Bevacizumab use and central nervous system (CNS) hemorrhage.

Bevacizumab is widely used and may cause life-threatening bleeding. We attempted to identify clinical characteristics associated with central nervous system (CNS) hemorrhage in a broad population. We performed a retrospective review of the FDA MedWatch database of adverse events reported with bevacizumab from 11/1997 to 5/2009. Our search used keywords: bleeding, hemorrhage, cerebral, intracranial, subarachnoid, cerebellar, hemorrhagic stroke and brain. A total of 17,466 reports were included in the database: 154 described CNS hemorrhage in 99 patients, and 1,041 reports described non-CNS bleeds. Median age was 62 years, and the primary cancers were consistent with indications for bevacizumab. Patients received a median of three (1-36) doses of bevacizumab prior to the bleed. Thirty percent had documented history of hypertension. Sixteen patients with CNS hemorrhage were reported to have CNS metastases. Death was reported as a complication of hemorrhage in 48 %. The most common predisposing factor for CNS bleeds was use of medications associated with bleeding, followed by thrombocytopenia. In this database, 154 of 1,195 reports of bleeding associated with bevacizumab described a CNS bleed. Although CNS bleeds were not common, they were the reported cause of death in two-thirds of cases.

5047 Background: Hemorrhagic complications have been reported in pts treated with various angiogenesis inhibitors, however, reports of intracranial bleeding are rare. Intracranial hemorrhage has been reported during therapy with multitargeted tyrosine kinase inhibitors (TKIs) at higher dose levels during phase I evaluation. Given the occurrence of CNS metastases in RCC and the common use of TKIs, a review of the safety of TKIs in RCC pts with CNS metastases was undertaken. Methods: All pts with mRCC and CNS metastases who were treated with TKIs at the Cleveland Clinic Taussig Cancer Center were investigated. Results: Between 8/2005 and 10/2006, 23 pts with mRCC and CNS metastases were treated utilizing either sunitinib or sorafenib. 7/23 pts received sequential therapy with both TKIs. The median time to development of CNS metastases was 16.0 months (range: 0 - 288 months). Thirteen pts received sunitinib (50 mg daily, 4 out of 6 weeks) and 10 pts received sorafenib (400 mg BID continuously). All 23 pts had known CNS lesions at initiation of TKI treatment and had received prior therapy to the CNS. This consisted of either surgery and whole brain radiation therapy (WBRT; 4pts), WBRT alone (3 pts), conformal radiotherapy in the form or gamma knife or Intensity Modulated Radiation Therapy (13 pts), WBRT and gamma knife (2 pts) or surgical resection alone (1 pt). The median TKI treatment duration (including sequential TKI therapy), was 5.6 months (range: 0.3–20.3 months). No evidence of CNS intratumoral bleeding or other hemorrhagic complications have been observed. Three pts developed new metastatic foci in the brain while on sunitinib. Overall, the median time to progression was 6.5 months (0.9 - 20.3 months). Conclusions: These data suggest sunitinib or sorafenib can be safely administered to RCC pts with previously treated CNS metastases The safety of these agents in patients with untreated CNS lesions is unclear, and therefore pretreatment CNS imaging should be considered. [Table: see text]

