Incidence Of Brain Metastases Research Articles

The relationship between brain metastasis and HER2 expression status in gastric cancer.

Brain metastasis (BM) in gastric cancer (GC) is underestimated, and human epidermal growth factor receptor 2 (HER2) overexpression is a durable poor prognostic factor. We explored the relationship between the two and made a survival analysis. HER2 expression and BM status were collected from GC patients who were diagnosed between December 2009 and May 2021. We collected GC patients diagnosed between 2010 and 2016 from the SEER database. The primary endpoint was survival from the diagnosis of BM. Multivariable logistic regression was used to determine potential risk factors of BM at diagnosis in SEER database. Survival analysis was performed using the Kaplan-Meier method. There were 513 HER2-positive GC patients, including 16 (3.1%) with BM. Among 38 brain metastasis GC patients we collected, 16 (42.1%) patients were HER2 positive. We collected 34,199 GC patients from the SEER database and there were 260 (0.76%) patients with BM at diagnosis. GC patients that are male, white,of younger age, with primary lesions located in the proximal stomach or with distant lymph nodes, liver, bone, or lung metastasis are more likely to develop BM. The median overall survival time from diagnosis of BM was 12.73months, and the survival time from brain metastasis of HER2-positive patients was numerically shorter, though the difference was not significant (5.30months vs.16.13months, P = 0.28.) CONCLUSION: The incidence of BM in patients with HER2-positive gastric cancer is 4.08 times higher than that in general patients. The median overall survival time from BM is shorter for HER2-positive patients.

RARRES2 regulates lipid metabolic reprogramming to mediate the development of brain metastasis in triple negative breast cancer

BackgroundTriple negative breast cancer (TNBC), the most aggressive subtype of breast cancer, is characterized by a high incidence of brain metastasis (BrM) and a poor prognosis. As the most lethal form of breast cancer, BrM remains a major clinical challenge due to its rising incidence and lack of effective treatment strategies. Recent evidence suggested a potential role of lipid metabolic reprogramming in breast cancer brain metastasis (BCBrM), but the underlying mechanisms are far from being fully elucidated.MethodsThrough analysis of BCBrM transcriptome data from mice and patients, and immunohistochemical validation on patient tissues, we identified and verified the specific down-regulation of retinoic acid receptor responder 2 (RARRES2), a multifunctional adipokine and chemokine, in BrM of TNBC. We investigated the effect of aberrant RARRES2 expression of BrM in both in vitro and in vivo studies. Key signaling pathway components were evaluated using multi-omics approaches. Lipidomics were performed to elucidate the regulation of lipid metabolic reprogramming of RARRES2.ResultsWe found that down-regulation of RARRES2 is specifically associated with BCBrM, and that RARRES2 deficiency promoted BCBrM through lipid metabolic reprogramming. Mechanistically, reduced expression of RARRES2 in brain metastatic potential TNBC cells resulted in increased levels of glycerophospholipid and decreased levels of triacylglycerols by regulating phosphatase and tensin homologue (PTEN)-mammalian target of rapamycin (mTOR)-sterol regulatory element-binding protein 1 (SREBP1) signaling pathway to facilitate the survival of breast cancer cells in the unique brain microenvironment.ConclusionsOur work uncovers an essential role of RARRES2 in linking lipid metabolic reprogramming and the development of BrM. RARRES2-dependent metabolic functions may serve as potential biomarkers or therapeutic targets for BCBrM.

Exosomal miR-21 determines lung-to-brain metastasis specificity through the DGKB/ERK axis within the tumor microenvironment

BackgroundBrain metastasis affects 20–40 % of lung cancer patients, severely diminishing their quality of life. This research focuses on miR-21, overexpressed in these patients and inversely associated with DGKB in the ERK/STAT3 pathway, suggesting a dysregulated pathway with therapeutic potential. AimsThe objective was to investigate miR-21's role in lung cancer patients with brain metastases and whether targeting this pathway could improve treatment outcomes. We also examined the miR-21 content in tumor spheres-derived extracellular vesicles (EVs) and their influence on ERK/STAT3 signaling and metastasis. Materials and methodsTumor spheres were created from metastatic lung cancer cells. We studied miR-21 levels in these spheres, their impact on macrophage polarization, and the transition of nonmetastatic lung cancer cells. Furthermore, we analyzed miR-21 content in EVs derived from these spheres and their effect on ERK/STAT3 signaling and metastasis potential. Key findingsWe found tumor spheres had high miR-21 levels, promoting macrophage polarization and, epithelial–mesenchymal transition. These spheres-derived EVs, enriched with miR-21, accelerated ERK/STAT3 signaling and metastasis. Silencing miR-21 and inhibiting ERK signaling with ulixertinib notably mitigated these effects. Moreover, ulixertinib reduced brain metastasis incidence and increased survival in a mouse model and led to reduced tumor sphere generation and miR-21 levels in EVs. SignificanceOur study highlights the exacerbation of lung-to-brain metastasis via miR-21-rich EV secretion. This underlines the therapeutic promise of targeting the miR-21/ERK/STAT3 pathway with ulixertinib for managing brain metastasis from lung cancer.

