Brain Metastases In Breast Cancer Patients Research Articles

Improved outcomes for triple negative breast cancer brain metastases patients after stereotactic radiosurgery and new systemic approaches.

Although ongoing studies are assessing the efficacy of new systemic therapies for patients with triple negative breast cancer (TNBC), the overwhelming majority have excluded patients with brain metastases (BM). Therefore, we aim to characterize systemic therapies and outcomes in a cohort of patients with TNBC and BM managed with stereotactic radiosurgery (SRS) and delineate predictors of increased survival. We used our prospective patient registry to evaluate data from 2012 to 2023. We included patients who received SRS for TNBC-BM. A competing risk analysis was conducted to assess local and distant control. Forty-three patients with 262 tumors were included. The median overall survival (OS) was 16 months (95% CI 13-19 months). Predictors of increased OS after initial SRS include Breast GPA score > 1 (p < 0.001) and use of immunotherapy such as pembrolizumab (p = 0.011). The median time on immunotherapy was 8 months (IQR 4.4, 11.2). The median time to new CNS lesions after the first SRS treatment was 17 months (95% CI 12-22). The cumulative rate for development of new CNS metastases after initial SRS at 6 months, 1 year, and 2 years was 23%, 40%, and 70%, respectively. Thirty patients (70%) underwent multiple SRS treatments, with a median time of 5 months (95% CI 0.59-9.4 months) for the appearance of new CNS metastases after second SRS treatment. TNBC patients with BM can achieve longer survival than might have been previously anticipated with median survival now surpassing one year. The use of immunotherapy is associated with increased median OS of 23 months.

NDRG1 is a prognostic biomarker in breast cancer and breast cancer brain metastasis

AbstractBrain metastases are secondary brain tumours characterised by their aggressive nature and poor prognosis. Breast cancer is one of the most common primary tumours in women to spread to the brain. A lack of biomarkers predicting likely spread to the brain and limited therapeutic interventions represents major areas of clinical unmet need. We investigated N‐myc downregulated gene‐1 (NDRG1) as a clinically relevant biomarker in breast cancer brain metastasis patients. NDRG1 expression was investigated using immunohistochemistry on tissue microarrays of two clinical cohorts: (i) brain metastatic breast cancers (n = 48) and brain metastases (n = 64; including a subset of 39 patient‐matched breast and brain metastasis cases) and (ii) unselected primary breast cancers (n = 336). NDRG1 was highly expressed in breast‐to‐brain metastases, as well as in high‐grade primary breast cancers. High NDRG1 expression and also an absence of expression were associated with worse survival outcomes in both breast cancer and breast cancer brain metastasis patients. This establishes NDRG1 as a ‘Goldilocks’ protein, where too much or too little has a negative effect on survival. We pose that this accounts for its previous categorisation as both tumour suppressor and oncoprotein. Additionally, a shift in NDRG1 localisation with a gain of nuclear expression was seen at the brain metastasis stage. Significant survival benefit in cases expressing cytoplasmic NDRG1 was observed, whereas NDRG1 localisation in the nucleus showed a clear association with poorer survival. In vitro analyses revealed that hypoxic stress significantly elevated NDRG1 expression and resulted in its nuclear localisation. Our findings suggest NDRG1 expression and subcellular localisation are clinically relevant biomarkers for poor prognosis in breast cancer and breast cancer brain metastasis.

New insights into HER2-low breast cancer brain metastasis: A retrospective analysis

BackgroundA considerable number of patients with breast cancer will suffer from brain metastasis in the advanced setting. The HER2 status serves as a significant prognostic factor and the reference of applying treatment for patients with breast cancer brain metastasis (BCBM). MethodsBetween January 2010 and July 2021, patients with BCBM who had available HER2 status were identified. The patients with HER2 1+ in immunohistochemistry (IHC) or IHC 2+ and fluorescence in situ hybridization (FISH) negative were categorized as HER2-low. Comparisons were conducted between the HER2-low and HER2-zero population. The primary endpoint was overall survival (OS) after the diagnosis of BCBM. Survival outcomes were assessed using Kaplan-Meier curves with log-rank test and Cox proportional hazards model. ResultsIn this study, we analyzed 71 patients with the HER2-low breast cancer subtype and 64 patients with the HER2-zero subtype. Despite the limited sample size, our findings revealed a significantly better OS for patients with HER2-low cancer compared to their HER2-zero counterparts (26 m vs 20 m, p = 0.0017). This trend was particularly notable in the HR-negative group (26 m vs 13 m, p = 0.0078), whereas no significant difference was observed among the HR-positive patients. Furthermore, Cox regression analysis revealed that the HER2-low status was an independent prognostic factor for better survival in the HR-negative patients (p = 0.046 in multivariate analysis). ConclusionsPatients diagnosed with HER2-low BCBM exhibited a more favorable prognosis than those with HER2-zero BCBM, particularly within the HR-negative subgroup. The low expression of HER2 is supposed to be linked to the prolonged survival of BCBM patients.