BackgroundNeratinib has efficacy in central nervous system (CNS) metastases from HER2‐positive metastatic breast cancer (MBC). We report outcomes among patients with CNS metastases at baseline from the phase III NALA trial of neratinib plus capecitabine (N + C) versus lapatinib plus capecitabine (L + C).Materials and MethodsNALA was a randomized, active‐controlled trial in patients who received two or more previous HER2‐directed regimens for HER2‐positive MBC. Patients with asymptomatic/stable brain metastases (treated or untreated) were eligible. Patients were assigned to N + C (neratinib 240 mg per day, capecitabine 750 mg/m2 twice daily) or L + C (lapatinib 1,250 mg per day, capecitabine 1,000 mg/m2 twice daily) orally. Independently adjudicated progression‐free survival (PFS), overall survival (OS), and CNS endpoints were considered.ResultsOf 621 patients enrolled, 101 (16.3%) had known CNS metastases at baseline (N + C, n = 51; L + C, n = 50); 81 had received prior CNS‐directed radiotherapy and/or surgery. In the CNS subgroup, mean PFS through 24 months was 7.8 months with N + C versus 5.5 months with L + C (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.41–1.05), and mean OS through 48 months was 16.4 versus 15.4 months (HR, 0.90; 95% CI, 0.59–1.38). At 12 months, cumulative incidence of interventions for CNS disease was 25.5% for N + C versus 36.0% for L + C, and cumulative incidence of progressive CNS disease was 26.2% versus 41.6%, respectively. In patients with target CNS lesions at baseline (n = 32), confirmed intracranial objective response rates were 26.3% and 15.4%, respectively. No new safety signals were observed.ConclusionThese analyses suggest improved PFS and CNS outcomes with N + C versus L + C in patients with CNS metastases from HER2‐positive MBC.Implications for PracticeIn a subgroup of patients with central nervous system (CNS) metastases from HER2‐positive breast cancer after two or more previous HER2‐directed regimens, the combination of neratinib plus capecitabine was associated with improved progression‐free survival and CNS outcomes compared with lapatinib plus capecitabine. These findings build on previous phase II and III studies describing efficacy of neratinib in the prevention and treatment of CNS metastases, and support a role for neratinib as a systemic treatment option in the management of patients with HER2‐positive brain metastases following antibody‐based HER2‐directed therapies.

Background: The use of more effective systemic therapies in the management of metastatic breast cancer has led to increased response rates, progression-free survival and overall survival. The incidence of central nervous system (CNS) metastases has become an increasingly important area of unmet need. It is important to identify tumour-related factors which may predict for CNS occurrence and assess the efficacy of treatments in current use. Methods: Consecutive patients (pts) with breast cancer (BC) seen at 2 institutions following establishment of breast cancer databases were included: January 2000 (institution A) and January 2003 (institution B) to December 2012. Patient demographic data, tumour pathology and systemic treatment given were reviewed in those patients who developed CNS metastases. Multivariate analysis of factors impacting on overall survival in this patient population will be performed. Results: Over the study period, 4751 pts with a median age of 52.7 yrs were seen, where 86.4% and 13.6% of pts presented with early and metastatic disease, respectively. In the entire population, 77% of tumours were hormone receptor positive, 21% HER2 positive, and 15% triple negative. Overall, 228 (4.8%) pts had CNS metastases with a median age of 48.9 yrs. CNS involvement was present at the time of first metastatic recurrence in 27% of pts who had CNS metastases. The proportion of pts developing CNS metastases according to tumour subtypes were: 48% hormone receptor positive, 36% Her2 positive, and 20% triple negative. Median time from diagnosis to development of CNS metastases (excluding pts with CNS involvement at the time of first metastatic disease) was 48.9 (4.7-248 months, m). The median time to development of CNS recurrence was 61m, 43m, 23m respectively, according to tumour subtype. CNS disease was parenchymal only, leptomeningeal only or both in 78%, 9%, 13% respectively. Pts who died from BC, had a median overall survival from initial BC diagnosis of 53.6m, whereas median overall survival from CNS metastases was 4.8 m. The impact of whole brain radiation with or without stereotactic therapy, surgical resection of brain metastases and type of systemic therapy administered following development of CNS disease on overall survival will be presented. Discussion: CNS metastases occurred in up to 5% of breast cancer pts seen at two large cancer centres. Despite improvements in overall survival of metastatic BC pts with the use of more effective systemic treatments, the prognosis following CNS involvement remains extremely poor. Until specific interventions are available to manage CNS metastases in pts with breast cancer, it remains important to assess outcomes from current standard treatment in these pts. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-11-10.

