhibitors, or chemotherapy alone.

Immune checkpoint inhibitors (ICIs) and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are commonly used in the systemic management of non-small cell lung cancer (NSCLC) brain metastases (BMs). However, optimizing control of NSCLC BM with stereotactic radiosurgery (SRS) and various systemic therapies remains an area of investigation. Between 2016 and 2019, the authors identified 171 NSCLC BM patients with 646 BMs treated with single-fraction SRS within 3 months of receiving treatment with ICIs (n = 56; 33%), EGFR-TKI (n = 30; 18%), chemotherapy and ICIs (n = 23; 14%), or standard chemotherapy alone (n = 62; 36%). Time-to-event analysis was conducted, and outcomes included distant intracranial control (DIC), local control (LC), and overall survival from SRS. The median follow-up from BM diagnosis was 8.9 months (range 0.3-127 months). The 12-month Kaplan-Meier DIC rates were 37%, 53%, 41%, and 21% (p = 0.047) for the ICI, EGFR-TKI, ICI and chemotherapy, and chemotherapy-alone groups, respectively. On multivariate analysis, DIC was improved with EGFR-TKI (HR 0.4, 95% CI 0.3-0.8, p = 0.005) compared with conventional chemotherapy and treatment with SRS before systemic therapy (HR 0.5, 95% CI 0.3-0.9, p = 0.03) compared with after; and LC was improved with SRS before (HR 0.4, 95% CI 0.2-0.9, p = 0.03) or concurrently (HR 0.3, 95% CI 0.1-0.6, p = 0.003) compared with after. No differences in radionecrosis were noted by timing or type of systemic therapy. The authors' analysis showed significant differences in DIC based on receipt of systemic therapy and treatment with SRS before systemic therapy improved DIC. Prospective evaluation of the potential synergism between systemic therapy and SRS in NSCLC BM management is warranted.

Prognostic value of human epidermal growth factor receptor 2 status and systemic therapy in breast cancer with brain metastases treated with radiotherapy.

To evaluate the prognostic value of human epidermal growth factor receptor 2 (HER2) status and how to use HER2-targeted therapy in breast cancer (BC) with brain metastases (BM) treated with radiotherapy. We retrospectively reviewed the data of 103 BC patients with parenchymal BM treated with radiotherapy. We collected data on the hormone receptor (HR), HER-2 amplification status, and systemic therapy after treatment for BM. The primary outcome was overall survival (OS), which was calculated from the diagnosis of BM to death. The median follow-up time from the diagnosis of the first BM was 9.1 months (range, .7-88 months). The 2-year OS of the HR-positive and HER2-positive (HR+HER2+) BC (31.3 mo) was significantly better than those of the HR-HER2+ (9,5 mo, p=.002), HR+HER2- (9.9mo, p=.003), and triple-negative BC (3.9 mo, p<.001) ( . Of the 36 HER2-positive patients, 31 patients treated with HER2-targeted therapy after radiotherapy for BM had a significantly better 2-year OS than those who did not receive HER2-targeted therapy (43%vs. 0%; p<.001). Among the 31 patients treated with HER2-targeted therapy, the 2-year OS for those treated with multiple anti-HER2 agents during the entire course of treatment was significantly higher than that for patients treated with a single agent (60%vs. 24%; p=.006). HR+HER2+ BC patients with BM treated with radiotherapy show a better prognosis than other subtypes. For HER2-positive patients with good prognosis, it may be important to continue HER2-targeted therapy appropriately after radiotherapy for BM.

Brain Metastases from Biliary Tract Cancer: Case Series and Clinicogenomic Analysis

<h3>Purpose/Objective(s)</h3> Biliary tract cancers (BTCs) are uncommon and generally carry a poor prognosis; with novel targeted therapies for specific tumor-related molecular alterations, outcomes for BTC patients appear to be improving. Brain metastases (BM) from BTC (BM-BTC) are rare, with limited data suggesting BM incidence rates between 0.15% and 1.4% among all BTC patients. Here, we report the largest series of BM-BTC patients to date and characterize these patients by tumor-related molecular alterations. <h3>Materials/Methods</h3> Retrospective review of 822 BTC patients seen at our center (a major tertiary referral center) from 2005 to 2021 was performed; BM-BTC patients were identified, and demographic, clinical, and molecular data were extracted. <h3>Results</h3> Twenty of 822 BTC patients (2.4%) were identified to have BM. Median follow-up time after primary BTC diagnosis was 99.8 months, and 33.8 months after BM diagnosis. Median time from primary diagnosis to BM development (diagnosis of BM) was 15.6 months (range, 1.1-66.0 months). Median overall survival (OS) from primary diagnosis was 32.0 months (2.9-99.8), and median OS from BM diagnosis was 6.5 months (0.3-33.8). Patients who underwent BM-directed therapy had significantly higher median OS from BM diagnosis than patients receiving supportive care only (6.7 vs 0.7 months, p<0.001). The BM-BTC cohort was enriched for TP53 (37%) and <i>BRAF</i> (26%) mutations. BM-BTC patients with <i>BRAF</i> mutation had improved OS after BM diagnosis (19.6 vs 4.2 months, p=0.048). <h3>Conclusion</h3> This study provides the largest series of BM-BTC patients to date, providing molecular characterization of this subgroup of BTC patients. <i>BRAF</i> mutations appear to be enriched among BM-BTC patients, found in 26% of BM-BTC patients in this series compared with 5-7% in larger non-BM BTC cohorts. With advances in targeted therapy for BTC patients with actionable mutations, examining a changing landscape of patterns of failure, with emphasis on brain metastases, is warranted.