Analysis of clinicopathological features and prognostic factors of breast cancer brain metastasis.

Breast cancer (BC) has become the most common malignancy in women. The incidence and detection rates of BC brain metastasis (BCBM) have increased with the progress of imaging, multidisciplinary treatment techniques and the extension of survival time of BC patients. BM seriously affects the quality of life and sur-vival prognosis of BC patients. Therefore, clinical research on the clinicopathological features and prognostic factors of BCBM is valuable. By analyzing the clinicopathological parameters of BCBM patients, and assessing the risk factors and prognostic indicators, we can perform hierarchical diagnosis and treatment on the high-risk population of BCBM, and achieve clinical benefits of early diagnosis and treatment. To explore the clinicopathological features and prognostic factors of BCBM, and provide references for diagnosis, treatment and management of BCBM. The clinicopathological data of 68 BCBM patients admitted to the Air Force Medical Center, Chinese People's Liberation Army (formerly Air Force General Hospital) from 2000 to 2022 were collected. Another 136 BC patients without BM were matched at a ratio of 1:2 based on the age and site of onset for retrospective analysis. Categorical data were subjected to χ2 test or Fisher's exact probability test, and the variables with P < 0.05 in the univariate Cox proportional hazards model were incorporated into the multivariate model to identify high-risk factors and independent prognostic factors of BCBM, with a hazard ratio (HR) > 1 suggesting poor prognostic factors. The survival time of patients was estimated by the Kaplan-Meier method, and overall survival was compared between groups by log-rank test. Multivariate Cox regression analysis showed that patients with stage III/IV tumor at initial diagnosis [HR: 5.58, 95% confidence interval (CI): 1.99-15.68], lung metastasis (HR: 24.18, 95%CI: 6.40-91.43), human epidermal growth factor receptor 2 (HER2)-overexpressing BC and triple-negative BC were more prone to BM. As can be seen from the prognostic data, 52 of the 68 BCBM patients had died by the end of follow-up, and the median time from diagnosis of BC to the occurrence of BM and from the occurrence of BM to death or last follow-up was 33.5 and 14 mo, respectively. It was confirmed by multivariate Cox regression analysis that patients with neurological symptoms (HR: 1.923, 95%CI: 1.005-3.680), with bone metastasis (HR: 2.011, 95%CI: 1.056-3.831), and BM of HER2-overexpressing and triple-negative BC had shorter survival time. HER2-overexpressing, triple-negative BC, late tumor stage and lung metastasis are risk factors of BM. The presence of neurological symptoms, bone metastasis, and molecular type are influencing prognosis factors of BCBM.

RADT-08. IS THERE A CORRELATION BETWEEN ANEMIA AND RADIATION NECROSIS IN BREAST CANCER PATIENTS WITH BRAIN METASTASES UNDERGOING RADIOSURGERY? A PRELIMINARY SINGLE-INSTITUTION COHORT STUDY

Abstract INTRODUCTION Stereotactic radiosurgery (SRS) is a highly effective treatment for brain metastases. Radiation necrosis (RN) is a prominent dose-limiting toxicity, occurring in 5-10% of patients. Data on differences in RN incidence based on tumor molecular markers and the potential correlation with anemia have not been explored. The objective of this study was to 1) report our institutional rates of RN in patients with breast cancer brain metastases (BCBM) undergoing radiosurgery; and 2) investigate the correlation of anemia with RN rates. METHODS A retrospective review of patients with BCBM treated with SRS between May 2006 and October 2020 was conducted. To ensure homogeneity, only patients with oligometastatic disease (1-4 BM) and only 1 session of SRS were included. Hemoglobin (Hb) was assessed from 3 months before or 6 months post SRS, and diagnosis of anemia was made for Hb &amp;lt;13 g/dL in males and Hb &amp;lt;12 g/dL in females. Logistic regression was used to analyze correlation of anemia and RN. RESULTS 44 patients were included (82 total lesions treated by SRS, median 2). Seventy-seven lesions were treated with SRS to a median dose of 20 Gy (15-24 Gy). Five lesions were treated with fractionated SRS (30Gy, 3-5 fractions). Five patients (11.4%) developed RN based on imaging; two went on to biopsy with one having pathological confirmation of RN. Anemia was identified in twenty-eight (63.7%) patients; 1 was treated with iron supplementation. Although anemia was not significantly associated with RN, patients with anemia did have significantly lower OS than those without (p = 0.04). CONCLUSION Our institutional data suggest similar RN rates in BCBM patients as the literature. Our sample size was too small to investigate correlation between anemia and RN, though survival may be impacted. Larger, multi-institutional studies are underway to further study this possibility.