Metformin is associated with improved clinical outcomes in patients with melanoma: a retrospective, multi-institutional study.

Pre-clinical studies have shown that metformin reduces intratumoral hypoxia, improves T-cell function, and increases sensitivity to PD-1 blockade, and metformin exposure has been associated with improved clinical outcomes in various types of cancer. However, the impact of this drug in diabetic melanoma patients has not yet been fully elucidated. We reviewed 4,790 diabetic patients with stage I-IV cutaneous melanoma treated at the UPMC-Hillman Cancer Center and Memorial Sloan Kettering Cancer Center between 1996-2020. The primary endpoints included recurrence rates, progression free survival (PFS), and overall survival (OS) with and without metformin exposure. Tabulated variables included BRAF mutational status, immunotherapy (IMT) by type, and incidence of brain metastases. The five-year incidence of recurrence in stage I/II patients was significantly reduced with metformin exposure (32.3% vs 47.7%, p=0.012). The five-year recurrence rate for stage III patients was also significantly reduced (58.3% vs 77.3%, p=0.013) in the metformin cohort. OS was numerically increased in nearly all stages exposed to metformin, though this did not reach statistical significance. The incidence of brain metastases was significantly lower in the metformin cohort (8.9% vs 14.6%, p=0.039). This is the first study to demonstrate significantly improved clinical outcomes in diabetic melanoma patients exposed to metformin. Overall, these results provide further rationale for ongoing clinical trials studying the potential augmentation of checkpoint blockade with metformin in advanced melanoma.

Cavernous sinus syndrome as the first presenting sign of metastatic cholangiocarcinoma

Cholangiocarcinoma is poorly treatable and highly lethal adenocarcinoma of the hepatobiliary system. The incidence of brain metastases was 0.15%, 0.47% and 1.4% in three large case series. Cavernous sinus syndrome (CSS) refers to any disease involving the cavernous sinus. It is characterized by ophthalmoplegia, proptosis, chemosis, but also trigeminal sensory loss and Horner’s syndrome. We report the case of a 56-year-old Caucasian woman evaluated due to partial Horner syndrome, periorbital and retroorbital unilateral moderate-to-severe headache involving the left frontal and temporal areas of about 2 weeks duration.

Wolf in sheep’s clothing: Effect of primary lung tumor cells equipped with elevated neuron-like properties on brain metastases formation.

e14009 Background: It is clinically significant to decipher the mechanisms underlying lung cancer-associated brain metastases. However, comparative studies on primary tumors between patients with and without brain metastases failed to unveil such mechanisms. Moreover, the clinical observation that the incidence of brain metastases after resection of the primary tumor was as high in lymph node-negative (non-LNM) patients as in those with lymph node metastases (LNM) challenges our established knowledge that lymph node staging correlates with distant metastases. Here, we hypothesized that tumor cells in non-LNM patients might acquire a unique mechanism to develop brain metastases. Methods: We ran whole-transcriptome sequencing and methylation sequencing on paired primary tumor and brain metastases samples from 15 NSCLC patients. We compared the differentially expressed genes (DEGs) between patients with LNM and non-LNM patients. Results: Pathway enrichment analysis showed that GO and KEGG pathways associated with neuronal transmission and synaptic signaling were upregulated in primary tumors of the non-LNM group vs. that of the LNM group. In contrast, brain metastases revealed an inversed trend of differential expression for these pathways between non-LNM and LNM groups. Exploratory validation at methylation level revealed that high expression of the neuronal transmission-associated gene GABRG3 correlated with hypomethylation of this gene (R=-0.39, p=0. 042), responsive to increased expression of GABRG3 in brain metastases. Brain metastases expressed higher neuronal transmission-related signatures than paired primary tumors. Intriguingly, this upregulation of tumor-neuron interactions was more pronounced in patients with lymph node metastases, suggesting that i) lymph node metastases might aid primary tumor to develop brain metastases by promoting the adaptation of tumor cells to the brain microenvironment, while ii) non-LNM patients already acquired neuron-like traits at primary sites, heralding the potential of brain metastases. Conclusions: The hypothetical mechanism of lymph node-negative lung cancer developing brain metastases might be that these tumor cells acquired properties of brain cells as early as in primary sites, masking themselves as ‘sheep’ to communicate with the host’s brain cells, and eventually unmasked as ‘wolf’: brain metastases. Further functional studies are warranted to validate this hypothesis.

