Progressive Brain Metastases Research Articles

Abstract B019: Mathematical modeling-based optimization of gamma knife surgery after checkpoint blockade in melanoma brain metastases

Abstract Gamma knife radiotherapy (RT) treatment is often used as a salvage therapy after progression of melanoma brain metastasis (MBM) lesions under immune checkpoint inhibitor (ICI) blockade therapy; however, waiting until progression of nonresponsive lesions can result in significant symptomatic progression, and the toxicity of RT is greater for larger lesions as it is directly proportional to lesion volume. Robust and reliable standards for consistently maximizing the benefit of combination ICI + RT therapy remain elusive, likely in part due to the complexity of mechanistic interactions between each therapy. Addressing this clinical need will require optimizing the effects of their reported synergistic interactions such as tumor microenvironment modulation and immune activation while mitigating inhibitory effects such as immunosuppressive radiation effects. The ability to identify lesions unlikely to respond to ICI shortly after start of treatment would offer immediate clinical benefit by enabling earlier RT delivery, reduce the volume-dependent toxicities of RT, and reduce symptoms from lesion progression. To address the unmet clinical need for methods to optimize outcomes of combination ICI and RT therapy, we have developed a mechanistic mathematical model based on the biological and physical underpinnings of these complex therapies, and their interactions, which is able to describe and quantify interactions between ICI and RT and their interactions on the tumor. This builds upon our previous ICI modeling work by expanding the model based on the assumption that therapeutic outcome is not only a result of direct interaction between the treatment and disease, but is also a result of complex interplay between heterogeneous tumor populations that may be sensitive or resistant to treatment and their unique interactions with the immune system that serve to maintain or disrupt the tumor-immune equilibrium. RT further modulates this tumor-immune dynamic both by killing T cells in the tumor interior and by stimulating release of T cell activating antigens which can alter T cell activation exterior to the tumor, thereby affecting T cell recruitment into the tumor. By capturing how the complex time-dependent dynamics of tumor-immune interaction and recruitment influences – and is influenced by – transient shifts in treatment sensitive and resistant populations, our model aims to describe and quantify long-term tumor dynamics after ICI + RT therapy. This platform provides a consistent framework for systematically evaluating various proposed mechanisms underlying treatment interactions and how these may determine treatment failure or success. By applying the model to a retrospective, in-house generated melanoma brain metastasis data set, we are examining and refining our model structure with a goal of capturing a wide range of observed tumor dynamics using only clinically available data. This may lead to robust, quantitative methods to maximize treatment outcomes based on the unique characteristics of individual tumors. Citation Format: Alexander R. J. Silalahi, Caroline Chung, James W. Welsh, Zhihui Wang, Joseph D. Butner. Mathematical modeling-based optimization of gamma knife surgery after checkpoint blockade in melanoma brain metastases. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B019.

Astrocyte plasticity shapes brain metastasis progression through tumor-astrocyte crosstalk

Brain metastases are ten times more common than primary brain tumors and pose a significant clinical challenge. How brain metastatic tumor cells adapt to the unique and hostile brain microenvironment remains unclear. Astrocytes, the most abundant glial cells in the brain, are emerging as key mediators regulating the development of brain metastases. Initially anti-metastatic, astrocytes are reprogrammed by tumor-derived signals, transitioning into a pro-metastatic phenotype. Here, we review the roles of astrocytes in brain metastasis and describe the evidence for their phenotypic plasticity, the basis of astrocyte-tumor interactions, and potential therapeutic strategies targeting these processes.

Outcomes of Management of Progressive Radiosurgery-Treated Brain Metastasis With Resection Followed by Pathology-Informed Management: A Retrospective Study

BACKGROUND AND OBJECTIVES: In patients treated with stereotactic radiosurgery (SRS) for brain metastases, follow-up imaging demonstrating progression may result from treatment effect/radionecrosis (RN) or tumor progression. We report long-term outcomes for a cohort of patients who demonstrated radiological progression on serial imaging after initial radiation and who underwent resection, at which point histology informed further management. METHODS: A retrospective chart review identified 76 patients with an associated 82 brain lesions between 2009 and 2022, that were initially treated with SRS, and then demonstrated suspicious imaging developing through at least 2 scan time points with either pathologic confirmation of tumor or RN. RESULTS: Of the 82 lesions, 55 lesions (67.1%) were found to be tumor and were treated with repeat radiation and 27 (32.9%) were found to have pathologically confirmed RN and conservatively managed. 14/27 lesions ultimately found to be radionecrotic required steroids preoperatively due to neurological symptoms. None of these lesions required further intervention with median postsurgery follow-up of 24.4 months (range 1-104 months). There were 55 instances (in 51 patients) of confirmed recurrent/progressive tumor who we treated with repeat aggressive radiation with either Cs-131 brachytherapy (12 [21.8%]) or SRS (43 [78.2%]). Among patients treated with reirradiation, the median follow-up to local failure was 15.2 months (95% CI 7.3-26.6 months). The 2-year local control rate was 79.5% (95% CI 68.3%-92.5%). CONCLUSION: These results support resection of radiosurgery-treated lesions with progression continuing through serial imaging, and this pathology-informed management results in excellent control of both RN and tumor progression after radiosurgery.