Objective To investigate the clinical characteristics, treatment and prognosis of hepatoblastoma (HB) patients with the central nervous system (CNS) metastasis. Methods The clinical data of 12 patients with CNS metastasis who were admitted to Beijing Tongren Hospital, Capital Medical University from January 2011 to June 2016 were retrospectively analyzed.The clinical features, treatment and prognosis of HB patients with CNS metastasis were summarized. Results (1) Clinical features: all 12 patients were diagnosed as stage-Ⅳ patients according to posto-perative Children ′s Oncology Group (COG ) stage system.The primary positions of extrahepatic metastatic characteristics were as follows: lung metastasis in 12 cases, bone metastasis in 3 cases, and adrenal metastasis in 2 cases, right atrial metastasis in 1 case, and abdominal lymph node metastasis in 1 case.Fetal and epithelial mixed type was the most common type in pathologic Pathologic classification of HB (50%, 6/12 cases). CNS metastasis was detected in all 12 cases during the course of treatment.Brain metastasis were found in 11 cases of CNS imaging features, and 1 case had spinal metastatic tumors.(2)The treatment for CNS metastasis: all cases were given chemotherapy-based comprehensive treatment after being diagnosed as CNS metastasis of HB.Ten cases of CNS metastasis were treated by maintenance chemotherapy and 2 cases received chemotherapy plus intracranial tumor resection.(3)The prognosis of HB with CNS metastasis: the follow-up time was from 7 months to 54 months in 12 HB cases with CNS metastasis, and the median follow-up time was 20 months.The survival time of HB was 1-15 months, and the median survival time was 3.5 months after the diagnosis of CNS metastasis.Two cases of CNS metastasis were given intracranial tumor resection and chemotherapy and were followed up to June 2016, and survival time was 15 months and 5 months respectively.The survival time of other 10 cases without intracranial surgery was 1-6 months, and the median survival time was 3 months.By drawing survival function curve and applying Log-Rank test for CNS transfer children, the survival time of patients given intracranial tumor resection and chemotherapy was longer than those without surgery (P<0.05). Conclusions The occurrence of CNS metastasis occurred in HB patients in phase-Ⅳ patients with pulmonary metastasis.The most common site of CNS metastasis is brain metastasis, which is hematogenous metastatic pathway, and 1 case of spinal cord metastasis was considered as the local invasion and metastasis.For HB cases with CNS metastasis, the survival time is short and the prognosis is poor, but the survival time might be prolonged for the phase-Ⅳ patients with intracranial tumor resection. Key words: Hepatoblastoma; Metastasis; Prognosis

COVID-19-related coagulopathy is a known complication of SARS-CoV-2 infection and can lead to intracranial hemorrhage (ICH), one of the most feared complications of extracorporeal membrane oxygenation (ECMO). We sought to evaluate the incidence and etiology of ICH in patients with COVID-19 requiring ECMO. Patients at two academic medical centers with COVID-19 who required venovenous-ECMO support for acute respiratory distress syndrome (ARDS) were evaluated retrospectively. During the study period, 33 patients required ECMO support; 16 (48.5%) were discharged alive, 13 died (39.4%), and 4 (12.1%) had ongoing care. Eleven patients had ICH (33.3%). All ICH events occurred in patients who received intravenous anticoagulation. The ICH group had higher C-reactive protein (P = 0.04), procalcitonin levels (P = 0.02), and IL-6 levels (P = 0.05), lower blood pH before and after ECMO (P < 0.01), and higher activated partial thromboplastin times throughout the hospital stay (P < 0.0001). ICH-free survival was lower in COVID-19 patients than in patients on ECMO for ARDS caused by other viruses (49% vs. 79%, P = 0.02). In conclusion, patients with COVID-19 can be successfully bridged to recovery using ECMO but may suffer higher rates of ICH compared to those with other viral respiratory infections.

Incidence of bleeding symptoms in 100 patients with inherited afibrinogenemia or hypofibrinogenemia.