Clinical and molecular characterization of a cohort with breast cancer brain metastases.

e13122 Background: Breast cancer (BC) is the most common cancer in Women in the United States, it is the second most frequent cause of brain metastases (BM). Despite steady improvement in BC treatment (tx) and prognosis, BM continues to be an unmet need. With most BM patients excluded from clinical trials, the study of cohorts remains an important source of information regarding this aspect of the disease. We aim to characterize incidence, disease course, tx, and molecular profile of BM for BC subtypes. Methods: In this single-center retrospective analysis, we identified all adult patients (>18 years) diagnosed (dx) with BC as well as secondary malignant neoplasm of the brain from 1/1/15 to 10/1/22 using database query from EMR. Baseline characteristics were obtained through chart review. Molecular profiling was performed in a total of 41 patients, 8 of which was from brain tissue. Next generation sequencing (NGS) was the most used method. Results were generated using descriptive statistics. Results: We identified 304 BC patients with BM (median age = 60 years [range: 24 to 88]). Baseline characteristics are described in table 1. Hormone receptor positive/HER2-neu negative (HR+/HER2-) was the most commonly observed BC subtype (41.4%), and triple negative BC (TNBC) was the least frequent (16.8%). On primary tissue biopsy, five patients with recurrent BC had a subtype shift that differed from their initial disease: 2 patients with HR +/HER2 – BC subtype recurred with TNBC, 2 patients with a HR+/HER2- recurred with HR+/HER2+ BC, and 1 patient with TNBC at initial dx had their disease shift to HR+/HER 2- BC at first metastatic recurrence then back to TNBC 4 years after initial dx. NGS was available for 41 patients, with TP53, MSS, PIK3CA and ERBB2 being the most frequently observed mutations. On average, 3 lines of therapy were used before dx of BM. In the metastatic setting, capecitabine was one the most commonly used drugs. Targeted central nervous system (CNS) tx used in this study population include WBRT, SRS, SBRT and surgical resection. Conclusions: Studying patterns of disease presentation, progression during standard tx, and the molecular characteristics accompanying BM will enable us to develop more effective tx for patients. Our cohort includes a spectrum of BC subtypes and natural histories. Further characterization of this cohort with tx interactions, progression and survival timeline is ongoing and will be reported at the meeting. [Table: see text]

Extensive‐stage small cell lung cancer: Is prophylactic cranial irradiation necessary in the era of immunotherapy with MRI surveillance?

AbstractObjectiveThe role of prophylactic cranial irradiation (PCI) in treating extensive‐stage small‐cell lung cancer (ES‐SCLC) has been controversial. This study aimed to comprehensively analyze the efficacy of PCI for the treatment of ES‐SCLC under active brain magnetic resonance imaging (MRI) surveillance.MethodsPatients with ES‐SCLC with no brain metastases (BM) confirmed by MRI at the time of diagnosis who responded well to first‐line chemoimmunotherapy at three general hospitals were retrospectively included. Overall survival (OS), progression‐free survival (PFS), and cumulative incidence of BM were compared between patients who underwent PCI and those who did not.ResultsIn total, 66 consecutive patients treated between March 2019 and December 2021 were included in our dataset. Seventeen patients underwent PCI (PCI group) and 49 patients did not (non‐PCI group). In comparison with the non‐PCI group, PCI did not provide OS (median OS: 18.53 vs. 17.35 months, p = 0.28) or PFS (median PFS: 8.61 vs. 7.56 months, p = 0.41) benefits. When death was counted as a competing risk, the difference in the cumulative incidence rate of BM was not statistically significant (1‐year: 12.79% vs. 38.09%; p = 0.14).ConclusionCompared to active MRI surveillance, first‐line chemoimmunotherapy followed by PCI did not improve the prognosis of patients with ES‐SCLC. Further studies are warranted to evaluate the therapeutic effects of PCI following chemoimmunotherapy.