PATH-67. THE ROLE OF STATUS OF HER-2, ESTROGEN-RECEPTOR, BRCA 1, AND BRCA 2, IN THE INCIDENCE OF BRAIN METASTASIS IN BREAST CANCER

Abstract Breast cancer (BC) is the most diagnosed tumor in women and the second-leading cause of brain metastasis (BM), with a prevalence ranging from 10-36%. According to the Epidemiological Strategy and Medical Economics research program, advanced BC patients face an estimated 25% risk of developing BM within 2-3 years after the initial diagnosis. The frequency of BM is significantly increased by the primary tumor profile, including larger tumors, higher nuclear grade, HER-2 positivity, estrogen-receptor negativity, and triple-negative status. A gap remains in the classification of the BM site relative to primary tumor biomarkers, and the absence of multimodality treatment methodologies poses challenges to survival rates and quality of life in BC patients. This retrospective cross-sectional study at Aga Khan University Hospital identified 52 cases of brain metastasis secondary to breast cancer over a 10-year period. The median age of patients was 55 years, ranging from 32 to 78 years. Primary breast tumors were predominantly high-grade ductal carcinomas (65%), followed by lobular carcinomas (25%) and other rare histological types (10%). Secondary brain metastases were primarily located in the cerebrum (60%), cerebellum (25%), and brainstem (15%). Tumor profiles indicated a significant correlation between HER-2 positivity and the development of brain metastasis, with 70% of HER-2 positive patients presenting with extensive brain metastasis. Tumor progression varied, with a median time to brain metastasis of 2.5 years from the initial breast cancer diagnosis. Despite aggressive multimodality treatments, including surgery, radiation, and chemotherapy, the overall prognosis remained poor. The study found that early detection of HER-2 positive and triple-negative tumors could potentially delay the progression of brain metastasis through targeted therapies. Mortality rates in this cohort were high, with a median survival of 8 months following the diagnosis of brain metastasis. These findings underscore the need for improved diagnostic, preventive, and therapeutic strategies to manage brain metastasis in breast cancer patients.

SURG-06. IMPACT OF LASER INTERSTITIAL THERMAL THERAPY VERSUS RESECTION FOR METASTASES ASSOCIATED WITH THE MOTOR CORTEX

Abstract BACKGROUND For brain metastases (BM), resection remains a mainstay for the upfront management of large, symptomatic lesions, while laser interstitial thermal therapy (LITT) has become a key treatment for radiographically progressive BM following stereotactic radiosurgery (SRS). Compared to LITT, resection-associated morbidity may delay systemic therapies. We evaluated functional outcomes for resection versus LITT to primary motor cortex (PMC)-associated metastases. METHODS Patients receiving resection or LITT for BM radiographically associated with the PMC from 2015-2023 were retrospectively reviewed. Demographic and survival data were collected, with patient Karnofsky Performance Status (KPS) or modified Rankin Scale (mRS) scores assessed out to 1-year by independent raters. RESULTS Forty-one patients underwent resection and 30 underwent LITT to a PMC-associated lesion. Median age was 67 (range 38 – 80) vs 65 (44 – 80) for resection vs LITT; median pre-operative KPS (70 vs 80, P = 0.1) or mRS (2 vs 2, P = 0.66) did not differ between groups. Lung was the most common primary (56.1% resections vs 56.7% LITTs). Resected lesions were of larger median diameter than LITT, 2.8 vs 1.9 cm, P = 0.0001. For resections, length of stay was longer, median 2 vs 1 day, P = 0.0002, and ICU use more frequent (75.6% versus 20.0%, P < 0.0001). At 1-month post-op, 66.7% of resection patients and 51.7% of LITT patients had stable or improved symptoms from pre-op, P = 0.21, with parity at 3-months (65.7% vs 62.9%) and therafter. Further, there was no significant decrement in KPS or mRS score out to a year for either intervention. CONCLUSIONS While there is a short-term increased risk of post-operative neurologic worsening due to LITT-associated edema, our data shows that, relative to resection, this is a transient and clinically limited phenomenon. With careful patient selection, LITT to lesions involving the PMC is feasible.

A study method using early dynamic acquisition of [18F]fluorodopa positron emission tomography for the differential diagnosis between progression and radionecrosis of brain metastases after radiotherapy

BackgroundIt is difficult to distinguish between the brain metastasis progression (BMP) and brain radionecrosis (BRN) on the basis of 18F-3,4-dihydroxyphenylalanine positron emission tomography/computed-tomography (18F-FDOPA PET/CT) data. The advent of silicon photomultiplier (SiPM) PET technology makes it possible to study dynamic volumes and potentially improve diagnostic accuracy. We developed a method for processing 18F-FDOPA PET/CT in the differential diagnosis between BMP and BRN. The method involves a short (3-second) sampling time during a 4-minute acquisition on a SiPM-PET/CT machine. We prospectively included 15 patients and 19 metastases. All acquisitions were performed in list mode acquisition for 25 min on a four-ring SiPM PET/CT system. We calculated the ratios between the maximum activity in the lesion’s voxel and the mean activity in the contralateral region (VOImax/CLmean) or the mean activity in the white matter (VOImax/WMmean).ResultsSeven lesions were classified as BMP and twelve were classified as BRN. Statistically significant intergroup differences in the VOImax/CLmean and VOImax/WMmean activity ratios were observed for both the clinical volume and the early acquisition. The best performing quantitative variable was the VOImax/CLmean ratio on early acquisition, with a diagnostic accuracy of 94.7%, a sensitivity of 100%, and a specificity of 91.7%.ConclusionThe 18F-FDOPA PET/CT data acquired a few minutes after the bolus injection confirms its value in differentiating between BMP and BRN, compared to the much longer classic clinical protocol.