TMIC-46. SINGLE-CELL MAPPING OF HUMAN BREAST CANCER BRAIN METASTASES REVEALS PROGNOSTICALLY RELEVANT IMMUNE LANDSCAPES

Abstract Brain metastases are associated with a particularly poor prognosis in breast cancer and improved treatment strategies are much needed. The patient-individual role of immunotherapy and anti-tumor immune control in breast cancer brain metastases (BCBM) is still poorly understood. Here, we characterized the niche-specific tumor microenvironment of BCBM at single-cell resolution in a clinically annotated patient cohort that underwent surgery at Heidelberg University Hospital (n = 156). Quantification of T cell infiltrates across whole tissue sections of n = 137 BCBM revealed strong inter-patient heterogeneity of T cell abundance. Of note, high CD8 T cell densities predicted prolonged overall survival independent of established prognostic factors. Deeper phenotyping of BCBM T cells and matched blood samples by flow cytometry showed a specific enrichment of a CD103+ tissue resident-like CD8 T cell subset expressing high levels of activation markers and checkpoint molecules in BCBM. In contrast to a general T cell enrichment in the stroma, this subset was detected more frequently within tumor islands, which might suggest its anti-tumor reactivity. We investigated potential regulators of T cell infiltration and function in the brain metastatic niche focusing on the triple negative breast cancer sub-cohort (n = 49) concluding the following: i) The quantification of a broad range of immune cells, incl. myeloid cells, NK, and B cells, in whole tissue sections revealed distinct immune ecotypes associated with T cell infiltrates. ii) An in-depth characterization of all major immune and stromal cells by single nuclei RNA-sequencing (n = 28/49) allowed for identification of potential cellular and molecular interaction partners, which was confirmed by iii) analysis of their neighborhoods by spatial transcriptomics in a targeted, single-cell resolving approach (n = 8/28). We anticipate that our findings will reveal immunoregulatory cell subsets and molecules and potentially contribute to improving immunotherapeutic approaches for BCBM patients in the future.

New insights of miRNA molecular mechanisms in breast cancer brain metastasis and therapeutic targets

Brain metastases in breast cancer (BC) patients are often associated with a poor prognosis. Recent studies have uncovered the critical roles of miRNAs in the initiation and progression of BC brain metastasis, highlighting the disease's underlying molecular pathways. miRNA-181c, miRNA-10b, and miRNA-21, for example, are all overexpressed in BC patients. It has been shown that these three miRNAs help tumors grow and metastasize by targeting genes that control how cells work. On the other hand, miRNA-26b5p, miRNA-7, and miRNA-1013p are all downregulated in BC brain metastasis patients. They act as tumor suppressors by controlling the expression of genes related to cell adhesion, angiogenesis, and invasion. Therapeutic miRNA targeting has considerable promise in treating BC brain metastases. Several strategies have been proposed to modulate miRNA expression, including miRNA-Mimics, antagomirs, and small molecule inhibitors of miRNA biogenesis. This review discusses the aberrant expression of miRNAs and metastatic pathways that lead to the spread of BC cells to the brain. It also explores miRNA therapeutic target molecular mechanisms and BC brain metastasis challenges with advanced strategies. The targeting of certain miRNAs opens a new door for the development of novel therapeutic approaches for this devastating disease.

Favorable prognosis of breast cancer brain metastases patients with limited intracranial and extracranial metastatic lesions

BackgroundBreast cancer brain metastases (BCBM) are highly heterogenous with widely differing survival. The prognosis of the oligometastatic breast cancer (BC) patients with brain metastases (BM) has not been well studied. We aimed to investigate the prognosis of BCBM patients with limited intracranial and extracranial metastatic lesions.MethodsFour hundred and forty-five BCBM patients treated between 1st January 2008 and 31st December 2018 at our institute were included. Clinical characteristics and treatment information were obtained from patient’s medical records. The updated breast Graded Prognostic Assessment (Breast GPA) was calculated.ResultsThe median OS after diagnosis of BM were 15.9 months. Median OS for patients with GPA 0–1.0, 1.5–2, 2.5–3 and 3.5–4 were 6.9, 14.2, 21.8, 42.6 months respectively. The total number of intracranial and extracranial metastatic lesions, in addition to the Breast GPA, salvage local therapy and systemic therapy (anti-HER2 therapy, chemotherapy and endocrine therapy) were demonstrated to be associated with prognosis. One hundred and thirteen patients (25.4%) had 1–5 total metastatic lesions at BM diagnosis. Patients with 1–5 total metastatic lesions had a significantly longer median OS of 24.3 months compared to those with greater than 5 total metastatic lesions with a median OS of 12.2 months (P < 0.001; multivariate HR 0.55, 95% CI, 0.43–0.72). Among the patients with 1–5 metastatic lesions, median OS for GPA 0–1.0 was 9.8 months, compared to 22.8, 28.8 and 71.0 for GPA 1.5–2.0, 2.5–3.0 and 3.5–4.0 respectively, which is much longer than the corresponding patients with greater than 5 total metastatic lesions, with medium OS of 6.8, 11.6, 18.6 and 42.6 months respectively for GPA 0–1.0, 1.5–2.0, 2.5–3.0 and 3.5–4.0.ConclusionsThe patients with 1–5 total metastatic lesions demonstrated better OS. The prognostic value of the Breast GPA and the survival benefit of salvage local therapy and continuation of systemic therapy after BM were confirmed.