Clinical and Genomic Characterization of Esophageal Cancer Brain Metastases

<h3>Purpose/Objective(s)</h3> Brain metastases from esophageal cancer are a rare and understudied form of metastatic spread with limited treatment options. We characterized the clinical and genomic features of esophageal cancer brain metastases. <h3>Materials/Methods</h3> We identified 129 patients who were diagnosed with brain metastases secondary to esophageal cancer at a single institution between 2002 and 2020. Survival analysis was performed using multivariable Cox proportional hazards regression. Results of targeted next-generation sequencing (NGS) panels were obtained for 56 patients representing 62 adenocarcinoma samples and compared to a cohort of 1344 esophageal adenocarcinoma samples identified from the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) v11.0. <i>ERBB2</i>/<i>HER2</i> amplified/overexpressed (<i>HER2</i>+) status was determined using routine clinical assays and/or NGS results. <h3>Results</h3> Median age at the time of esophageal cancer diagnosis was 63 years (interquartile range 58-68 years). 14% of the cohort (n=18) was female, 93% (n=120) had adenocarcinoma, and 98% (n=126) of primary tumors involved the distal esophagus and/or gastroesophageal junction. 50% (n=64) of patients had distant metastases at presentation, including 18 patients with brain metastases. 51% (n=66) underwent resection for brain metastases, and 84% (n=108) underwent radiation therapy (n=26 for whole brain, n=55 for partial brain or stereotactic, and n=27 for both). With median follow-up of 19 months for the entire cohort, median overall survival following primary cancer diagnosis was 22 months and significantly higher for <i>HER2</i>+ disease (31 vs 19 months, hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.47-0.87, <i>P</i>=0.004). For patients without brain metastases initially, the median time between initial diagnosis and brain metastasis diagnosis was 13 months and significantly higher for patients without distant metastasis initially (14 vs 12 months, HR 0.59, 95% CI 0.39-0.89, <i>P</i>=0.012). Median overall survival after brain metastasis diagnosis was 7 months and significantly higher for <i>HER2</i>+ disease (14 vs 4 months, HR 0.60, 95% CI 0.45-0.82, <i>P</i>=0.001). NGS results were notable for an enrichment of <i>HER2</i> high amplification events (42% vs 19%, <i>P</i><0.0001), <i>HER2</i> mutations (10% vs 4%, <i>P</i>=0.036), and <i>TP53</i> mutations (97% vs 73%, <i>P</i><0.00001; all with Fisher's exact test) compared to the GENIE cohort. <h3>Conclusion</h3> Esophageal cancer brain metastases are associated with a poor prognosis and have a distinct molecular profile. Further efforts are necessary to elucidate the drivers of this unique and aggressive entity in order to develop novel treatment strategies.

CNS Outcomes in ALK Fusion Positive NSCLC Patients with BM Who Received Alectinib with or without Local Therapy