Lipocalin-2 promotes breast cancer brain metastasis by enhancing tumor invasion and modulating brain microenvironment.

Breast cancer is the leading cancer diagnosed in women globally, with brain metastasis emerging as a major cause of death, particularly in human epidermal growth factor receptor 2 positive and triple-negative breast cancer subtypes. Comprehensive understanding of the molecular foundations of central nervous system metastases is imperative for the evolution of efficacious treatment strategies. Lipocalin-2 (LCN2), a secreted iron transport protein with multiple functions, has been linked to the progression of breast cancer brain metastasis (BCBM). In primary tumors, LCN2 promotes the proliferation and angiogenesis of breast cancer cells, triggers the epithelial-mesenchymal transition, interacts with matrix metalloproteinase-9, thereby facilitating the reorganization of the extracellular matrix and enhancing cancer cell invasion and migration. In brain microenvironment, LCN2 undermines the blood-brain barrier and facilitates tumor seeding in the brain by modulating the behavior of key cellular components. In summary, this review meticulously examines the fuel role of LCN2 in BCBM cascade, and investigates the potential mechanisms involved. It highlights the potential of LCN2 as both a therapeutic target and biomarker, indicating that interventions targeting LCN2 may offer improved outcomes for patients afflicted with BCBM.

Nerve growth factor inducible (VGF) is a secreted mediator for metastatic breast cancer tropism to the brain.

Brain metastases are one of the most serious clinical problems in breast cancer (BC) progression, associated with lower survival rates and a lack of effective therapies. Thus, to dissect the early stages of the brain metastatic process, we studied the impact of brain organotropic BC cells' secretomes on the establishment of the brain pre-metastatic niche (PMN). We found that BC cells with specific tropism to the brain caused significant blood-brain barrier (BBB) disruption, as well as microglial activation, in both in vitro and in vivo models. Further, we searched for a brain-organotropic metastatic signature, as a promising source for the discovery of new biomarkers involved in brain metastatic progression. Of relevance, we identified VGF (nerve growth factor inducible) as a key mediator in this process, also impacting the BBB and microglial functions both in vitro and in vivo. In a series of human breast tumors, VGF was found to be expressed in both cancer cells and the adjacent stroma. Importantly, VGF-positive tumors showed a significantly worse prognosis and were associated with HER2 (human epidermal growth factor receptor 2) overexpression and triple-negative molecular signatures. Further clinical validation in primary tumors from metastatic BC cases showed a significant association between VGF and the brain metastatic location, clearly and significantly impacting on the prognosis of BC patients with brain metastasis. In conclusion, our study reveals a unique secretome signature for BC with a tropism for the brain, highlighting VGF as a crucial mediator in this process. Furthermore, its specific impact as a poor prognostic predictor for BC patients with brain metastasis opens new avenues to target VGF to control the progression of brain metastatic disease. © 2024 The Pathological Society of Great Britain and Ireland.

The role of immunotherapy in patients with lung cancer and brain metastases: a narrative review of the literature.

Worldwide, approximately half of the patients diagnosed with lung cancer (LC) will develop, simultaneously or asynchronously, brain metastases (BMs). The existence of BMs negatively affects the quality of life and constitutes a poor prognostic factor, linked with high mortality. Locoregional therapy with surgery or radiation is, until now, the treatment of choice, especially for symptomatic patients; however, both options are linked to a high complication rate. The question arising here is whether, in asymptomatic patients, the benefit outweighs the risk and whether an alternative method can be used to treat this special category of patients. Over the last decade, immune checkpoint inhibitors (ICIs) have represented a major breakthrough in the field of oncology, and several molecules have been approved as a treatment option for LC. This review tried to analyze the tumor microenvironment of both the primary lung tumor and the BMs in order to evaluate the intracranial activity of ICIs, outline the main challenges of including these agents in the treatment of LC with BMs, highlight the available information from the main clinical trials, and mark the potential positive effect of choosing a combination therapy. In conclusion, it appears that immunotherapy has a positive effect, inhibiting the progression of BMs, but more data should be published specifically for this category of patients.

Reirradiation of metastases of the central nervous system: part 1-brain metastasis.

