The inflammatory microenvironment in brain metastases: potential treatment target?

BACKGROUND: Density of tumor-infiltrating lymphocytes (TILs) has a prognostic impact in various extracranial solid tumors. While a favorable correlation of CD3+ effector TIL, CD8+ cytotoxic TIL and CD45RO+ memory TIL density was observed, high density of FOXP3+ regulatory TILs is associated with impaired survival prognosis in previous studies of primary extracranial solid tumors. So far, TILs have not been analyzed in brain metastases (BM) from solid tumors. METHODS: 118 BM specimens (primary tumor: lung cancer (62/118; 52%); breast cancer (17/118; 14%); melanoma (6/118; 5%); kidney cancer (10/118; 8%); another primary tumor (23/118; 19%)) were available. All patients had one single BM and received neurosurgical resection as first treatment for BM. Preoperative MRT was available in all patients. Clinical data was retrieved by chart review. Overall survival (OS) was defined as time from first diagnosis of BM to last follow up or death. Analysis of for CD3, CD8, CD45RO and FOXP3 was performed by immunohistochemical methods on full section slides and analyzed using previously published semiquantitative evaluation criteria. RESULTS: Dense infiltration with CD3+ TILs was observed in 64/118 (54%) specimens, with CD8+ TILs in 70/118 (59%), with CD45R0+ TILs in 72/118 (61%) and with FOXP3+ TILs in 26/118 (22%) specimens. Dense CD3+ TILs infiltration was more frequently observed in lung cancer, melanoma and kidney cancer BM than in breast cancer BM (p = 0.024; Chi square test). Melanoma BM had more frequently dense infiltration with FOXP3+ TILs (p = 0.003; Chi square test). Density of CD3 + , CD8 + , CD45RO + , or FOXP3+ TILs did not correlate with preoperative steroid application (p > 0.05; Chi Square test). Patients with dense infiltration of CD3+ TIL had significantly improved OS (27 vs. 12 months; p = 0.002; log rank test). Further, dense infiltration with CD8+ TILs was associated with improved OS (16 vs. 12 months; p = 0.048; log rank test) and large peritumoral edema on the preoperative MRI (p = 0.03; Chi Square test). Dense infiltration with CD45RO+ TILs was correlated with improved survival prognosis (18 vs. 8 months; p = 0.01; log rank test). Patients with dense infiltration of FOXP3+ TILs had an impaired survival prognosis (6 vs. 16 months; p = 0.05; log rank test). A composite “immuno score” showed a strong association with median OS (27 months for cases CD8 + /CD45RO + /FOXP3- infiltrates and 6 for cases with CD8-/CD45RO-/FOXP3+ infiltrates; p = 0.001 log-rank test). CONCLUSION: Dense TILs infiltrates are common in BM and correlate with the amount of peritumoral brain edema and improved survival prognosis. Further studies should investigate the therapeutic impact of immunomodulatory agents in patients with BM.

Background Immunotherapy (IO) has changed the treatment landscape of metastatic cancer patients, however, treatment resistance is frequent. We aimed to characterize the inflammatory tumor microenvironment in brain metastases (BM) after IO to gain a deeper understanding of immunologic escape mechanisms. Material and Methods Solid cancer patients who had BM resection after IO progression (IO cohort) were retrospectively identified. We analyzed tumor-infiltrating immune cell subsets (CD3, CD8, CD45RO, FOXP3) and expression of immune checkpoint molecules (PD-L1, PD-1, LAG-3) by immunohistochemistry. A control cohort of BM tissue samples without prior IO served for comparison (no immunotherapy cohort, NIO). Results Twenty-eight IO patients (12/28, 42.9% females; 16/28, 57.1% males; median 61 years; 14/28, 50% lung cancer; 5/28, 17.9% melanoma; 4/28, 14.3% renal cell carcinoma; 1/28, 3.6% breast cancer; 4/28, 14.3% other cancer entities) and 57 NIO patients (28/57, 49.1% females; 29/57, 50.9% males; median 58 years; 35/57, 61.4% lung cancer; 9/57, 15.8% breast cancer; 4/57, 7.0% melanoma; 3/57, 5.3% renal cell carcinoma; 6/57, 10.5% other cancer entities) were included. IO patients had a median of one (range 0-4) systemic therapy line prior to IO. Median time from last IO application until BM resection was 5.6 months (range 0.2-49.8 months). Patients received a median number of 7 (range 1-56) IO applications (14/28, 50% PD-1-targeting IO; 8/28, 28.6% PD-L1; 2/28, 7.1% CTLA4; 4/28, 14.3% CTLA4+PD-1; 3/28, 10.7% IO+chemotherapy). No statistically significant differences in the densities of investigated TILs or PD-L1 expression between the IO and the NIO cohort were observed. Patients of the IO cohort showed higher PD-L1 expression compared to the NIO cohort (57.1 vs. 42.1%, Chi-square, p>0.05). Overall survival (OS) was similar in both cohorts, with a median OS of 11.0 months (range 5.0-17.0) in the IO cohort and 11.0 months (range 5.5-16.5) in the NIO cohort. Conclusion Our findings show an upregulation of PD-L1 in BM occurring after prior IO therapy in the absence of other overt changes in the inflammatory microenvironment. Ongoing analyses in this cohort are investigating possible molecular driver of resistance by analyzing DNA methylation profiles of pre-and post-IO tissue samples of the IO cohort to potentially gain insights on inflammatory IO resistance mechanisms in BM patients.