<h3>Purpose/Objective(s)</h3> Brain metastases (BM) are common in patients (pts) with anaplastic lymphoma kinase (<i>ALK</i>) fusion positive non-small cell lung cancer (NSCLC). <i>ALK</i>-rearrangements are observed in approximately 5% of NSCLC patients. Alectinib is a highly selective, central nervous system (CNS)-penetrant tyrosine kinase inhibitor which may allow patients with BMs to defer local therapy (LT) such as surgery, stereotactic radiosurgery (SRS) or whole brain radiation therapy (WBRT). We characterized the CNS outcomes in pts with <i>ALK</i> fusion positive NSCLC BM treated with alectinib with or without LT. <h3>Materials/Methods</h3> We retrospectively reviewed <i>ALK</i> fusion-positive NSCLC pts with BMs who received alectinib at the diagnosis of BM from 1/2012 and 5/2021. CNS response rates (RR) were assessed via modified Response Assessment in Neuro-Oncology (RANO)-BM criteria. Surgically resected lesions were excluded from this analysis. A complete response (CR) was defined as complete disappearance of the lesion and a partial response (PR) was defined as a >30% decrease in size relative to baseline. Intracranial progression (iPFS) was analyzed using the Kaplan-Meier (KM) method with log-rank test, with death factored in as a competing risk. <h3>Results</h3> We identified 39 pts with <i>ALK</i> fusion positive NSCLC who initiated alectinib at BM diagnosis: 27 pts received alectinib only and 12 pts received alectinib and upfront LT including surgical resection (<i>n</i> = 2, 17%), comprehensive surgical resection followed by SRS (<i>n</i> = 2, 17%), SRS 4 (<i>n</i> = 4, 33%) or WBRT (<i>n</i> = 4; 33%). Alectinib was first-line therapy for 26 (67%) pts and second-line therapy for 12 (31%) pts. Median follow-up from BM diagnosis was 50.6 months (IQR 33.3-56.7). Patients treated with alectinib and LT were more likely to have pre-treatment neurologic symptoms (83% vs 33%), larger median BM size (median 12 mm vs 5 mm), and BM > 1 cm in size (83% vs 30%) compared to pts who received alectinib only. Despite these negative factors, there were no differences between both groups with regards to iPFS (TKI only, HR 1.31, 95% CI 0.55-3.11; p=0.54). A total of 28 and 55 lesions were assessed for CNS RR in the alectinib + LT and alectinib only groups, respectively. At 6-months, the CNS RR were 46% (PR) and 54% (CR) vs. 19% (PR) and 74% (CR) in the alectinib + LT and alectinib only groups, respectively. <h3>Conclusion</h3> To our knowledge, this study represents the largest yet reported series of alectinib-treated NSCLC BM with detailed patient and lesion-level CNS-specific outcomes. Despite the fact that patients with <i>ALK</i> fusion positive NSCLC treated with alectinib + LT had larger BM and a greater likelihood of pre-treatment neurologic symptoms, the iPFS was similar between the patients treated with alectinib only and alectinib + LT. With newer generation TKIs which may have CNS penetrance, further prospective studies are required to identify which patients are most likely to benefit from the addition of LT to <i>ALK</i>-directed therapy.

Brain Metastases in Japanese NSCLC Patients: Prognostic Assessment and the Use of Osimertinib and Immune Checkpoint Inhibitors

<h3>Purpose/Objective(s)</h3> To validate the Graded Prognostic Assessment for lung cancer using molecular markers (Lung-molGPA) for Japanese non-small cell lung cancer (NSCLC) patients with brain metastasis (BM) and assess the factors impacting survival. <h3>Materials/Methods</h3> We retrospectively analyzed 294 NSCLC patients who were newly diagnosed with brain metastases (BM) between 2013 and 2020 and received radiotherapy for BM initially at the Hokkaido Cancer Center. Lung-molGPA items, sequence of therapy, use of osimertinib, expression of PD-L1 (classified as high, low, and no) and use of immune checkpoint inhibitors (ICI) were evaluated for influence. The main outcome measure was survival from the day of diagnosis of BM, and log-rank tests were performed to compare the results. <h3>Results</h3> The median survival times for adenocarcinoma by groupings of GPA score (0‒1.0, 1.5‒2.0, 2.5‒3.0, and 3.5‒4.0) were 5.5, 14.8, 28.3, and 39.0 months (p<0.0001), respectively. The median survival times for non-adenocarcinoma by groupings of GPA score (0‒1.0, 1.5‒2.0 and 2.5‒3.0) Group were 3.2, 11.0 and 16.0 months (p=0.0011), respectively. In adenocarcinoma patients with gene mutations, osimertinib significantly improved the outcome. The median survival times for the group with and without osimertinib treatment were 34.2 and 17.6 months, respectively (p=0.0164). In a comparison of treatment sequences, no significant differences were found between groups; however, patients who received both irradiation and tyrosine-kinase inhibitor for BM had better prognoses than patients with only irradiation for BM (35.8 months vs 14.8 months, p=0.0007). In patients tested for PD-L1 expression, the median survival times after diagnosis of brain metastasis were 5.6, 22.5 and 9.3 months for high-, low- and no-expression groups (p=0.2198), respectively. Also, in patients with high PD-L1 expression, those with ICI had better survival (median OS, 8.6 months) than those without (median OS, 3.6 months). <h3>Conclusion</h3> We conformed that Lung-molGPA successfully classified Japanese NSCLC patients with brain metastasis by prognosis. Osimertinib was shown to extend survival of EGFR-positive NSCLC patients with BM, and ICI proved effective in patients with high PD-L1 expression.

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.