Because of improved survival of cancer patients, more patients irradiated for brain metastases develop intracerebral recurrences requiring subsequent courses of radiotherapy. Five studies focused on reirradiation with whole-brain radiation therapy (WBRT) after initial WBRT for brain metastases. Following the second WBRT course, improvement of clinical symptoms was found in 31-68% of patients. Rates of neurotoxicity, such as encephalopathy or cognitive decline, were reported in two studies (1.4% and 32%). In another study, severe or unexpected adverse events were not observed. Survival following the second WBRT course was generally poor, with median survival times of 2.9-4.1 months. The survival prognosis of patients receiving two courses of WBRT can be estimated by a scoring tool considering five prognostic factors. Three studies investigated reirradiation with single-fraction stereotactic radiosurgery (SF-SRS) following primary WBRT. One-year local control rates were 74-91%, and median survival times ranged between 7.8 and 14 months. Rates of radiation necrosis (RN) after reirradiation were 0-6%. Seven studies were considered that investigated re-treatment with SF-SRS or fractionated stereotactic radiation therapy (FSRT) following initial SF-SRS or FSRT. One-year local control rates were 60-88%, and the median survival times ranged between 8.3 and 25 months. During follow-up after reirradiation, rates of overall (asymptomatic or symptomatic) RN ranged between 12.5% and 30.4%. Symptomatic RN occurred in 4.3% to 23.9% of cases (patients or lesions). The risk of RN associated with symptoms and/or requiring surgery or corticosteroids appears lower after reirradiation with FSRT when compared to SF-SRS. Other potential risk factors of RN include the volume of overlap of normal tissue receiving 12 Gy at the first course and 18 Gy at the second course of SF-SRS, maximum doses ≥40 Gy of the first or the second SF-SRS courses, V12 Gy >9 cm3 of the second course, initial treatment with SF-SRS, volume of normal brain receiving 5 Gy during reirradiation with FSRT, and systemic treatment. Cumulative EQD2 ≤100-120 Gy2 to brain, <100 Gy2 to brainstem, and <75 Gy2 to chiasm and optic nerves may be considered safe. Since most studies were retrospective in nature, prospective trials are required to better define safety and efficacy of reirradiation for recurrent or progressive brain metastases.

Brain metastases in clinical trial participants with KRAS-mutated advanced non-small cell lung cancer receiving docetaxel: Pooled data analysis

ObjectivesLimited data are available on central nervous system (CNS) efficacy with standard-of-care therapies for KRAS-mutated (KRASmut) advanced non-small cell lung cancer (NSCLC). The objective of this study was to investigate the incidence and progression of brain metastases in KRASmut advanced NSCLC treated with docetaxel using pooled data from historical clinical trials. Materials and MethodsData from phase 2/3 trials of docetaxel-containing regimens in advanced NSCLC were sourced from the Medidata platform. Analysis was restricted to stage IIIB-IV KRASmut NSCLC with disease progression after ≥ 1 systemic anticancer therapy. Participants with asymptomatic, treated, and stable brain metastases were included. Endpoints included 12-month CNS disease control rate (CNS-DCR) and CNS progression per Response Evaluation Criteria in Solid Tumors; progression-free survival (PFS); and overall survival (OS). Data were pooled and analyses stratified by baseline brain metastases status. ResultsA total of 595 participants were included in the analysis (62 [10%] with baseline brain metastases and 533 [90 %] without). Among participants with brain metastases, 17 (27.4 %) had CNS progression during docetaxel treatment and 12-month CNS-DCR was 75.8 %; 45 (8.4 %) participants without baseline brain metastases developed brain metastases during treatment. In an analysis restricted to patients with metastatic disease, outcomes with and without baseline brain metastases included: median PFS, 3.3 and 4.9 months (p < 0.005); 12-month PFS, 5 % and 16 %; median OS, 6.9 and 10.4 months (p < 0.005); and 12-month OS, 20 % and 44 %, respectively. ConclusionThese findings establish CNS progression rates with docetaxel in previously treated KRASmut advanced NSCLC and facilitate interpretation of data from ongoing randomized clinical trials of novel KRAS-targeted therapeutic strategies vs. docetaxel.

A Phase II Trial of Bevacizumab in Patients with Recurrent/Progressive Solid Tumor Brain Metastases That Have Progressed Following Whole-Brain Radiation Therapy.

Patients with solid tumor brain metastases that progress after whole-brain radiation have limited options. This prospective trial investigated the efficacy, safety, and tolerability of bevacizumab as salvage therapy in this population. Eligible patients received bevacizumab 10 mg/kg intravenously every 2 weeks until progression. The primary endpoint was radiologic response using Response Assessment in Neuro-Oncology (RANO) criteria. The secondary endpoints were progression-free survival (PFS), overall survival (OS), duration of response, and safety. Quality of life (QOL) was studied using the Functional Assessment of Cancer Therapy-Brain (FACT-Br) scale. Twenty-seven patients were enrolled, with twenty-four having evaluable data for response. The majority of histologies (n = 21, 78%) were breast cancer. The remaining histologies were non-small-cell lung cancer (n = 4, 15%), neuroendocrine cancer (n = 1, 3%), and papillary fallopian serous adenocarcinoma (n = 1, 3%). Eighteen patients had radiologic response, with two patients demonstrating partial response (8.33%) and sixteen patients demonstrating stable disease (66.7%). The median duration of response was 203 days. PFS at 6 months was 46%, median PFS was 5.3 m, and median OS was 9.5 m. Treatment was well tolerated, with six patients experiencing grade 3 lymphopenia and hypertension. There was one grade 3 thromboembolism. QOL was not negatively impacted. Bevacizumab is a safe and feasible salvage treatment with durable response and favorable overall survival for patients with progressive brain metastases after whole-brain radiation.

Phase II study of enasidenib in IDH2-mutated malignant sinonasal and skull base tumors.