Introduction T-DM1 is an antibody–drug conjugate that was recently approved by the FDA for patients with HER2-positive MBC who have received prior treatment with trastuzumab and a taxane. In the phase 3 EMILIA trial, T-DM1 significantly prolonged progression-free survival (PFS) and overall survival (OS) compared with XL in patients with previously treated HER2-positive MBC (Verma 2012). Because the CNS is a common site of progression in HER2-positive MBC, it is of interest to characterize the incidence of CNS metastases in patients treated with TDM1 vs XL and the efficacy of T-DM1 in patients with pre-existing CNS metastases. Methods EMILIA is a multicenter, randomized, open-label trial in which patients with HER2-positive, unresectable, locally advanced or MBC previously treated with trastuzumab and a taxane were randomized (1:1) to T-DM1 (3.6 mg/kg every 21 days) or XL (X: 1000 mg/m2 bid on days 1–14 of each 21-day cycle; L: 1250 mg/day on days 1–21). Treatment continued until disease progression or unacceptable toxicity. All patients underwent brain magnetic resonance imaging or computed tomography at screening, and follow-up scans were performed as clinically indicated. Those with untreated or symptomatic brain metastases and those who required therapy for symptom control ≤2 months before randomization were excluded from the trial. Patients with CNS metastases at baseline or who developed CNS metastases on study were retrospectively identified using independent review committee data, and exploratory analyses were performed on data from these patients. Results Of the 896 patients without CNS metastases at baseline (T-DM1 = 450; XL = 446), 9 (1.8%) and 3 (0.6%), respectively, developed CNS progression on study. Of the 95 patients with CNS metastases at baseline (T-DM1 = 45; XL = 50), 10 (2.0%) and 8 (1.6%), respectively, developed CNS progression on study. Median PFS in patients with CNS metastases at baseline was 5.9 months in the T-DM1 arm and 5.7 months in the XL arm (HR = 1.000; 95% CI: 0.542–1.844; P = 0.9998). Median OS was 26.8 months and 12.9 months in the T-DM1 and XL arms, respectively (HR = 0.382; CI: 0.184–0.795; P = 0.0081). Multivariate analysis adjusting for baseline risk factors produced similar results. Safety profiles of T-DM1 and XL in patients with CNS metastases at baseline (T-DM1 = 43; XL = 49) were consistent with those for the overall study population. Grade ≥3 adverse events (AEs) were reported in 17 (39.5%) patients in the T-DM1 arm and 29 (59.2%) patients in the XL arm. Serious AEs were reported in 5 (11.6%) and 11 (22.4%) patients in the T-DM1 and XL arms, respectively. No new safety signals were identified. Conclusions In this retrospective exploratory analysis of data from EMILIA, the rate of CNS progression in patients with or without baseline CNS metastases was low in both treatment arms. In the subset of patients with brain metastases at baseline, similar to the intent-to-treat population, T-DM1 was associated with significantly improved OS compared with XL. Prospective phase 3 trials are necessary to confirm these results. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-27.