Risk of brain metastases in metastatic non-small cell lung cancer without baseline brain metastasis: Pooled analysis of individualized patient data from three randomized clinical trials involving first-line atezolizumab treatment.

2032 Background: Data on the efficacy of immune checkpoint inhibitors on delaying or preventing the occurrence of brain metastases (BMs) in metastatic NSCLC without initial BMs is limited. We explored the benefit of first-line atezolizumab versus chemotherapy in the occurrence of BMs in patients without baseline BMs. Methods: Individual patient data from IMpower1301, IMpower131, and IMpower150 were pooled. All patients in the intention to treat population were analyzed. Primary endpoints included BM free survival (BMFS) and the cumulative incidence of BM. Patients without baseline BMs were categorized into two groups: patients who received treatment including atezolizumab (atezolizumab group) and patients who received comparator chemotherapies (chemotherapy group). Results: In 2543 patients without baseline BMs, 87 (3.4%) developed BM, including 58 (3.4%) and 29 (3.4%) in the atezolizumab group and the chemotherapy group, respectively. The median BMFS was 8.31 months (95% CI 7.79-8.67). The cumulative incidence of BM at 6 months, 12 months, and 24 months was 1.9%, 3.1%, and 3.8%, respectively. Compared to the chemotherapy group, BMFS was significantly improved in the atezolizumab group (8.6 months versus 7.3 months, p < 0.001). After taking the competing risk events into account, no significant difference of the cumulative incidence of BM was observed between the two groups ( p = 0.671), suggesting that the significantly better BMFS in the atezolizumab group analyzed by Kaplan-Meier method should be due to the lower incidence of extracranial progression or death. Baseline bone metastasis and non-squamous NSCLC were identified as two risk factors for BM. Conclusions: In patients with NSCLC without baseline BMs, first-line atezolizumab improved BMFS but not the cumulative incidence of BM compared to chemotherapy, indicating that atezolizumab could not reduce the intrinsic risk of intracranial tumor spreading. [Table: see text]

Brain metastasis of hepatocellular carcinoma- single center experience.

Although the most common intracranial neoplasm in the adult population is metastatic tumors, brain metastasis from hepatocellular carcnoma (HCC) are very rare. The aim of this study is to analyze patients with advanced HCC, in order to determine the incidence of brain metastasis and evaluate the clinicopathologic properties. The records of HCC patients treated in our university between 2011 and 2019 were reviewed retrospectively. Patient characteristics, symptoms, laboratory data, treatment modalities, and survival after both the diagnosis of HCC and detection of brain metastasis were recorded. Of the 119 hepatocellular carcinoma patients, 34 had metastasis, 8 of which were to the brain. The median time elapsed between the diagnosis of HCC and brain metastasis was 14.6 months and the median overall survival after the detection of brain metastasis was 1.6 months. In 34 patients with metastasis, median survival was 26.2 months for those without brain metastasis, whereas it was 15.8 months for those with brain metastasis ( P = 0.460). The survival times after brain metastasis were 11.6 and 3.9 months for the two patients treated with regorafenib and sorafenib after the detection of brain metastasis, respectively. In this study, it was found that patients who were clinically eligible to receive tyrosine kinase inhibitors survived longer after the detection of brain metastasis. Our study shows that multidisciplinary evaluation of these patients is vital for treatment guidance, and survival outcomes can be improved with the advancements in surgical and radiotherapy techniques even in patients with poor prognosis.

EGFR-Driven Mutation in Non-Small-Cell Lung Cancer (NSCLC) Influences the Features and Outcome of Brain Metastases.