TPS3183 Background: Advanced sinonasal malignancies are rare and heterogeneous cancers with limited therapeutic options. Tumor types include olfactory neuroblastoma (ONB), sinonasal undifferentiated carcinoma (SNUC) and large cell neuroendocrine carcinoma (LCNEC), chondrosarcoma, and sinonasal adenocarcinoma (SNAC). Pathogenic driver mutations in isocitrate dehydrogenases 1 and 2 ( IDH1 and IDH2) were identified first in glioma and myeloid malignancies. IDH1/2 enzymatic activity catalyzes conversion of isocitrate and NADP+ to α-ketoglutarate (α-KG) and NAPDH, which are critical for cellular metabolism and for α-KG-dependent dioxygenases; mutant IDH1/2 catalyze conversion of α-KG to the oncometabolite 2-hydroxyglutarate (2-HG), a competitive antagonist of α-KG in regulating dioxygenases activity, with subsequent impact on DNA histone methylation and cellular differentiation. R172S or R172T IDH2mut have been detected in up to 80% of SNUCs and in a minority of ONB, chondrosarcoma, LCNEC and SNAC. Enasidenib is an oral small molecule inhibitor of the mutant IDH2 protein which prevents 2-HG accumulation and releases cancer cells from the differentiation block. It is currently approved for relapsed/refractory IDH2mut myeloid malignancies with proven clinical efficacy. Methods: This is a phase 2, single arm clinical trial conducted at the Center for Cancer Research (CCR) of the National Cancer Institute. The trial investigates the activity of enasidenib in adult patients with histologically or cytologically confirmed locally advanced or metastatic IDH2mut sinonasal cancers (SNUC, ONB, LCNEC, chondrosarcoma, SNAC). Participants must have RECIST 1.1 measurable disease and must have progressed following at least one prior systemic treatment line administered in the recurrent/metastatic setting; those with locally advanced disease must not be amenable to potentially curative approaches. Participants must also have ECOG performance status ≤ 2, be 18 years old or higher, and have adequate organ function. Participants with active, either new or progressive brain metastases or leptomeningeal disease are excluded. Enasidenib will be given continuously at a fixed dose of 100 mg orally daily in a 28-day cycle, until disease progression, unacceptable toxicity, or consent withdrawal. Imaging will be performed every 8 weeks. Baseline and on-treatment research biopsies will be mandatory, where clinically feasible. The trial aims to accrue a total of 25 participants. The primary end point is progression free survival. Secondary outcomes include safety, overall survival, and clinical benefit rate, defined as complete response, partial response and stable disease (per RECIST 1.1) lasting above 4 months. Correlative studies include evaluating changes in 2-HG plasma levels during treatment, and transcriptomic profiling. The study has just started enrolling in the CCR. Clinical trial registry: NCT06176989. Clinical trial information: NCT06176989 .

A phase II trial combining SHR-1316, bevacizumab, and cisplatin/carboplatin in patients with TNBC with active brain metastases.

e13133 Background: Triple-negative breast cancer (TNBC) has a high risk of brain metastases (BM), leading to poor survival. Treatment options for BMs are limited, and the combination of chemotherapy and immune checkpoint inhibitor is the standard-of-care for PD-L1 positive metastatic TNBC. Platinum-based systematic therapy is the mainstay of TNBC treatment and the addition of bevacizumab has shown improvement in the progression-free survival (PFS) of patients with BM. Therefore, this study aims to investigate the efficacy and safety of SHR-1316 (anti-PD-L1) in combination with bevacizumab and cisplatin/carboplatin in TNBC patients with BMs. Methods: In this single-center phase II trial, TNBC patients with active BM received SHR-1316, bevacizumab, and cisplatin/carboplatin. Prior treatment with bevacizumab or anti-PD-1/PD-L1 were not allowed. Prior platinum was allowed only in cases of previous platinum-sensitive response. The primary endpoint was objective response rate (ORR) of central nervous system (CNS), as assessed according to the response assessment in neuro-oncology brain metastases. The secondary endpoint included clinical benefit rate (CBR) of CNS, PFS, overall survival (OS), first progression site and safety. Results: As of January 12th, 2024, a total of 23 female patients with ECOG PS≥1(100%) were enrolled. The median number of previous lines of therapy for metastatic disease was 1 (0-3). All patients had active BM, of which 87% (20/23) were BM treatment-naïve and 13% (3/23) had BM progression after previous local therapy, 26.1% (6/23) had received a prior platinum agent. Of the 23 evaluable patients, the confirmed CNS ORR was 65.2% (95%CI: 42.7%-83.6%), with 3 complete response (CR), 12 partial response (PR), 7 stable disease (SD), and 1 progressive disease (PD). The median CNS-PFS was 11.2 months (95%CI, 5.8 to not reached), median PFS was 7.6 months (95%CI, 5.7-11.9), and median OS was 13.2 months (95%CI, 9.5 to not reached). Treatment-related adverse events (TRAEs) were reported in all 23 patients, and the most common TRAEs were neutrophil count decreased (69.6%, 16/23), anemia (65.2%, 15/23), asthenia (60.9%, 14/23), Hypomagnesaemia (56.5%, 13/23), leukopenia (52.2%, 12/23) and electrocardiogram T wave abnormal (52.2%, 12/23). The incidence of grade ≥3 TRAEs was 43.5% (10/23), including neutropenia (13%, 3/23), platelet count decreased (8.7%, 2/23), and hypertension (8.7%, 2/23). Only one patient had a grade 4 TRAE (lymphocytopenia), and SHR-1316 related serious adverse event (facial nerve disorder) occurred in only one patient. No grade 5 AEs were noted. Conclusions: SHR-1316 plus bevacizumab and cisplatin/carboplatin achieves a significant improvement in CNS ORR and brings PFS and OS benefits in TNBC patients with active BMs. As an effective and safe treatment, this triple-combination warrants further investigation. Clinical trial information: NCT04303988 .