Introduction: Central nervous system (CNS) metastasis are detected in approximately 10-30% of breast cancer (BC) patients, being associated with poor prognosis despite local and systemic therapeutics available. In the current study, we aimed to evaluate the association between BC subtypes and CNS metastasis development and prognosis. Methods: Retrospective analysis of 258 BC patients’ records with pathological and/or radiological documented CNS metastasis, treated at a Cancer Center between 2003-2019, median follow-up of 61 months (range: 0-351). For analysis purpose, three BC subtypes were considered according to hormone receptor status and HER-2 expression: luminal, HER-2 positive and triple negative. Survival was evaluated by Kaplan-Meier method and groups were compared with log-rank test. Independent prognostic factors were identified using Cox regression model. A p value &amp;lt; 0.05 was considered statistically significant. Results: Ninety four (42%) patients had HER-2 positive, 87 (39%) luminal and 41 (19%) triple negative disease. The median time between the diagnosis of BC and the detection of CNS metastasis was significantly shorter in triple negative group (18 months) compared to the others (HER-2 positive: 31 months; luminal: 54 months; p=0.001), and CNS was more often the first site of recurrence (with or without concomitant extracranial disease progression) in this group (triple negative: 25 (61%) vs. HER-2 positive: 31 (33%) vs. luminal: 27 (31%); p=0.002). Most of the patients had parenchymal metastasis (n=245), being exclusively parenchymal in 227 (88%), and 31 (12%) had leptomeningeal (LM) disease, that was isolated in 13 (5%). More than half (n=136) had multiple (&amp;gt;3 lesions) CNS metastasis, without differences between BC subtypes. Among the patients with LM disease, 17 (68%) had luminal tumors, 5 (20%) HER2-positive and 3 (12%) triple negative (p=0.007). Forty five patients (17%) were treated with surgery for CNS metastasis, with similar proportions between BC groups. In the patients submitted to CNS surgery, the concordance between primary tumor and metastasis subtype was higher in HER-2 positive (73%) compared to 57% in triple negative and 50% in luminal groups (p=0.004). After CNS involvement, 62% (n=24) of patients with triple negative disease did not receive any systemic therapy, compared to 44% (n=37) in luminal and 33% (n=29) in HER-2 positive groups (p=0.010). Median survival after CNS metastasis documentation was longer in HER-2 positive group (27 months vs. luminal: 18 months vs. triple-negative: 14 months, p=0.004) and also in patients submitted to surgical resection of CNS metastasis (38 months vs. 6 months in other treatment modalities). In multivariate Cox regression analysis, having HER-2 positive tumor was an independent prognostic factor for increasing survival after CNS metastasis (HR 0.62, 95% CI: 0.47-0.84, p=0.002), regardless the therapeutic strategy. Conclusions: Pattern of CNS metastasis development and prognosis varies according to BC subtype. The association between LM disease and luminal tumors should be explored in future studies. Treatment modalities also play a decisive role in the prognosis of this patients, therefore, new and effective therapeutic strategies are needed. Citation Format: IoIanda Vieira, Miguel Abreu, Tiago Alpoim, Isabel Pereira, Susana Sousa, Isabel Azevedo, Machado Carvalho, Deolinda Pereira. Patterns of development and prognostic factors in central nervous system metastasis according to breast cancer subtypes [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-60.

1069 Background: Ten to 15% of patients (pts) with breast cancer will be diagnosed with central nervous system (CNS) metastases, and autopsy series suggest that up to 30% of pts have evidence of CNS disease at the time of death. The idenfication of factors that may predispose to CNS metastasis may help lead to earlier detection and possibly to improvement in disease management. Methods: Breast cancer pts with CNS metastases were identified within a database of 1300 breast cancer diganoses from 1995 to 2007 at the Department of Oncology, Azienda ULSS 13 VE. Pathologic features of tumor samples were examined using standard immunohistochemical assays. Results: Fifty-one pts with CNS metastases were identified. Median age at primary breast cancer diagnosis was 49 years (range, 28–78); median time to CNS metastases was 45 months (range, 3–244). HER2 overexpression was found in tumors from 25 pts (49.0%); 23 pts had tumors lacking overexpression of HER2, estrogen receptors (ER), and progesterone receptors (PgR) (ie, “triple negative” disease). Overexpression of p53 (at least 20% tumor cells positive), Ki67 (at least 20%), and BCL2 (at least 30%) were detected in tumors from 16 pts (31.4%), 32 pts (62.7%), and 14 pts (27.5%), respectively. Median survival from CNS involvement was 3.67 months (95% CI 2.05–5.28), with 24.4% and 15.3% of patients estimated to be alive at 12 and 24 months, respectively (Kaplan-Meier product limit method). A Cox proportional hazards analysis found that Ki67 overexpression was the only factor independently associated with a significantly increased risk of death (2.7-fold increase, p=0.028), while triple negative status was associated with a 1.8-fold increase in the risk of death (P=0.08) (Table). Conclusions: In our series of breast cancer pts with CNS metastases, nearly all had either HER2 overexpression or triple-negative disease. Pts whose tumors had higher proliferative indices, assessed by Ki67, had the poorest prognosis. [Table: see text] [Table: see text]