Prognosis of patients with HER2-low breast cancer brain metastasis: A single-institution experience.

e13109 Background: Many patients with breast cancer were reported to suffer from brain metastasis in the advanced setting. Traditionally, the HER2-low entity was classified as HER2-negative when evaluating prognosis and administrating treatment in patients with breast cancer brain metastasis (BCBM). Trastuzumab deruxtecan (T-DXd) was proved to have potent efficacy in HER2-low breast cancer, even with brain metastasis, which made this subtype a distinct entity. However, the evidence regarding HER2-low BCBM is scarce. Methods: Based on the clinical database of our institution, the BCBM patients with available HER2 status between January 2010 and July 2021 were selected. The enrolled patients with HER2 1/2+ in immunohistochemistry and negative for fluorescence in situ hybridization (FISH) were classified as HER2-low. The comparisons were conducted between HER2-low and HER2-zero category. We predefined the primary endpoint as the overall survival (OS) after the diagnosis of BCBM, which were further analyzed basing the status of hormone receptor (HR). The Kaplan–Meier curves with log-rank test and Cox proportional hazards model were utilized to analyze the survival outcomes. Results: A total of 272 cases were included in the database, among which the patients with HER2-zero (n=64) and HER2-low (n=71) subtypes were analyzed eventually. The OS of patients with HER2-low BCBM was better than the HER2-zero counterparts in the overall population (p=0.002) and the HR-negative group (p=0.008), while the similar tendency was not observed in the HR-positive patients. Moreover, the Cox regression analysis demonstrated that the HER2-low status was a significant prognostic factor for the better clinical outcome in the HR-negative patients (p=0.046 for multivariate analysis). Conclusions: The patients with HER2-low BCBM had better prognosis than the HER2-zero counterparts, especially in the HR-positive subgroup. The low expression of HER2 is supposed to be related to the long-term survival of BCBM patients.

Preclinical and early clinical data of ZN-1041, a best-in-class BBB penetrable HER2 inhibitor to treat breast cancer with CNS metastases.

1040 Background: HER2+ breast cancer brain metastases (BCBM) is an aggressive malignancy with high prevalence and limited treatment options. ZN-1041 is a best-in-class HER2 inhibitor designed to be delivered across the blood-brain barrier (BBB) with high selectivity and broader safety margin to treat HER2+ BCBM. Methods: Brain penetration of ZN-1041 and other approved HER2 tyrosine kinase inhibitors (TKI) were evaluated. Anti-tumor activity of ZN-1041 alone or in combination were evaluated in xenograft models. ZN-A-1041-101 (NCT04487236) is an on-going phase 1, multicenter, open-label study. The study comprises first-in-human dose escalation of ZN-1041 monotherapy (phase 1a) in HER2+ solid tumor patients (pts) with or without BM, dose escalation (phase 1b) and expansion (phase 1c) of ZN-1041 in combination with capecitabine and trastuzumab in pts with HER2+ BCBM (including active BM). The primary objective was safety and tolerability. The secondary objective includes pharmacokinetics and anti-tumor response including ORR per RECIST 1.1 and intracranial ORR (iORR) per RANO-BM. Results: Unlike currently approved HER2 TKIs which are strong human efflux transporter P-gp and BCRP substrates, ZN-1041 is not a substrate of either and has high BBB permeability, therefore predicted to have good BBB penetration. ZN-1041 alone demonstrated dose-dependent and significant anti-tumor activity when compared to tucatinib in BM model. ZN-1041 could synergize with capecitabine and trastuzumab to demonstrate significantly improved intracranial efficacy in BM models, while maintaining good tolerability. In total, 21 HER2+ mBC pts were enrolled to complete phase 1a and 1b. No dose-limiting toxicities or treatment-related SAE were observed across all dose levels. PK exposure was increased with dose escalation and Kpuu,CSF of ZN-1041 was 4.9. In ZN-1041 monotherapy, the overall ORR and iORR were 50% in TKI naïve, unequivocal HER2+ pts. The longest treatment duration was 15 months. As of data cutoff (Dec 02, 2022), totally 35 TKI naïve, HER2+ BCBM pts with median 2L treatments were enrolled for phase 1c and all pts were well tolerated to date. Adverse reactions of grade 3 or higher (≥5%) were hepatic function impairment (8.7%), headache (8.7%), hyperbilirubinemia (5.7%), ALT increased (5.7%), AST increased (5.7%), GGT increased (5.7%) and WBC decreased (5.7%). Among 19 BCBM pts with at least twice tumor assessment, the overall ORR was 78.9% (95% CI: 54.4–93.9) and iORR was 73.7% (95% CI: 48.8–90.9), DCR was 100%. In addition, 6 pts completed first tumor assessment and 5 achieved PR and 1 had SD per RECISIT 1.1. Conclusions: Encouraging efficacy and tolerability was observed for ZN-1041 monotherapy or combined with capecitabine and trastuzumab in TKI naïve, HER2+ BCBM patients. A Phase 2 pivotal trial for HER2+ BCBM with ZN-1041, capecitabine and trastuzumab combination therapy is planned. Clinical trial information: NCT04487236 .