Background: Brain metastases (BMs) is one of the most frequent metastatic sites for non-small-cell lung cancer (NSCLC). It is a matter of debate whether EGFR mutation in the primary tumor may be a marker for the disease course, prognosis, and diagnostic imaging of BMs, comparable to that described for primary brain tumors, such as glioblastoma (GB). This issue was investigated in the present research manuscript. Methods: We performed a retrospective study to identify the relevance of EGFR mutations and prognostic factors for diagnostic imaging, survival, and disease course within a cohort of patients affected by NSCLC-BMs. Imaging was carried out using MRI at various time intervals. The disease course was assessed using a neurological exam carried out at three-month intervals. The survival was expressed from surgical intervention. Results: The patient cohort consisted of 81 patients. The overall survival of the cohort was 15 ± 1.7 months. EGFR mutation and ALK expression did not differ significantly for age, gender, and gross morphology of the BM. Contrariwise, the EGFR mutation was significantly associated with MRI concerning the occurrence of greater tumor (22.38 ± 21.35 cm3 versus 7.68 ± 6.44 cm3, p = 0.046) and edema volume (72.44 ± 60.71 cm3 versus 31.92 cm3, p = 0.028). In turn, the occurrence of MRI abnormalities was related to neurological symptoms assessed using the Karnofsky performance status and mostly depended on tumor-related edema (p = 0.048). However, the highest significant correlation was observed between EGFR mutation and the occurrence of seizures as the clinical onset of the neoplasm (p = 0.004). Conclusions: The presence of EGFR mutations significantly correlates with greater edema and mostly a higher seizure incidence of BMs from NSCLC. In contrast, EGFR mutations do not affect the patient's survival, the disease course, and focal neurological symptoms but seizures. This contrasts with the significance of EGFR in the course and prognosis of the primary tumor (NSCLC).

Update on Emerging Therapies for Advanced Colorectal Cancer.

Colorectal cancer (CRC) is the third most common malignancy worldwide. It is projected to increase by 3.2 million new cases and account for 1.6 million deaths by 2040. Mortality is largely due to limited treatment options for patients who present with advanced disease. Thus, the development of effective and tolerable therapies is crucial. Chemotherapy has been the backbone of systemic treatment of advanced CRC, but utility has been limited because of invariable resistance to therapy, narrow mechanisms of action, and unfavorable toxicity profile. Tumors that are mismatch repair-deficient have demonstrated remarkable response to immune checkpoint inhibitor therapy. However, most CRC tumors are mismatch repair-proficient and represent an unmet medical need. Although ERBB2 amplification occurs only in a few cases, it is associated with left-sided tumors and a higher incidence of brain metastasis. Numerous combinations of HER2 inhibitors have demonstrated efficacy, and antibody-drug conjugates against HER2 represent innovative strategies in this area. The KRAS protein has been classically considered undruggable. Fortunately, new agents targeting KRAS G12C mutation represent a paradigm shift in the management of affected patients and could lead the advancement in drug development for the more common KRAS mutations. Furthermore, aberrant DNA damage response is present in 15%-20% of CRCs, and emerging innovative combinations with poly (ADP-ribose) polymerase (PARP) inhibitors could improve the current therapeutic landscape. Multiple novel biomarker-driven approaches in the management of patients with advanced CRC tumors are reviewed in this article.

Tumor lineage-specific immune response in brain metastatic disease: opportunities for targeted immunotherapy regimen?

Metastases in the brain are the most severe and devastating complication of cancer. The incidence of brain metastasis is increasing. Therefore, the need of finding specific druggable targets for brain metastasis is demanding. The aim of this study was to compare the brain (immune) response to brain metastases of the most common tumor lineages, viz., lung adenocarcinoma and breast cancer. Targeted gene expression profiles of 11 brain metastasis of lung adenocarcinoma (BM-LUAD) were compared to 11 brain metastasis of breast cancer (BCBM) using NanoString nCounter PanCancer IO 360™ Panel. The most promising results were validated spatially using the novel GeoMx™ Digital Spatial Profiler (DSP) Technology. Additionally, Immune cell profiles and expression of drug targets were validated by multiplex immunohistochemistry. We found a more active immune response in BM-LUAD as compared to BCBM. In the BM-LUAD, 138 genes were upregulated as compared to BCBM (adj. p ≤ 0.05). Conversely, in BCBM 28 genes were upregulated (adj. p ≤ 0.05). Additionally, genes related to CD45 + cells, T cells, and cytotoxic T cells showed to be expressed higher in BM-LUAD compared to BCBM (adj. p = 0.01, adj. p = 0.023, adj. p = 0.023, respectively). The spatial quantification of the immune cells using the GeoMx DSP technique revealed the significantly higher quantification of CD14 and CD163 in tumor regions of BM-LUAD as compared to BCBM. Importantly, the immune checkpoint VISTA and IDO1 were identified as highly expressed in the BM-LUAD. Multiplex immunohistochemistry confirmed the finding and showed that VISTA is expressed mainly in BM-LUAD tumor cells, CD3 + cells, and to fewer levels in some microglial cells in BM-LUAD. This is the first report on differences in the brain immune response between metastatic tumors of different lineages. We found a far more extensive infiltration of immune cells in BM-LUAD as compared to BCBM. In addition, we found higher expression of VISTA and IDO1 in BM-LUAD. Taken together, targeted immune therapy should be considered to treat patients with BM-LUAD.