Lung cancer is the leading cause of cancer-related death worldwide. Numerous studies have been performed to investigate the correlation between epidermal growth factor receptor (EGFR) mutation status and the incidence of brain metastases (BMs) in patients with non-small cell lung cancer (NSCLC), however, the outcomes were inconsistent. Thus, we performed this study to establish the role of EGFR mutation status in BMs. Electronic databases PubMed, Embase, Cochrane Library, CBM, WanFang, CNKI were searched to identify relevant trials. The primary endpoint was the incidence of BMs in EGFR mutations or wild type NSCLC and the secondary endpoint was overall survival calculated from the BMs emerging (BMOS). Twenty-two studies incorporating 8,152 participants were eligible. EGFR mutations group possessed a significantly higher risk of BMs (OR =1.99; 95% CI, 1.59-2.48; P=0.000) than EGFR wild type group. In the stratified analysis, compared with EGFR wild type group, EGFR mutations group had a significant higher incidence (OR =2.01; 95% CI, 1.56-2.59; P=0.000) of subsequent BMs while only a trend of increasing the incidence of initial BMs (OR =1.38; 95% CI, 0.98-1.94; P=0.066). Moreover, exon 19 deletion had a trend of increasing the incidence of BMs than exon 21 mutation (OR =1.44; 95% CI, 0.77-2.68; P=0.252). Compared with EGFR wild type group, EGFR mutations group possessed a prolonged overall BMOS (HR =0.68; 95% CI, 0.47-0.98; P=0.038) and a longer BMOS in initial BMs (HR =0.50; 95% CI, 0.31-0.80; P=0.004) but no significant difference in NSCLC with subsequent BMs (HR =0.95; 95% CI, 0.42-2.15; P=0.901). Patients with EGFR mutations were more susceptible to develop into BMs than those with EGFR wild type, especially during the course of disease.

1081 Background: In patients with brain metastasis (BM) of melanoma or lung cancer, significant activity of immune checkpoint inhibitors has been reported. However, details of the immune microenvironment in BM has not been unveiled. In this study, we used immunohistochemistry (IHC) to compare primary breast tumors and BM tumor samples with respect to tumor infiltrating lymphocytes (TILs) and tumor characteristics related to the immune system. Methods: We retrospectively identified 107 patients with breast cancer, diagnosed with BM, who had undergone surgery between 2001 and 2012 at 8 institutions. We collected 191 samples which included both BM samples alone and pair-matched samples (primary and BM). Hematoxylin and eosin (H&E) stained slides were evaluated for stromal TILs in 10% increments (0–1%, > 1– < 10%, 10%–100%). IHC was performed using the following primary antibodies: CD4, CD8, Foxp3, PD-L1, PD-L2 and HLA class I. The cells positive for each antibody signal were counted automatically using ImageJ (NIH). The expression of PD-L1, PD-L2, and HLA on the tumor cells was scored as 0 (negative), 1 (weak or focal), or 2 (strong). Results: The median category of TILs of BM tumors was > 1– < 10% (range: 1–30%). Forty-six pair-matched samples were analyzed and the percentage of TILs in the primary breast tumor was significantly higher than that in BM samples (paired t-test, P < 0.01). The number of CD4/CD8/Foxp3 positive cells in primary breast tumor was also significantly higher than in BM samples (paired t-test, P < 0.05 for all categories). The negative/positive conversion occurred with the expression of HLA/PD-L2 on tumor cells (paired t-test, P = 0.03/0.06, respectively). No significant difference was observed in the overall survival (OS) of patients, from initial BM, based on high or low TILs (log-rank test, P = 0.131). However, triple negative breast cancer patients with low TILs had significantly shorter OS compared with patients with high TILs (log-rank test, P = 0.04). Conclusions: We demonstrated that TILs in BM tumors was significantly lower as compared to primary breast tumors. The expression of immune related molecules on tumor cells was converted in BM tumors.