Safety of Bevacizumab Therapy in Subjects with Brain Metastases due to Non–Small-Cell Lung Cancer (NSCLC)

Central nervous system (CNS) metastases from epithelial ovarian cancer (EOC) are rare. We investigated the clinico-pathological prognostic factors of patients with CNS metastases from EOC and compared the outcomes of various treatment modalities. We retrospectively reviewed the records of patients with CNS metastases from EOC between 2000 and 2020. Information on the clinical and pathological characteristics, treatment, and outcomes of these patients was retrieved from Samsung Medical Center and National Taiwan University Hospital. A total of 94 patients with CNS metastases were identified among 6,300 cases of EOC, resulting in an incidence of 1.49%. Serous histological type [hazard ratio (HR): 0.49 (95% confidence interval [CI] 0.25-0.95), p=0.03], progressive disease [HR: 2.29 (95% CI 1.16-4.54), p=0.01], CNS involvement in first disease relapse [HR: 0.36 (95% CI 0.18-0.70), p=0.002], and gamma knife radiosurgery (GKS)-based combination treatment for EOC patients with CNS lesions [HR: 0.59 (95% CI 0.44-0.79), p<0.001] significantly impacted survival after diagnosis of CNS metastases. In a subgroup analysis, superior survival was observed in patients with CNS involvement not in first tumor recurrence who underwent GKS-based combination therapeutic regimens. The survival benefit of GKS-based treatment was not significant in patients with CNS involvement in first disease relapse, but a trend for longer survival was still observed. In conclusion, GKS-based combination treatment can be considered for the treatment of EOC patients with CNS metastases. The patients with CNS involvement not in first disease relapse could significantly benefit from GKS-based combination strategies.

Acceptable Safety of Bevacizumab Therapy in Patients with Brain Metastases as a Result of Non—Small-Cell Lung Cancer