P172 Different incidence of brain metastasis according to HER2 expression level in patients with triple negative breast cancer

P172 Different incidence of brain metastasis according to HER2 expression level in patients with triple negative breast cancer

Brain metastasis and survival outcomes after first-line therapy in metastatic melanoma: a multicenter DeCOG study on 1704 patients from the prospective skin cancer registry ADOREG

BackgroundDespite the availability of effective systemic therapies, a significant number of advanced melanoma patients develops brain metastases. This study investigated differences in incidence and time to diagnosis of brain metastasis...

The progress of microenvironment-targeted therapies in brain metastases.

The incidence of brain metastases (BrM) has become a growing concern recently. It is a common and often fatal manifestation in the brain during the end-stage of many extracranial primary tumors. Increasing BrM diagnoses can be attributed to improvements in primary tumor treatments, which have extended patients' lifetime, and allowed for earlier and more efficient detection of brain lesions. Currently, therapies for BrM encompass systemic chemotherapy, targeted therapy, and immunotherapy. Systemic chemotherapy regimens are controversial due to their associated side effects and limited efficacy. Targeted and immunotherapies have garnered significant attention in the medical field: they target specific molecular sites and modulate specific cellular components. However, multiple difficulties such as drug resistance and low permeability of the blood-brain barrier (BBB) remain significant challenges. Thus, there is an urgent need for novel therapies. Brain microenvironments consist of cellular components including immune cells, neurons, endothelial cells as well as molecular components like metal ions, nutrient molecules. Recent research indicates that malignant tumor cells can manipulate the brain microenvironment to change the anti-tumoral to a pro-tumoral microenvironment, both before, during, and after BrM. This review compares the characteristics of the brain microenvironment in BrM with those in other sites or primary tumors. Furthermore, it evaluates the preclinical and clinical studies of microenvironment-targeted therapies for BrM. These therapies, due to their diversity, are expected to overcome drug resistance or low permeability of the BBB with low side effects and high specificity. This will ultimately lead to improved outcomes for patients with secondary brain tumors.

Description of a Retrospective Cohort of Epithelial Ovarian Cancer Patients with Brain Metastases: Evaluation of the Role of PARP Inhibitors in this Setting

The incidence of brain metastases (BM) in patients with epithelial ovarian cancer (EOC) is low: 0.3-11%. The onset of BM has been regarded as a late event with limited treatment options and poor prognosis. This retrospective case series aims to explore the current management strategies with particular emphasis on the use of PARP inhibitors and outcomes, as well as identification of other prognostic indicators. A total of 39 ovarian cancer patients with brain metastases were identified from eight cancer centres in the UK. Clinical characteristics, details of management, and survival data were collected. A total of 14/39 had BM as their first site of relapse. The majority (29 patients) received systemic treatments in addition to local radiotherapy (RT)/surgery. Nineteen patients had BRCA mutations (one somatic), one had a RAD51C mutation, and eighteen were BRCA wild type; one was unknown. A total of 14/39 patients received maintenance PARP inhibitors. As is well known, patients who received PARPi had consistently better outcomes. This was no different for those who received PARPi as part of the management of their BM. Platinum sensitivity and receiving more than one modality of therapy (e.g., radiation +/- chemotherapy and PARPi) for BM were also good prognostic indicators. Median PFS/OS for those treated with chemotherapy and either RT or surgery, then PARP inhibitor maintenance, have not been reached after a median of 33 months follow up. As with abdominal relapse, maintenance treatment with PARP inhibitors also has a valuable role in managing BMs in EOC patients.

Real-world clinical outcomes of the combination of anti-PD-1 antibody, trastuzumab, and chemotherapy for HER2-positive gastric/gastroesophageal junction cancer.