Tyrosine kinase inhibitors in HER2-positive breast cancer brain metastases: A systematic review and meta-analysis.

Small tyrosine kinase inhibitors (TKIs) show activity against breast cancer brain metastases (BCBM) of the human epidermal growth factor receptor 2 (HER2)-positive subtype. This meta-analysis aimed to objectively explore the efficacy and safety of TKIs. Electronic databases were searched for relevant clinical trials. We conducted a pairwise meta-analysis, pooled analysis, and estimated summary survival curves to compare survival outcomes following TKIs therapy for BCBM patients using Stata version 16.0 or R x64 4.0.5. Thirteen clinical trials involving 987 HER2-positive BCBM patients were analyzed. A trend of longer progression-free survival (PFS) was observed in the TKI-containing arm compared to the non-TKI-containing arm (hazard ratio = 0.64, 95% confidence interval [CI]: 0.35-1.15, p = 0.132), although the difference is not statistically significant. Summary survival curves reported the summary median PFS and overall survival were 7.9 months and 12.3 months. Subgroup analysis revealed that TKIs combined with capecitabine (TKI + Cap) regimens resulted in improved survival outcomes. Tucatinib may be more effective in BCBM patients. The main grade 3-5 adverse events (AEs) were diarrhea (22%, 95% CI: 14%-32%), neutropenia (11%, 95% CI: 5%-18%), hepatic toxicity (7%, 95% CI: 1%-16%), and sensory neuropathy (6%, 95% CI: 2%-12%). TKIs therapy improved the survival outcomes of HER2-positive BCBM patients, especially when combined with capecitabine and tolerable AEs. We also identified the clinical value of tucatinib, which appears to be the most favorable TKI drug for BCBM patients.

Nanoparticle drug delivery to target breast cancer brain metastasis: Current and future trends.

Breast cancer brain metastasis (BCBM) is rapidly becoming an impediment to continuing survival gains seen in breast cancer patients. Drug delivery across the blood-brain barrier is the main issue hindering systemic therapy against BCBM. This review details recent advances in nanoparticle (NP) drug delivery systems to target BCBM. Their primary benefits are: enhanced circulating and intra-BCBM drug biodistribution, BCBM targeting through NP functionalization, opportunities for gene manipulation and their theragnostic applications. Multiple NPs have been synthesized to deliver therapeutic HER2 blockade, which is particularly important given HER2-positive breast cancer's tendency to form BCBM. Finally, we review the clinical context in which NP-based therapeutics have been investigated in BCBM patients. While a breakthrough in improving patient outcomes remain awaited, these clinical trials represent positive steps in the changing attitude towards BCBM as a treatable illness. Although multiple challenges remain in the clinical translation of BCBM-directed NP therapies, ongoing research in the field offers promising avenues for novel targeting of this devastating disease.

CLO23-063: Impact of Socio-Economic Disparity on Survival of HER 2 Neu (+) Breast Cancer Brain Metastasis Patients With Chemotherapy: A SEER Study

"CLO23-063: Impact of Socio-Economic Disparity on Survival of HER 2 Neu (+) Breast Cancer Brain Metastasis Patients With Chemotherapy: A SEER Study" published on 31 Mar 2023 by National Comprehensive Cancer Network.