An Evaluation of Risk Factors for Intracranial Metastases of Sarcomas: A Systematic Review and Meta-Analysis

Sarcomas, a group of neoplasms comprising both tissue and bone soft tissue tumors, has an increasing prevalence in recent years. Prognosis significantly hinges on early detection and if not detected early may consequently metastasize. This review will be the first systematic review and meta-analysis characterizing the presentation and progression of brain metastases from bone and soft tissue cancers. The PubMed, Scopus, and Web of Science databases were queried to identify studies reporting the incidence of intracranial brain metastases from primary sarcoma to the present. Abstract and full-text screening of 1822 initial articles returned by preliminary search yielded 28 studies for inclusion and data extraction. Qualitative assessment of the studies were conducted in accordance with the Newcastle-Ottawa Scale criteria. Meta-analyses were applied to assess risk factors on outcomes. The average age within the cohort was 27.9 years with a male and female prevalence of 59.1% and 40.9%, respectively. The odds rato for living status (dead/alive) were calculated for several risk factors - male/female [OR 1.14, 95% CI 0.62, 2.07], single/multiple metastases [OR 0.67, 95% CI 0.35, 1.28], lung metastases/not [OR 1.63, 95% CI 0.85, 3.13], surgery/no surgery [OR 0.49, 95% CI 0.20, 1.21]. The standardized mean differences for duration from diagnoses to metastases were likewise analyzed - male/female [SMD 0.13, 95% CI -0.15, 0.42], single/multiple metastases [SMD 0.11, 95% CI -0.20, 0.42], lung metastases/not [SMD -0.03, 95% CI -0.38, 0.32], surgery/no surgery [SMD 0.45, 95% CI -0.18,1.09]. The standardized mean differences for duration from metastases to death were analyzed - lung metastases/not [SMD 0.43, 95% CI -0.08, 0.95]. Our study observed no statistically significant differences in mortality rate among several patient risk factors. Consequentially, there lacks a clear answer as to whether or not an association between mortality rates exists with these patient factors. As such, it is important to continue research in brain-metastasizing sarcomas despite their relative rarity.

Abstract PO2-04-05: FINAL OUTCOME ANALYSIS FROM THE PHASE II TUXEDO-1 TRIAL OF TRASTUZUMAB-DERUXTECAN IN HER2-POSITIVE BREAST CANCER PATIENTS WITH ACTIVE BRAIN METASTASES

Abstract Background Brain metastases (BM) are a severe complication of HER2-positive metastatic breast cancer. In the absence of any immediate indication for local therapy, the tyrosine-kinase inhibitor tucatinib combined with trastuzumab and capecitabine (TTC) is regarded as the preferred systemic treatment option for active BM, while data on the activity of antibody-drug conjugates (ADC) is limited. In the primary outcome analysis of TUXEDO-1, an intracranial response rate (RR) of 73.3% was reported with the ADC trastuzumab-deruxtecan (T-DXd). Here, we report final progression-free survival (PFS) and overall survival (OS) results of this study. Patients and Methods: TUXEDO-1 is a prospective, single-centre, single-arm phase 2 trial. Adult patients with HER2-positive BC and active BM (newly diagnosed untreated or progressing after prior local therapy), prior treatment with trastuzumab and pertuzumab, ECOG performance status 0 or 1 without indication for immediate local therapy were accrued and received T-DXd until progression, inacceptable toxicity, or withdrawal for any other reason. The primary endpoint was intracranial RR centrally assessed by Response Assessment in Neuro-Oncology (RANO)-BM criteria in the intention-to-treat population; secondary endpoints included PFS, OS, safety, quality-of-life (QoL), and neurocognitive function. PFS and OS were estimated with the Kaplan-Meier method and analysed in the per-protocol population (PPP). Results A total number of 15 patients were accrued; one patient was found to have dural metastases only upon restaging, resulting in a PPP of 14 patients. Patients had received a median number of two prior treatment lines (range, 1-5), 60% had progressive brain metastases and 60% had received prior T-DM1. At 26.5 months median follow-up, median PFS was 21 months (95% CI 13.3-n.r.) and median OS was not reached (95% CI 22.2-n.r.). A total of 238 cycles of T-DXd were administered (median 11.5 cycles; range 4-42). With longer follow-up, no new safety signals were observed. The most common grade 3 adverse event (AE) was fatigue (n=3; 20%). A total of 8 serious AEs were reported in 8 patients. Grade 2 interstitial lung disease and a grade 3 symptomatic drop of left-ventricular ejection fraction were observed in one patient each. QoL and neurocognitive functioning were maintained over the entire treatment duration and a significant deterioration of global QoL was observed upon progression (p=0.036). Most patients received TTC (n=5) or local therapy (n=4) as next subsequent treatment line. Ancillary biomarker studies are ongoing, and results will be presented at the meeting. Discussion In TUXEDO-1, T-DXd yielded prolonged intra- and extracranial disease control in patients with active HER2-positive breast cancer BM. The safety profile was consistent with previous reports. T-DXd did not impair QoL and neurocognitive functioning was maintained. Results therefore support the concept of ADCs as systemic therapy for active BM. Citation Format: Rupert Bartsch, Anna Sophie Berghoff, Julia Furtner, Maximilian Marhold, Elisabeth Sophie Bergen, Sophie Roider-Schur, Angelika Maria Starzer, Maximilian Mair, Heidrun Forstner, Beate Rottenmanner, Marie-Bernadette Aretin, Karin Dieckmann, Zsuzsanna Bago-Horvath, Helmuth Haslacher, Georg Widhalm, Aysegül Ilhan-Mutlu, Christoph Minichsdorfer, Thorsten Fuereder, Thomas Szekeres, Leopold Oehler, Birgit Gruenberger, Georg Pfeiler, Christian F. Singer, Ansgar Weltermann, Luzia Berchtold, Matthias Preusser. FINAL OUTCOME ANALYSIS FROM THE PHASE II TUXEDO-1 TRIAL OF TRASTUZUMAB-DERUXTECAN IN HER2-POSITIVE BREAST CANCER PATIENTS WITH ACTIVE BRAIN METASTASES [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-04-05.