Previous clinical trials indicated the addition of anti-PD-1 antibody remarkably improved the efficacy of trastuzumab and chemotherapy in patients with HER2-positive gastric/gastroesophageal junction (GEJ) cancer. However, no real-world experiences have been reported yet. We retrospectively analyzed 1212 patients with gastric/GEJ cancer treated at Nanjing Drum Tower Hospital between 2019 and 2022. Among 138 patients with HER2-positive gastric/GEJ cancer, 47 patients receiving at least two doses of the combination regimen with anti-PD-1 antibody, trastuzumab, and chemotherapy were recruited in the study population, and 38 out of 47 patients with measurable disease were included in the efficacy population. Progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and toxicity profiles were reported. In the study population, 37 (78.7%) received the study therapy as a first-line treatment. In the efficacy population, the ORR and DCR were 76.3% and 94.7%, respectively. The overall median PFS was 9.1months (95% confidence interval [CI] 6.3-11.9months). For the first-line treatment, the mPFS was 10months, and 7months for the second-line. Among 14 patients who failed the study treatment, three (21.4%) developed brain metastasis as the first failure site. No significant association was found between PFS and the expression of PD-L1. 22.2% of patients developed grade 3 treatment-related adverse events (TRAEs). No treatment-related grade ≥4 adverse events or deaths occurred. This real-world study validated the combination regimen's high efficacy and good tolerance in patients with HER2-positive gastric/GEJ cancer. An increased incidence of brain metastasis was observed in patients who failed this regimen.

Abstract P4-02-27: Preliminary Attainability Assessment of Real-World Data for Answering Clinical Questions about Breast Cancer Brain Metastases

Abstract Background Brain metastases is one of breast cancer’s leading causes of death, and the incidence is increasing with advances in diagnosis and treatment techniques. Nevertheless, these patients have fewer opportunities to participate in prospective randomized clinical trials because of the design challenges of increasing target population heterogeneity or differentiating the definition of endpoints and how the endpoints are evaluated. Real-world data has the potential that reaches the information at a blinded area of RCT approaches. In recent years, observational studies using real-world data have gotten attention for their capability to enhance an understanding of hard-to-reach RCT approaches. However, the yet incomplete gold standard of the study protocol and the unpredictable ’hidden labor’ of secondary use of clinical data become barriers to clinical researchers. In the study, we demonstrate data attainability assessment focused on clinicians’ clinical unmet needs in breast cancer brain metastases (BCBM) as a preliminary step of the observational study for screening study feasibility on a certain data source. Methods A breast cancer registry based on the clinical data warehouse (CDW) of Samsung Medical Center has been used as the data source (N=45,219, up to 31 Dec 2021). A total of 5 clinical questions (CQ) were presented as the result of the interview of two breast cancer experts about BCBM for the study (Table 1). Additionally, we conducted an attainability assessment for the population size and core variables constrained by a clinical question and a survey of 7 breast cancer clinicians for evaluation of the recognized clinical significance and research methods’ suitability for each CQ. A working group was formed for data attainability tests withal a person with experience in clinical research for at least several years across interdisciplinary areas, including clinical expertise, medical informatics, and epidemiology. For the first step, we declare the operational definition for the study population and core variables in which the research question is inherent conceptually. And appropriate data fields and value sets are figured out from the data set. Data attainability is examined via RWD extraction on the population size and availability of core variables. Result The collected five CQs were mostly about the relationship between brain metastases, systemic metastases, and systemic treatments. Other CQs were related to the relationship between brain metastases incidence and the type of neoadjuvant treatment or patients’ described symptoms. Assessment of the importance of clinical questions aligned well, especially for the questions with higher scores. (r=- · 98) For CQ E, filtered out not to fit the SMC BCR dataset at the early stage of the data attainability screening process due to lack of explicit data field or semantically related value sets for one of the core variables, ‘neurological symptom.’ For CQ A, B, and D, we could confirm enough population size and dataset for conducting the study, but additional logical reconstruction of data elements had needed. For example, we used the ‘clinical subtype’ variable, which is provided from SMC BCR, as pre-processed feature variable using an expert-knowledge-based algorithm. For CQ C, we were able to obtain pertinent data for the study only with direct data field match and explicit code set definition. Conclusion To effectively use CDW, the variables have to be interpreted and defined in a clinically meaningful way with the cooperation of clinicians and data science experts. For observational studies based on RWD, understanding the data source contents and clarifying the research question enough to translate to the data level is essential. The step-by-step protocol presented in the study could be applied to the other clinical researcher using RWD at preliminary feasibility screening. Table 1. List of clinical questions from expert interviews Citation Format: Min-Jeong Kim, Hyo Jung Kim, Danbee Kang, Hee Kyung Ahn, Soo-Yong Shin, Seri Park, Juhee Cho, Yeon Hee Park. Preliminary Attainability Assessment of Real-World Data for Answering Clinical Questions about Breast Cancer Brain Metastases [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 P4-02-27.