Abstract P3-03-28: Clinicopathological Risk Factors of Brain Metastasis in Breast Cancer Patients: A Systematic Review and Meta-analysis

Abstract BACKGROUND: Breast cancer brain metastasis (BCBM) has an incidence rate of 5.1% among Breast Cancer (BC) patients. In BCBM, cancerous cells come from a primary tumor that implant and grow in the brain leading to potentially lethal neurologic symptoms and signs. With more clinical options and therapeutics strategies becoming available, a multi-disciplinary approach for treatment is needed in order to best meet BCBM patients’ needs, however, systematic guidelines for the screening of high-risk asymptomatic patients are still lacking and the BCBM diagnoses are performed only after symptoms manifestation. Therefore, understanding the clinical and pathologic drivers of BCBM aids in improving medical interventions by guiding future research directions. This study aims to determine the clinicopathological risk factors of brain metastasis (BM) among BC patients. METHODS: Retrospective cohort studies on the clinicopathological characteristics of BM versus non-BM (NBM) patients were retrieved through reputable search databases. Review Manager version 5.4.1 was used for statistical analyses. In the presence of heterogeneities, a pragmatic approach was undertaken to employ both random-effects (RE) and fixed-effect (FE) meta-analyses. The statistical significance of the pooled effect estimates was examined by the Z-test. Interstudy variations and heterogeneities were estimated using Cochran’s Q-statistic with P &amp;lt; 0.05 indicating a statistically significant heterogeneity. The risk of bias and the quality of studies were assessed at a study level using ROBINS-I tool. RESULTS: A total of four (4) retrospective cohort studies were included in the analyses. Random-effects meta-analyses with i2 &amp;lt; 50% (P &amp;gt; 0.05) had shown significant association (P &amp;lt; 0.05) on the increased incidences of BCBM development for HER2+ expression [OR: 2.43, 95% CI: 1.88 – 3.12, P &amp;lt; 0.00001] and for pre-menopausal status [OR: 1.77, 95% CI: 1.13 – 2.76, P = 0.01]. Fixed-effect meta-analyses had shown significant association (P &amp;lt; 0.05) on the decreased incidence of BCBM development for TNBC disease [OR: 0.66; 95% CI: 0.47 – 0.92; P = 0.02]. The risk of bias was low to moderate in the majority of studies. CONCLUSION: HER2 positivity and pre-menopausal status are risk factors for increased BCBM development while the absence of regional lymph node metastases and ILC findings are less likely to progress to BCBM. Higher T and N categories, higher histological grade, ER negativity, and PR negativity may be associated with higher risks of BCBM while lower T categories, HER2 negativity, and TNBC may likely be associated to less BCBM development. More powerful relevant and upcoming randomized clinical trials with larger sample sizes among BCBM patients versus non-BM patients must be made exploring certainty on the clinicopathological factors contributing to BM among BC patients. Keyword/s: risk factors, breast cancer, brain metastasis Citation Format: Korina Blanca C. Garcia, April Ann A. Lubay. Clinicopathological Risk Factors of Brain Metastasis in Breast Cancer Patients: A Systematic Review and Meta-analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-03-28.

Abstract P2-13-01: Enrollment Trends Among Patients With Breast Central Nervous System Metastasis in Active Clinical Trials