Background: The routine screening of brain metastasis (BM) is not recommended in patients with metastatic breast cancer (MBC) by guidelines. Due to survival improvement and increased use of magnetic resonance imaging (MRI) contribute the increasing of MBC BM incidence. The incidence of BM and survival from BM were various by molecular subtypes. The prognostic role of early detection of oligo BM and subsequent local treatment by subtypes is not clear. We aimed to compare BM free survival (BMFS) and BM overall survival (BMOS) by both treatment modalities and subtypes. Methods: In the Yonsei Breast Cancer MBC Database, we identified 1252 MBC patients who were diagnosed from 2006 to 2016. Data of 358 MBC patients (127 HR+/HER2-, 80 HR+/HER2+, 64 HR-/HER2+, 87 HR-/HER2-) with BM were available for the analysis. BMFS was defined as the time from the diagnosis of MBC to the diagnosis of BM. MBC patients with initial BM were excluded from analysis of BMFS. BMOS was defined as the time from the diagnosis of BM to any cause of death. Treatment modalities were analyzed as three categories; whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), and neurosurgery. Results: Among the 1252 MBC patients, 47.7%, 14.7%, 13.1%, 17.6%, and 6.9% had HR+/HER2-, HR+/HER2+, HR-/HER2+, HR-/HER2-, and unknown subtypes, respectively. The incidence of initial BM were highest among patients with HR-/HER2- (14.5%) and were lowest with HR+/HER2- (5.2%) Incidence of initial metastasisInitial metastatic sitesHR+/HER2-, n(%)HR+/HER2+, n(%)HR-/HER2+, n(%)HR-/HER2-, n(%)Unknown, n(%)PBrain31 (5.2)16 (8.7)12 (7.3)32 (14.5)6 (6.9)<0.001Lung197 (33)72 (39.1)62 (37.8)99 (45)33 (37.9)0.036Liver137 (22.9)46 (25)52 (31.7)56 (25.5)16 (18.4)0.122Bone403 (67.5)109 (59.2)66 (40.2)90 (40.9)48 (55.2)<0.001Distant LN176 (29.5)74 (40.2)60 (36.6)93 (42.3)22 (25.3)0.011Pleura116 (19.4)19 (10.3)23 (14)40 (18.2)13 (14.9)0.045 . The median BMFS was 17.3 months (95% confidence interval (CI); 14.32-20.28) among the all patients with BM. The median BMFS was significantly shorter in the ER-/HER- subtypes (12 months, 95% CI; 20.73-31.67), and followed by ER-/HER2+ (14.8 months, 95% CI; 11.50-18.10), ER+/HER2+ (20.9 months, 95% CI; 16.88-24.92), and ER+/HER2- (26.2 months, 95% CI; 20.73-31.67). The median BMOS was significantly better in the SRS (16.8 months; 95% CI; 13.53-20.07) and surgery group (13.4 months, 95% CI; 7.19-19.61) compared with WBRT (6.9 months, 95% CI; 5.04-8.76) and no treatment (1.2 months, 95% CI; 0.32-2.08). Conclusions: Incidence of initial BM and BMFS were significantly different by subtypes. Patients who were treated with SRS or neurosurgery showed better survival compared to WBRT. This findings support to consideration of screening of BM in HER2+ or triple negative subtypes for the early detection of oligo BM. Citation Format: Kim GM, Cho YU, Kim SI, Park S, Park HS, Kim JY, Chun YJ, Sohn J. Prognostic impact of initial treatment modality for brain metastasis in metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-17-05.