Abstract PO3-04-06: A comparison of the efficacy of trastuzumab deruxtecan in advanced HER2-positive breast cancer: active brain metastasis versus progressive extracranial disease alone

Abstract Background Trastuzumab deruxtecan (T-DXd) has demonstrated efficacy in patients with brain metastasis (BM), a group historically with poor outcomes. The prevalence of BMs in patients commencing T-DXd is currently unknown. To date, no direct comparisons have been made of the activity of T-DXd in patients with active BM versus those with extracranial progression alone. This real-world study explored the prevalence of BMs at commencement of T-DXd, the efficacy of T-DXd in active BM versus extracranial progression alone and the safety of T-DXd. Methods Patients with HER2-positive advanced breast cancer treated with T-DXd between June 2021 and February 2023 at our specialist cancer hospital were identified and notes reviewed. Clinico-pathological information, prior treatment, the presence or absence of CNS disease, outcomes and treatment-emergent adverse events (TEAE) were recorded. Data cut-off was 28th February 2023. Results 29 female patients: 16 extracranial disease alone, 12 BM and 1 LMD were identified. Prevalence of BM at commencement of T-DXd was 41% (12 of 29). Median age was 52 (IQR 44-62), with a median 2 (range 2-6) prior lines of HER2 directed and chemotherapy:86% (25 of 29) had received prior trastuzumab and pertuzumab, 100% (29 of 29) T-DM1 and 3% (1 of 29) patient trastuzumab duocarmazine. At a median follow-up of 13.8 months, median progression free survival (PFS) for overall population was 13.9 months (95% CI: 12.4-NE), 16.1 months (95% CI: 15.1-NE) for active BMs, and 12.4 months (95% CI: 8.3-NE) for progressive extracranial disease alone (P=0.106). 12-month OS rate was 74% (95% CI: 59-95) in the overall population, 83% (95% CI: 58-100) and 66% (95% CI: 45-96) for active BMs, and extracranial only disease respectively (P=0.678). Objective response rates: overall population was 69% (95% CI: 52-86), active BMs was 60% (95% CI: 30-90), and progressive extracranial disease alone was 69% (95% CI: 46-91). 6% (1 of 16) with extracranial disease alone developed BM during treatment with T-DXd. Reasons for treatment discontinuation: 67% (10 of 15) disease progression or death; 33% (5 of 15) toxicity. 48% (14 of 29) remain on treatment. Most common TEAEs were fatigue (97%; 28 of 29), alopecia (76%; 22 of 29), and constipation (72%; 21 of 29). Pneumonitis occurred in 9 patients (31%, included 2 deaths). 1 pathologically confirmed case of radionecrosis was documented. An updated analysis with an additional 9 patients who commenced T-DXd since February 2023 will be presented. Conclusion In this real-world study a significant number of patients had BM at the commencement of T-DXd. We demonstrate that in advanced HER2 positive breast cancer that T-DXd is as effective, in terms of PFS and OS, in active BMs as it is in progressive extracranial disease alone. These data provide the first evidence that in contrast to the historical data that active BM may no longer be a detriment to survival as compared to progressive extracranial disease alone when treated with T-Dxd. These observations warrant further investigations in larger series. The high rate of pneumonitis warrants further consideration. Citation Format: James Pearson, Adeel Khan, Talvinder Bhogal, Helen Wong, Andrea Law, Samantha Mills, Nuria Santamaria, Joanne Cliff, Douglas Errington, Allison Hall, Clare Hart, Zafar Malik, Raj Sripadam, Helen Innes, Helen Flint, Gabriella Langton, Eliyaz Ahmed, Jill Bishop, Richard Jackson, Carlo Palmieri. A comparison of the efficacy of trastuzumab deruxtecan in advanced HER2-positive breast cancer: active brain metastasis versus progressive extracranial disease alone [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-04-06.