Background: The incidence of central nervous system (CNS) metastases in breast cancer is increasing. While local treatments such as surgery and radiation remain standard, systemic therapies have shown promise in HER2-positive disease. However, data on the efficacy of systemic therapy in HER2-low breast cancer with CNS involvement remain limited. This study describes outcomes of upfront systemic therapy in HER2-low breast cancer patients with CNS metastases treated at a single institution. Methods: We retrospectively reviewed breast cancer patients with CNS metastases treated at Henry Ford Health between Jan 2014 and July 2024. HER2-low status was defined as: HER2 immunohistochemistry 1+, or 2+ with negative fluorescent in situ hybridization (FISH). Eligible patients received no concurrent local CNS therapy; prior local treatment was permitted if unrelated to the studied lesions. CNS responses were to be assessed using the Response Assessment in Neuro-Oncology for brain metastases (RANO-BM) or the modified RANO-LM (leptomeningeal metastases) criteria. Results: Sixteen HER2-low patients were included. The median age was 56 years (range, 38-93); 63% (n = 10) were African American. Most (75%) had hormone receptor-positive disease, and 53% presented with de novo metastatic disease. Thirteen patients (81%) had HER2 IHC 1+, and only three had HER2 IHC 2+/FISH-negative disease. The majority (88%) had parenchymal CNS metastases; one patient had leptomeningeal disease, and one had both. Eight patients (50%) had prior CNS metastases, and 38% received local therapy before study inclusion. Notably, a significant proportion of patients (88%) had non-measurable disease by RANO-BM criteria (lesions &amp;lt;10 mm), with 69% having lesions smaller than 5 mm. Systemic therapies for the CNS disease included cytotoxic chemotherapy in seven patients (44%), trastuzumab deruxtecan (T-DXd) in four (25%), abemaciclib in two (13%), other CDK4/6 inhibitors in two (13%), and sacituzumab govitecan in one (6%). Commonly utilized chemotherapy included taxanes (paclitaxel or nab-paclitaxel) in 4 of 7 patients. In the 16 patients, the overall response rate (ORR) was 31.3%, the disease control rate (DCR) was 56.3%, the median duration of response (DOR) was 7 months, and the median progression-free survival (PFS) was 2 months. In a comparison cohort of HER2-positive patients (n=17), ORR was 53%, DCR was significantly higher at 94% (p=0.017), with similar DOR (5 months), and numerically longer PFS (3 months, p=0.351). Outcomes among the African American patients (n=10) mirrored the overall HER2-low group, with ORR 30%, DCR 50%, DOR 5 months, and PFS 1 month. Notably, the patients with HER2 IHC 2+ tumors (n=3; all HR+) experienced higher benefit (ORR 67%, DCR 100%) with no disease progression at last follow-up. HER2-low patients treated with T-DXd (n=4) demonstrated a DCR of 75%, with only one progression. Chemotherapy yielded a poor ORR of 29%, though two patients achieved complete CNS responses with taxane-based regimens. Conclusion: This “real-world” experience highlights modest intracranial activity of systemic therapy in HER2-low breast cancer with CNS metastases. Although response rates were lower than in HER2-positive counterparts, HER2 2+ tumors and patients treated with T-DXd showed encouraging outcomes. These findings support the need for prospective studies focusing on HER2-low CNS disease and suggest T-DXd as a promising therapeutic option, even in the absence of concurrent local treatment. Additionally, our study underscores a unique challenge in the management of breast cancer and brain metastases: CNS lesions are often smaller than the &amp;gt;10 mm threshold typically required for clinical trial eligibility, necessitating special attention and adapted approaches for response assessment. Citation Format: B. Ghimire, L. Rogers, M. Girgis. Efficacy of systemic therapy in HER2-low breast cancer with CNS metastases: a “real-world” experience [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-05-28.

1018 Background: In the era of trastuzumab, HER2-positive breast cancer confers an increased risk of central nervous system (CNS) metastases. While several studies have examined CNS metastases in trastuzumab-treated patients, data are sparse regarding CNS metastases in trastuzumab-naïve HER2-positive patients. We evaluated time to CNS metastasis, death, and death subsequent to brain metastasis in relation to trastuzumab treatment. Methods: The study population included 750 patients diagnosed with HER2-positive metastatic breast cancer (HER2+ MBC) between June 1977 and January 2006. The association between trastuzumab treatment and the outcomes of time to CNS metastasis and time to death following CNS metastasis were determined using Cox proportional hazards models that included trastuzumab treatment as a time-dependent covariate. Multivariable Cox proportional hazards models were fit to determine the association between trastuzumab treatment and outcomes after adjustment for known prognostic factors. Patients with HER2+ MBC treated at our institution before trastuzumab was available served as our control group. Results: Of the 750 patients included, 689 patients received trastuzumab during the follow-up period while 61 patients were not treated with trastuzumab. Median follow-up was 32 months. A total of 251 patients developed CNS metastases. After adjusting for other prognostic variables including age, ER status, PR status, pathological stage, and site of initial metastasis, patients who received trastuzumab had 2.84 times the risk of CNS metastases (95 % CI = 1.87, 4.30, p &lt; 0.0001) compared to patients who did not receive trastuzumab. Time to death following brain metastasis did not differ significantly between trastuzumab- treated and -untreated patients. Conclusions: In our large series, patients with HER2+ MBC treated with trastuzumab were at significantly increased risk of developing CNS metastases compared to patients who did not receive trastuzumab. This finding warrants further investigation into biological mechanisms that may account for this difference. No significant financial relationships to disclose.