BackgroundHigh tumor-infiltrating lymphocytes (TILs) and hemorrhage are important prognostic factors in patients who have undergone craniotomy for melanoma brain metastases (MBM) before 2011 at the University of Pittsburgh Medical Center (UPMC). We have investigated the prognostic or predictive role of these histopathologic factors in a more contemporary craniotomy cohort from the University of North Carolina at Chapel Hill (UNC-CH). We have also sought to understand better how various immune cell subsets, angiogenic factors, and blood vessels may be associated with clinical and radiographic features in MBM.MethodsBrain tumors from the UPMC and UNC-CH patient cohorts were (re)analyzed by standard histopathology, tumor tissue imaging, and gene expression profiling. Variables were associated with overall survival (OS) and radiographic features.ResultsThe patient subgroup with high TILs in craniotomy specimens and subsequent treatment with immune checkpoint inhibitors (ICIs, n=7) trended to have longer OS compared to the subgroup with high TILs and no treatment with ICIs (n=11, p=0.059). Bleeding was significantly associated with tumor volume before craniotomy, high melanoma-specific expression of basic fibroblast growth factor (bFGF), and high density of CD31+αSMA- blood vessels. Brain tumors with high versus low peritumoral edema before craniotomy had low (17%) versus high (41%) incidence of brisk TILs. Melanoma-specific expression of the vascular endothelial growth factor (VEGF) was comparable to VEGF expression by TILs and was not associated with any particular prognostic, radiographic, or histopathologic features. A gene signature associated with gamma delta (gd) T cells was significantly higher in intracranial than same-patient extracranial metastases and primary melanoma. However, gdT cell density in MBM was not prognostic.ConclusionsICIs may provide greater clinical benefit in patients with brisk TILs in MBM. Intratumoral hemorrhage in brain metastases, a significant clinical problem, is not merely associated with tumor volume but also with underlying biology. bFGF may be an essential pathway to target. VEGF, a factor principally associated with peritumoral edema, is not only produced by melanoma cells but also by TILs. Therefore, suppressing low-grade peritumoral edema using corticosteroids may harm TIL function in 41% of cases. Ongoing clinical trials targeting VEGF in MBM may predict a lack of unfavorable impacts on TIL density and/or intratumoral hemorrhage.

340 Background: Tyrosine kinase inhibitors (TKIs) have been shown to improve overall survival (OS) in metastatic renal cell carcinoma (mRCC) but their effect on brain metastasis (BM) development is unclear. The purpose of our study is to evaluate the impact of TKIs on incidence of BM and OS in patients with mRCC. Methods: Searched the M. D. Anderson Cancer Center (MDACC) tumor registry for patients who presented with mRCC in 2002-2003 and 2006-2007 with no BM at initial staging. The following items were retrospectively collected: age, sex, Fuhrman grade, sites of disease, nephrectomy, systemic therapy including TKIs (sorafenib or sunitinib), MSKCC risk category, BM treatment, and vital status. Interaction between OS and incidence of BM and these variables was estimated using the Cox proportional hazards model. OS and incidence of BM were estimated using the Kaplan-Meier (K-M) method. Results: 338 patients were identified; 154 (46%) were treated with a TKI prior to BM, and 184 (54%) were not. There were no significant differences in age, histology, involved sites of disease other than lung, nephrectomy, or MSKCC risk category between the groups. A higher proportion of the nonTKI group received other systemic agents and had lung metastasis at initial staging (p=0.03). Median OS was longer in the TKI-treated group (25 months versus 12.1 months, p<0.0001). In Cox multivariate analysis, TKI treatment (HR=0.53, 95% CI 0.38-0.74, p<0.001) was associated with improved OS and lung/mediastinal involvement and ECOG performance status > 2 (HR 1.87, 95% CI 1.28-2.71, p=0.001) were associated with poor OS. Median OS after BM was not significantly different between TKI treated and untreated groups. 44 patients (13%) developed a BM, including 29 (15.8%) of the nonTKI group and 15 (9.7%) of the TKI group. In K-M analysis, the 5-year incidence of BM was 40% versus 17% respectively (logrank p<0.001). In Cox multivariate analysis, TKI treatment was associated with lower incidence of BM (HR=0.39, 95% CI 0.21-0.73, p=0.003). Lung metastasis increased the risk of BM (HR=9.61, 95% CI 2.97-31.1, p<0.001). Conclusions: Treatment with TKI agents reduces the incidence of BM in mRCC. Lung metastasis is a risk factor for BM development. No significant financial relationships to disclose.