Short-term predictors of stereotactic radiosurgery outcome for untreated single non-small cell lung cancer brain metastases: a restrospective cohort study.

Stereotactic radiosurgery (SRS) is an option for brain metastases (BM) not eligible for surgical resection, however, predictors of SRS outcomes are poorly known. The aim of this study is to investigate predictors of SRS outcome in patients with BM secondary to non-small cell lung cancer (NSCLC). The secondary objective is to analyze the value of volumetric criteria in identifying BM progression. This retrospective cohort study included patients >18 years of age with a single untreated BM secondary to NSCLC. Demographic, clinical, and radiological data were assessed. The primary outcome was treatment failure, defined as a BM volumetric increase 12 months after SRS. The unidimensional measurement of the BM at follow-up was also assessed. One hundred thirty-five patients were included, with a median BM volume at baseline of 1.1 cm3 (IQR 0.4-2.3). Fifty-two (38.5%) patients had SRS failure at follow-up. Only right BM laterality was associated with SRS failure (p=0.039). Using the volumetric definition of SRS failure, the unidimensional criteria demonstrated a sensibility of 60.78% (46.11%-74.16%), specificity of 89.02% (80.18%-94.86%), positive LR of 5.54 (2.88-10.66) and negative LR of 0.44 (0.31-0.63). SRS demonstrated a 61.5% local control rate 12 months after treatment. Among the potential predictors of treatment outcome analyzed, only the right BM laterality had a significant association with SRS failure. The volumetric criteria were able to identify more subtle signs of BM increase than the unidimensional criteria, which may allow earlier diagnosis of disease progression and use of appropriate therapies.

Anti-EGFR ScFv functionalized exosomes delivering LPCAT1 specific siRNAs for inhibition of lung cancer brain metastases.

Brain metastasis (BM) is one of the leading causes of cancer-related deaths in patients with advanced non-small cell lung cancer (NSCLC). However, limited treatments are available due to the presence of the blood-brain barrier (BBB). Upregulation of lysophosphatidylcholine acyltransferase 1 (LPCAT1) in NSCLC has been found to promote BM. Conversely, downregulating LPCAT1 significantly suppresses the proliferation and metastasis of lung cancer cells. In this study, we firstly confirmed significant upregulation of LPCAT1 in BM sites compared to primary lung cancer by analyzing scRNA dataset. We then designed a delivery system based on a single-chain variable fragment (scFv) targeting the epidermal growth factor receptor (EGFR) and exosomes derived from HEK293T cells to enhance cell-targeting capabilities and increase permeability. Next, we loaded LPCAT1 siRNA (siLPCAT1) into these engineered exosomes (exoscFv). This novel scFv-mounted exosome successfully crossed the BBB in an animal model and delivered siLPCAT1 to the BM site. Silencing LPCAT1 efficiently arrested tumor growth and inhibited malignant progression of BM in vivo without detectable toxicity. Overall, we provided a potential platform based on exosomes for RNA interference (RNAi) therapy in lung cancer BM.

Abstract 5515: Low body mass index (BMI) induces neuronal NPY and promotes brain metastasis of lung cancer

Abstract Brain metastases (BrMs) are a common occurrence in lung cancer with a dismal outcome. To develop a more effective therapeutic strategy, it is crucial to understand the underlying pathological mechanism of brain metastasis. Recent clinical data has unveiled a significant association between low body mass index (BMI) and an increased risk of brain metastasis in lung cancer patients, leading to reduced survival rates compared to other primary tumors. However, the molecular mechanism underlying this paradoxical relationship, often referred to as the "obesity paradox," in the context of lung cancer mortality presents a complex and intriguing puzzle and warrants in-depth investigation. Here, we examined biological mechanism of how low BMI promotes lung cancer brain metastasis. In this study, we conducted a retrospective pan-analysis of 5,516 patient cohorts with brain metastasis originating from lung, breast, melanoma, and renal cancers with their BMI status. We found that lung cancer patients with low BMI have significantly higher brain metastatic incidence compared to the high BMI patients, in contrast to breast, melanoma, and renal cancers. Furthermore, we found that low BMI plays a pivotal role in mediating neuron activation within the brain and that the secretion of neuronal neuropeptide Y (NPY), a protein involved in appetite and energy homeostasis via GHSR-receptor manner, promotes metabolic switching through NPY/NPY5R axis in the tumor cells in the brain thereby enabling metastasis. Elevated levels of neuronal NPY in the brains of cancer-free subjects with low BMI suggest its potential utility as a promising prognostic biomarker for identifying the increased risk of metastatic disease in lung cancer patients with low BMI. We also demonstrated that reversing low BMI or blocking the NPY/Y5R interactions effectively abrogated brain metastasis in our animal model. Our findings suggest a novel pro-metastatic role of low BMI-induced NPY in the progression of brain metastasis. We emphasize the importance of elucidating the clinical implications of this relationship to develop an updated intervention strategy for the clinical care of patients with lung cancer and low BMI. Citation Format: Abhishek Tyagi, Shih-Ying Wu, Ravindra Deshpande, Kerui Wu, Liang Liu, Kounosuke Watabe. Low body mass index (BMI) induces neuronal NPY and promotes brain metastasis of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5515.