Abstract Background: Breast cancer is the second leading cause of solid tumor brain metastasis. Up to 16% of patients with metastatic breast cancer (mBC), and 50% patients with HER2+ metastatic breast cancer will develop central nervous system (CNS) metastasis overtime. Prognosis in these patients is dismal with a median overall survival of 2-15 months. Despite advances in systemic therapy of mBC, treatment options for patients with breast cancer brain metastasis (BCBM) remain limited. Although newer approaches to treat BCBM are imminently needed, BCBM patients have traditionally been excluded from clinical trials. We aimed to examine the current state of BCBM-related enrollment in ongoing prospective systemic therapy clinical trials for mBC. Methods: We performed a systematic search of the clinicaltrials.gov website on May 1, 2022 to characterize current trends in clinical trial enrollment for BCBM patients in ongoing interventional trials using the key search term “Breast Cancer”. Trial search was further limited to “open” and “interventional studies”. Data was abstracted and verified by two independent researchers. Trials were excluded if they were specific for other disease types, did not include a systemic anticancer pharmaceutical, or excluded advanced/metastatic disease. Inclusion of active CNS disease [BCMB and leptomeningeal disease (LMD)] and exclusion of CNS disease were the co-primary end points. Covariates of interest were gender, location (US, international or both), disease site (breast cancer specific vs multi-disease trials), therapy category (immunotherapy (IO), targeted therapy, endocrine therapy, chemotherapy, or combination) and sponsor type. Logistic regression was used to model inclusion of active CNS disease. Results: A total of 1720 trials were identified, and 576 trials met the inclusion criteria. 179 (31.6%) were phase I, 129 (22.4%) were phase I/II, 196 (34.0%) were phase II, 60 (10.4%) were phase III and 9 (1.6%) were phase IV. 347 (60.4%) were breast cancer specific and 229 (39.6%) were multi-site trials. 66 (11.5%) trials were specific for HER-2+ cancer and 70 (12.1%) were triple negative breast cancer specific. 238 (41.3%) trials were US only and 290 (50.3%) were pharmaceutical industry sponsored. Overall, only 29 trials (5%) included patients with any form of BCBM and only 11 trials (1.9%) allowed patients with LMD. 12 (2.1%) trials allowed patients with treated BCBMs only. In univariate models, breast cancer only trials (OR 4.07, 95% CI 1.77-9.36, p= 0.0009), trials excluding men (OR 1.97, 95% CI 1.03-3.77, p=0.0412), non-IO therapy trials (non-IO vs IO OR 3.57, 95% CI 1.08-11.82, p=0.369), and non-pharmaceutical industry sponsored trials (OR 2.65, 95% CI 1.34-5.22, p =0.0049) were more likely to include patients with active CNS disease. Additionally, inclusion of LMD (OR 7.85, 95% CI 2.19-28.17, p = 0.0016) was a significant predictor of inclusion of active CNS disease. In a combined model, disease site remained significant (breast only vs multi-site OR 4.07, 95% CI 1.77-9.36, p = 0.0009). Conclusion: The vast majority of the ongoing breast cancer clinical trials continue to exclude patients with breast cancer brain metastasis. With an increasing prevalence of breast cancer brain metastasis, evaluating intracranial efficacy of novel therapies early on in drug development remains an area of urgent unmet need. Citation Format: Omar Elghawy, Walter Banfield, John Wang, Bethany Horton, Varinder Kaur. Enrollment Trends Among Patients With Breast Central Nervous System Metastasis in Active Clinical Trials [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-13-01.

TMIC-04. TARGETING AN ECM PROTEIN INVOLVED IN BREAST CANCER BRAIN METASTASES WITH AN ONCOLYTIC HSV-1

Abstract The beta-1 subunit of integrins (CD29) is important for cell-extracellular matrix interactions. CD29 expression is increased in breast cancer cells, and it promotes their invasion, migration, and intravasation, all of which can result in breast cancer brain metastasis (BCBM). While CD29 expression can be correlated to poor prognosis of breast cancer patients, the median survival of BCBM patients predicted to have better prognosis is 36 months. Despite current BCBM treatments such as craniotomy, reaching the metastatic site is often challenging. Modified viral vectors, such as oncolytic herpes simplex virus (oHSV), have been clinically approved for the treatment of malignant melanoma and brain tumors, as they infect and selectively kill tumor cells. Previously, we identified that combination of oHSV and humanized CD29 blocking antibody (OS2966, aCD29) enhanced viral replication by reducing antiviral immune response, increased tumor cell killing, and rendered survival benefit to tumor bearing mice with intra-tumoral, but not systemic, oHSV administration. These findings suggested that the antitumor efficacy of the therapeutic combination required intratumoral delivery of anti-CD29, since the antibody could not penetrate the blood brain barrier and reach intracranial tumors. To overcome this, we report the generation of an oHSV encoding the scFv-Fc fragment of this antibody (HSV-aCD29), which retains its oncolytic function, and evaluate the impact of HSV-aCD29 on the CD29 downstream signaling. We will further characterize the safety, antitumor efficacy, and assess the immune response to HSV-aCD29 in vitro and in vivo. We anticipate that compared to our control virus, HSV-aCD29 will block CD29 activity which will reduce antiviral immune responses and enhance tumor cell lysis, thus improving oHSV efficacy. Together, this study proposes the blockade of CD29 with the targeted delivery of a CD29 blocking antibody mediated by a novel oHSV as a potential synergistic therapy against BCBM.

280 (PB-104) Poster - Clinicopathologic Risk Factors of Brain Metastasis in Breast Cancer Patients: A Systematic Review and Meta-analysis

Background: Breast cancer brain metastasis (BCBM) has an incidence rate of 5.1% among Breast Cancer (BC) patients. In BCBM, cancerous cells come from a primary tumor that implant and grow in the brain leading to potentially lethal neurologic symptoms and signs. With more clinical options and therapeutics strategies becoming available, a multi-disciplinary approach for treatment is needed in order to best meet BCBM patients’ needs, however, systematic guidelines for the screening of high-risk asymptomatic patients are still lacking and the BCBM diagnoses are performed only after symptoms manifestation.