Cancer immunotherapy has been a subject of intense research over the last several years, leading to new approaches for modulation of the immune system to treat malignancies. Immune checkpoint inhibitors (anti-CLTA-4 antibodies and anti-PD-1/PD-L1 antibodies) potentiate the host's own antitumor immune response. These immune checkpoint inhibitors have shown impressive clinical efficacy in advanced melanoma, metastatic kidney cancer, and metastatic non-small cell lung cancer (NSCLC)-all malignancies that frequently cause brain metastases. The immune response in the brain is highly regulated, challenging the treatment of brain metastases with immune-modulatory therapies. The immune microenvironment in brain metastases is active with a high density of tumor-infiltrating lymphocytes in certain patients and, therefore, may serve as a potential treatment target. However, clinical data of the efficacy of immune checkpoint inhibitors in brain metastases compared with extracranial metastases are limited, as most clinical trials with these new agents excluded patients with active brain metastases. In this article, we review the current scientific evidence of brain metastases biology with specific emphasis on inflammatory tumor microenvironment and the evolving state of clinical application of immune checkpoint inhibitors for patients with brain metastases.

As survival of patients with central nervous system (CNS) metastases from breast cancer is poor and incidence rates are increasing, there is a growing need for better treatment strategies. In the current study, the efficacy of local and systemic therapies was analyzed in breast cancer patients with CNS metastases. Medical records from breast cancer patients with brain and/or leptomeningeal metastases (LM) treated at a tertiary referral center and a teaching hospital between 2010 and 2020 were retrospectively studied. Main outcomes of interest were overall survival (OS) and CNS progression free survival. Analyses were performed among patients with brain metastases (BM) and patients with LM, for the different systemic and local therapies for CNS metastases, and for subgroups based on breast cancer subtypes. We identified 155 patients, 97 with BM and 58 with LM. Median OS was 15.9months for patients with BM and 1.5months for patients with LM. Median OS was significantly longer for HER2-positive patients with BM (22.8months) vs triple negative (8.4months) and hormone receptor positive/HER2-negative (5.9months) (P < 0.001). Patients with BM receiving both local and systemic therapy also had a longer median OS (21.8months), compared to the other three subgroups (local therapy only: 9.9months, systemic therapy only: 4.3months, no therapy: 0.5months, P < 0.001). No significant difference in OS was observed between different systemic treatment regimens. Breast cancer patients with BM show longest median OS when the subtype is HER2-positive and when they are treated with both local and systemic therapy.

The brain is the most common site of distant metastasis from lung cancer. Thus, MRI of the brain at initial staging is routinely performed, but if this examination is negative a follow-up examination is often not performed. This study evaluates the incidence of asymptomatic brain metastases in non-small cell lung cancer patients detected on follow-up 18F-FDG PET/CT scans. Methods: In this Institutional Review Board-approved retrospective review, all vertex to thigh 18F-FDG PET/CT scans in patients with all subtypes of lung cancer from August 2014 to August 2016 were reviewed. A total of 1,175 18F-FDG PET/CT examinations in 363 patients were reviewed. Exclusion criteria included brain metastases on initial staging, histologic subtype of small-cell lung cancer, and no follow-up 18F-FDG PET/CT examinations. After our exclusion criteria were applied, a total of 809 follow-up 18F-FDG PET/CT scans in 227 patients were included in the final analysis. The original report of each 18F-FDG PET/CT study was reviewed for the finding of brain metastasis. The finding of a new brain metastasis prompted a brain MRI, which was reviewed to determine the accuracy of the 18F-FDG PET/CT. Results: Five of 227 patients with 809 follow-up 18F-FDG PET/CT scans reviewed were found to have incidental brain metastases. The mean age of the patients with incidental brain metastasis was 68 y (range, 60-77 y). The mean time from initial diagnosis to time of detection of incidental brain metastasis was 36 mo (range, 15-66 mo). When MRI was used as the gold standard, our false-positive rate was zero. Conclusion: By including the entire head during follow-up 18F-FDG PET/CT scans of patients with non-small cell lung cancer, brain metastases can be detected earlier while still asymptomatic. But, given the additional scan time, radiation, and low incidence of new brain metastases in asymptomatic patients, the cost-to-benefit ratio should be weighed by each institution.