Abstract P1-10-10: Radiation Treatment Patterns for Elderly Women with Breast Cancer Brain Metastases

Abstract Background Breast cancer is the second most common cause of brain metastases (BM). Despite increasing incidence of BM in elderly patients, there is limited data on the optimal management of BM in this age group. In this study, we assessed the survival outcomes and treatment patterns of elderly breast cancer patients with BM (≥ 65 yo) treated at our institution and compared them to younger patients. Methods An IRB-approved single-institutional review of biopsy-proven breast cancer patients with BM treated with 1 to 5-fraction stereotactic radiation therapy (SRT) from 2015 to 2020 was performed. Primary endpoint was intracranial progression free survival (PFS) defined as time interval between end of SRT to date of first CNS progression. Secondary endpoints were overall survival (OS) from end of SRT, and radiation treatment patterns. Kaplan-Meier estimates, and Cox proportional hazard regression method were used for survival analyses. SPSS v26.0 was used for statistical analysis and p-value < 0.05 was considered significant. Results A total of 115 metastatic breast cancer patients with BMs were included of which N=29 were ≥65 yo and N=86 were < 65 yo. They received a total of 43 and 143 courses of stereotactic linac-based radiation therapy (RT) respectively to a mean number of 4.3 BM lesions (range 1-22). Median age at RT was 70 years (range 65-84) compared to 50.5 years (31-64) in younger patients. About 55.2% of elderly patients were ER/PR positive/Her2 negative (vs 24.4% in younger cohort), 31% were Her2 positive (vs 41.9%) and 13.8% were triple negative (vs 33.7%). Among patient characteristics, there was significant difference among elderly and young patients in hormone receptor status (p = 0.016); CNS only oligometastatic disease (0% vs 11.2%, p = 0.005); and the presence of extracranial disease at SRS (97.7% vs 79.7%, p < 0.001). There was no significant difference between the two age groups in Karnofsky performance score (KPS) (62.7% vs 45.5% with KPS ≤ 80, p = 0.131), number of brain lesions treated (23.2% vs 30.1% with ≥ 5 BMs, p = 0.445), number of patients receiving prior whole brain radiotherapy (WBRT) (10.3% vs 19.8%, p = 0.062), surgery (23.2% vs 30.1%, p = 0.592), systemic therapy (including chemotherapy, targeted therapy and endocrine therapy) after SRT (86% vs 86.7%, p = 0.543), and salvage WBRT (10.3% vs 19.8%, p = 0.134). Median OS after RT was poorer in patients ≥ 65 yo compared to younger patients (7.9 months vs 14.4 months, p = 0.020), while intracranial PFS from RT was similar (8.5m vs 6.5m, p =0.345). The rates of freedom from neurological death and leptomeningeal disease (LMD) at 1 year were similar between the two groups (83.3% vs 87%, p = 0.780 and 87.6% vs 73.3%, p = 0.627, respectively). On univariate analysis, significant predictors of survival were age ≥65 yo (hazard risk, HR = 1.56), KPS < 80 (HR = 1.69), extracranial progression at RT (HR = 2.44), systemic therapy after RT (HR = 0.28) and LMD (HR = 1.57). On multivariate analysis, age was not a significant factor for survival after adjusting for KPS, extracranial progression and systemic therapy. Conclusions Although elderly women had poorer OS than younger women, OS was similar after adjusting for KPS, extracranial progression and systemic therapy; and there was no difference in rates of intracranial PFS, neurological deaths and LMD in the different age groups. This study suggests that age alone may not play an independent role in treatment-selection and outcomes for breast cancer patients with BMs and personalized decision making including other clinical factors should be considered. Future studies are warranted to assess neurocognitive outcomes and other radiation treatment toxicities in elderly patients. Citation Format: Rituraj Upadhyay, Haley K. Perlow, Nicole Williams, Brett Klamer, Julia White, Jose G. Bazan, Sachin R. Jhawar, Dukagjin M. Blakaj, John Grecula, Andrea Arnett, Evan Thomas, Arnab Chakravarti, Raju R. Raval, Maryam Lustberg, Joshua Palmer, Sasha Beyer. Radiation Treatment Patterns for Elderly Women with Breast Cancer Brain Metastases [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 P1-10-10.