Intralesional TLR4 agonist treatment strengthens the organ defense against colonizing cancer cells in the brain

Brain metastasis in breast cancer remains difficult to treat and its incidence is increasing. Therefore, the development of new therapies is of utmost clinical relevance. Recently, toll-like receptor (TLR) 4 was correlated with IL6 expression and poor prognosis in 1 215 breast cancer primaries. In contrast, we demonstrated that TLR4 stimulation reduces microglia-assisted breast cancer cell invasion. However, the expression, prognostic value, or therapeutic potential of TLR signaling in breast cancer brain metastasis have not been investigated. We thus tested the prognostic value of various TLRs in two brain-metastasis gene sets. Furthermore, we investigated different TLR agonists, as well as MyD88 and TRIF-deficient microenvironments in organotypic brain-slice ex vivo co-cultures and in vivo colonization experiments. These experiments underline the ambiguous roles of TLR4, its adapter MyD88, and the target nitric oxide (NO) during brain colonization. Moreover, analysis of the gene expression datasets of breast cancer brain metastasis patients revealed associations of TLR1 and IL6 with poor overall survival. Finally, our finding that a single LPS application at the onset of colonization shapes the later microglia/macrophage reaction at the macro-metastasis brain-parenchyma interface (MMPI) and reduces metastatic infiltration into the brain parenchyma may prove useful in immunotherapeutic considerations.

An Insight into Molecular Targets of Breast Cancer Brain Metastasis.

Brain metastasis is one of the major reasons of death in breast cancer (BC) patients, significantly affecting the quality of life, physical activity, and interdependence on several individuals. There is no clear evidence in scientific literature that depicts an exact mechanism relating to brain metastasis in BC patients. The tendency to develop breast cancer brain metastases (BCBMs) differs by the BC subtype, varying from almost half with triple-negative breast cancer (TNBC) (HER2− ER− PR−), one-third with HER2+ (human epidermal growth factor receptor 2-positive, and around one-tenth with luminal subclass (ER+ (estrogen positive) or PR+ (progesterone positive)) breast cancer. This review focuses on the molecular pathways as possible therapeutic targets of BCBMs and their potent drugs under different stages of clinical trial. In view of increased numbers of clinical trials and systemic studies, the scientific community is hopeful of unraveling the underlying mechanisms of BCBMs that will help in designing an effective treatment regimen with multiple molecular targets.

Comparative Efficacy of Tyrosine Kinase Inhibitors and Antibody-Drug Conjugates in HER2-Positive Metastatic Breast Cancer Patients with Brain Metastases: A Systematic Review and Network Meta-Analysis.

Simple SummaryComparisons between the efficacy of tyrosine kinase inhibitors (TKIs) and antibody–drug conjugates (ADCs) in treating HER2-positive breast cancer brain metastasis (BCBM) patients have not previously been conducted. We performed a systematic review and Bayesian-based network meta-analysis to pool the estimates of progression-free survival, overall survival, and incidence of central nervous system (CNS) disease progression. The current study indicated that both T-DXd and T-DM1 presented better efficacy than TKIs regarding survival outcomes. Treatments containing neratinib or T-DM1 tended to rank the best in reducing the recurrent rate of CNS. Our study provides more evidence for the clinical decision making for patients with HER2-positive BCBM. More high-quality studies with standardized entry criteria and comparable CNS-related endpoints are warranted in the future.HER2-positive breast cancer brain metastasis (BCBM) is an important clinical problem. A systematic review and network meta-analysis were conducted to compare the efficacy of tyrosine kinase inhibitors (TKIs) and antibody–drug conjugates (ADCs), two categories of emerging agents in this field. We implemented a comprehensive literature search of PubMed, Embase, the Cochrane Library, ClinicalTrials.gov, and abstracts of oncology conferences. A network meta-analysis following Bayesian approaches was performed. Pooled hazard ratios (HRs) and odds ratios (ORs) with credible intervals (CrIs) were calculated to estimate progression-free survival (PFS), overall survival (OS), and the incidence of central nervous system (CNS) disease progression. Sixteen studies were included. Pairwise comparisons of PFS showed salient divergency between T-DXd and the physician’s choice of treatment (HR 0.17; 95% CrI 0.03–0.82) or afatinib (HR 0.14; 95% CrI 0.02–1.00). T-DXd and T-DM1 ranked first regarding PFS and OS, respectively, followed by TKI-containing regimens. The incidence of CNS disease progression was analyzed separately according to baseline BCBM status, among which neratinib-containing regimens were most likely to rank the best. In conclusion, ADCs including T-DXd and T-DM1 showed better efficacy than TKIs in the survival outcomes for HER2-positive BCBM patients. Treatments based on neratinib or T-DM1 revealed favorable results in reducing the recurrent rate of CNS.