Effectiveness and Timing of Prophylactic Cranial Irradiation (PCI) in Limited Stage Small Cell Lung Carcinoma (LS-SCLC) Patients: A Single Institution Experience

Previous studies have demonstrated the association between EGFR mutations and distant metastasis. However, the association for subsequent brain metastasis (BM) in stages I-III non-small cell lung cancer (NSCLC) patients remains inconclusive. We conducted a retrospective analysis to clarify the impact of EGFR mutations on the incidence of BM and associated survival in patients with stage I-III NSCLC. A total of 491 patients screened for EGFR mutations were retrospectively enrolled. Brain MRI or CT was used to detect the BM. Cumulative incidence of subsequent BM and overall survival (OS) after diagnosis of BM were estimated by the Kaplan-Meier method and compared using log-rank test. We performed Cox proportional hazard regression for predictors of subsequent BM and determinants of OS after BM. The cumulative incidence of BM seemed higher in patients harboring EGFR mutations than those without EGFR mutations although it did not reach statistical significance (hazard ratio [HR] = 1.75, 95% confidence interval [CI] = 0.73~1.81). After adjusting possible confounders, including age, smoking, stage, and tumor size, EGFR mutation became one of the predictors for subsequent BM (HR = 1.89, 95% CI = 1.12~3.17, p = 0.017). Though there was no statistical difference in survival after BM between patients with EGFR mutations and wild-type EGFR (median survival: 17.8 vs. 12.2 months, HR = 0.79, 95% CI = 0.45–1.40), patients with EGFR 19 deletion (Del) tended to have a longer survival after BM than the non-EGFR 19 Del group (median survival: 29.4 vs. 14.3 months, HR 0.58, 95% CI = 0.32–1.09, p = 0.089). In conclusion, our data suggested EGFR mutation to be one of the predictors for subsequent BM in stage I-III patients. Given the small sample size, more studies are warranted to corroborate our results.

Spatial oriented single-cell proteomic assay of low grade serous ovarian carcinoma identifies tumor oncogenic pathways associated with brain metastases (233)

Background: The incidence of brain metastases (BM) from primary breast cancer (BC) increased over the past decades. Despite the increasing incidence of BM in BC, the biology and development of BM are still poorly understood. Therefore, it is crucial to understand the pathogenesis of BM development in order to find prophylactic and therapeutic approaches. The Brain Metastases in Breast Cancer Registry (BMBC) has collected clinical data of more than 4000 BC pts. with BM and tumor tissue samples (n= 400). Methods: For this study, gene expression data (HTG EdgeSeq Oncology Biomarker Panel) was generated from BM and the corresponding primary BC tissue samples (n= 76), followed by differential gene expression analysis. Molecular subtypes were classified according to classical IHC (ultralow, 0, 1+, 2+, 3+) based on HER2 protein overexpression and additionally Absolute Intrinsic Molecular Subtyping (AIMS) was assessed using HTG data. Results: In total 76 corresponding BM and primary BC tissue samples were included in this analysis. Median age at BM diagnosis was 55 years. 50% of the patients had singular BM, 27.6% 2-3 BM and 22.4% &amp;gt;=4 BM. 46.7% were HER2-pos., 17.3% triple-negative and 36.0% ER-positive. Subtypes according to AIMS in BC were 35.5% HER2-pos., 27.6% lum. A, 17.1% lum. B, 14.5% basal-like and 5.3% normal-like. Distribution of AIMS subtypes in the corresponding BM were 43.4% HER2-pos., 11.8% lum. A, 22.4% lum. B, 21.1% basal-like and 1.3% normal-like. Following AIMS switches could be identified from BC to BM: Lum. A BC switches to lum. B and HER2-pos. BM; primary normal-like BC switch to lum. A, HER2-pos. and basal-like BM; primary lum. B BC switch to HER2-pos., normal-like, lum. A BM; primary HER2-pos. BC switch to lum. B and basal-like BM. There were no AIMS switches detected in basal-like BC to BM. AIMS subtypes in BC and BM were not statistically associated with overall survival in patients with metastatic BC and BM (primary BC p= 0.13; BM p= 0.19). HER2 IHC in primary BC were: 7.1% ultralow, 44.6% IHC 0, 16.1% 1+, 32.1% 3+. HER2-IHC in BM were: 12.5% ultralow, 37.5%, IHC 0, 14.3% 1+, 5.4% 2+ and 30.4 % 3+. HER2 switches from primary BC to BM were detected as following: ultralow to IHC 1+, 0, ultralow; IHC 0 to ultralow, 1+ and 0; IHC 1+ to ultralow, 0, 1+, 2+ and 3+; IHC 3+ to 1+, 2+ and 3+. HER2 status was not statistically associated with OS in BC and BM (Primary BC p= 0.42 and BM p= 0.46). Among the significantly upregulated genes (logFC &amp;gt; 0.58) in BMs in comparison to primary tumors heat shock proteins (HSPA1B), mitochondria-related genes (COX5 and MRPL13) as well as cell cycle-related factors (CDC20, CCNF and PTTG1) were detected. Conclusions:Our analysis identified AIMS subtype and HER2 IHC classification switches from primary BC to BM in matched pairs that could be relevant for prognosis and treatment decisions. In addition, our preliminary differential gene expression analyses showed clear differences in various cellular processes between BC and BM tissues. Whether these differences reflect a selection process or rather an adaptation mechanism to a new environment remains to be investigated. Citation Format: Elena Laackmann, Kerstin Riecke, Sivaramakrishna Rachakonda, Volkmar Müller, Isabell Witzel, Marcus Schmidt, Klaus Junker, Peter A. Fasching, Mustafa Aydogdu, Leticia Oliveira-Ferrer, Paul Jank, Kristina Lübbe, Maria M. Karsten, Thomas Karn, Patricia von Kroge, Julia Teply-Szymanski, Thomas Decker, Martin Peters, Akira Hattesohl, Marion van Mackelenbergh, Marc Thill, Uta Ringsdorf, Anika Pehl, Christoph Mundhenke, Tanja Fehm, Julia Rey, Bärbel Felder, Sibylle Loibl, Carsten Denkert, Elena Laakmann. Biomarkers in metastatic breast cancer with brain metastases – a subanalysis of matched tumor samples of the BMBC registry [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-02-26.

Background: Patients with esophageal squamous cell carcinoma typically have poor outcomes. The lungs, liver, bone, pleura and adrenal gland are the most common sites of visceral metastasis, though metastasis to the brain is exceedingly rare. To date, there have been few reports concerning the clinical outcome of brain metastasis in esophageal squamous cell carcinoma. Therefore, we performed a retrospective review of esophageal squamous cell carcinoma patients with brain metastasis to assess the incidence of brain metastasis and their prognosis.Methods: Between January 1996 and December 2011, 1011 patients with esophageal squamous cell carcinoma were retrospectively reviewed, and 14 patients with brain metastases were identified. The review and diagnoses of brain metastasis were established using brain computer tomography (CT) scan, or magnetic resonance imaging (MRI).Results: The incidence of brain metastasis in our series was 1.4%, and the median survival duration from the diagnosis of brain metastasis in these 14 patients with esophageal squamous cell carcinoma was 1.9 months. The median follow-up period from the diagnosis of esophageal cancer to the diagnosis of brain metastasis was 6.6 months. Systemic metastasis upon diagnosis of brain metastasis was found in 10 patients (71%), a single brain metastasis was found in 6 patients (43%), two brain lesions were found in 2 patients (14%), and multiple brain metastases were found in 6 patients (43%). Primary treatment consisted of whole brain irradiation therapy (WBRT) alone in 5 patients (36%), surgical resection in 6 patients (43%), 5 of whom (36%) subsequently were treated with WBRT, and best supportive care in three patients (21%). Univariate analysis showed that patients with single brain metastasis (P = 0.004), treatment with surgical resection plus whole brain radiation therapy (P = 0.002), and absence of systemic metastasis (P = 0.03) were significantly associated with better clinical outcome.Conclusions: The incidence of brain metastasis in esophageal squamous cell carcinoma is 1.4%, and the prognosis is poor. Patients without systemic metastases or with single brain metastasis have significantly superior survival rates, suggesting that aggressive therapy should be considered in these groups of patients.