Gastric cancer, most of which is gastric adenocarcinoma (GaC), is the fifth most common malignancy and the fourth most frequent cause of cancer-associated death worldwide, with approximately 1,100,000 new incident cases and about 800,000 related mortalities estimated in 2020 (1–4). Metastatic GaCs (mGaCs) with malignant involvement of distant sites take up about 1/3 of all GaCs on diagnosis and are associated with inferior survival because of aggressive progression (1, 5–7).

We previously reported that within cases with mGaC, the proportions of people having brain metastasis (BM) were 2% and 1% in the USA and the Netherlands, respectively, among overall patients with mGaC, and 1% and <1%, respectively, within those with resected mGaC (5). Although BM is rare among mGaCs, it may have been underestimated (8–11). BM from GaC was first reported in 1960 (12) and can occur synchronously with, or early, or even years after, curative resection for early GaCs because of residual micrometastases, and its incidence keeps increasing as disease-associated prognosis improves with the advancement of treatment (13–18). BM represents a severe condition and may cause early onset of neurological symptoms, markedly undermining prognosis, and deteriorating quality of life (QoL) (19–22), and it can even cause the initial symptoms of gastric cancer (23–26). The prognosis of patients with GaC involving the central nervous system remains very poor (27–29), and early identification of BM is vital for guiding clinical treatment and preventing related complications. People with GaC and BM represent a unique and largely heterogeneous population (30–33), and there have been few studies with a sufficient number of cases pertaining to the factors that were associated with BM and its prognostic significance within cases with GaC, which might be because of the underestimation of diagnosis and/or rarity of the disease.

In this comprehensive investigation, a large-scale population-based cohort was analyzed to delineate features of GaC cases having BM, who were compared with cases having distant metastasis that spared the brain and those without distant metastasis, and to reveal factors that were associated with BM in different subgroups of GaC cases. We further computed GaC-specific cumulative mortalities at various follow-up time-points with the cumulative incidence function (CIF) and explored prognostic factors with competing risk (CR) regression among patients with GaC and BM. The findings might help with individualized care for this special patient group.

In our large population-based cohort investigation, 231 patients with BM were identified within about 30,000 cases with GaC encompassing a follow-up of about 40,000 person-years, and their characteristics were described comprehensively, with comparison to those with distant involvement sparing brain or without distant metastasis. Unique risk characteristics specific to BM were identified and further verified with multivariable-adjusted analyses. Taking into account CRs, the overall and categorized tumor-specific death rates of cases with GaC and BM were further shown utilizing CIFs, representing a more trustable prognosis estimation. We further supported comparisons of cumulative death rates by utilizing multivariable-adjusted CR analyses. The findings provide vital hints for screening and treatment of BM from GaCs.

Patients having BM comprised 1% and 2% of cases with overall and metastatic GaC, respectively. While much rarer than metastases to other sites like the liver and lung and from other malignancies like melanoma, lung, and breast cancers, BM from GaC is quickly progressing and could markedly deteriorate survival and undermine QoL (40–42). The overall cumulative death rate increased quickly to 57% at 6 months and 71% at 12 months, with a median overall survival of merely 3 months. With the advancements in techniques of diagnosis and treatment, BM was more often detected and had an enhanced prognosis in more recent years. Long-term survival beyond 5 years may be possible in a small minority of selected brain-metastatic GI cancer patients with specific characteristics, including only one brain metastasis without metastasis to extracranial sides, age <60 years, Karnofsky performance status score of 100, surgical resection, brain metastasis-directed treatment, and additional systemic therapy (43).

There are some methods to identify BM from GaC. BM arising from gastric cancer is frequently revealed by hypointensity on T2-weighted MRI, which may be due to the accumulation of collagen in the tissues (44). FDG-PET can provide additional information on BM (45). Measurements of pre- and postoperative brain blood flow may be helpful in the case of chronic subdural hematoma after dural metastasis from gastric cancer (46). Cerebrospinal fluid cytology may also be used to diagnose leptomeningeal metastasis from HER2+ gastric cancer (47). The peroxidase-antiperoxidase method for carcinoembryonic antigen (CEA) may increase the diagnostic accuracy of cytology in the cerebrospinal fluid for BM from GaC (48). Despite these methods, it remains challenging to detect BM from GaC early, which could often be underestimated and/or misdiagnosed. There may be a great intrapatient heterogeneity in circulating cancer cells at the single-cell level in the cerebrospinal fluid of patients with gastric cancer and BM (49). The expressions of ZEB2 and miRNA-200 family members are correlated with BM from GaC (50). Nonetheless, the driving force behind BM remains largely unclear. It would be important to investigate risk factors associated with BM to facilitate early and efficient detection of this clinically significant but rare condition (51).

We found that BM from GaC occurred more often with younger age, nonblack ethnicities, gastric cardiac location, SRC histology, and LN involvement. Younger patients, cases having antrum/pylorus tumors, and cases having LN involvement had increased death hazards, while surgical resection was associated with a lower mortality hazard. Of note, cases younger than 50 years comprised 19% of all cases with GaC and BM compared with 8% for cases who were ≥80 years. Older cases had generally slower tumor progression, and the preference of BM for younger cases with longer anticipated survival is worthy of doctors’ attention. Cardiac tumors, which are different from noncardiac cancers in various aspects, are correlated with poorer prognosis (18), and we found them to be more frequently correlated with BM, which was supported by an institution-based study (52). Interestingly, they were correlated with higher survival rates among cases with GaC and BM who received radiotherapy. SRC, which is a special histology type, might have higher biologic aggressiveness and lower sensitivity to systemic therapy, making immediate upfront resectional surgery of critical value. While positive LN was more often correlated with BM, 40% of patients with GaC and BM had uninvolved LNs. LN involvement rather than adjacent structure involvement was associated with prognosis among patients with GaC and BM receiving radiotherapy. GaCs with multiple metastasis sites including the brain are noteworthy clinically, while bone, liver, or lung involvement was not correlated significantly with worse survival among patients with GaC and BM in this investigation.

At present, there exist no screening or treatment guidelines for GaCs with BM (8), and managing BM from GaC can be challenging. Multidisciplinary treatment may enhance long-term survival and QoL (53–55). We found that 7% of GaC cases with BM underwent resection, which may increase the overall survival time for this specific patient population (41, 56, 57). Of note, although surgical resection was correlated with better prognosis in GaC cases with BM, causality and definitive management benefits cannot be derived from this observational investigation. Tailored and timely management is vital, and notably, nowadays, radiotherapy and immune checkpoint inhibitor therapy may be particularly effective for cases with GaC affecting the brain (58). We found that within GaC patients with BM receiving radiotherapy, younger age, antrum/pylorus location, and LN metastasis were correlated with worse survival, which should call for clinicians’ attention.

Gamma-knife stereotactic radiosurgery seems a safe and effective treatment modality for the treatment of BM from GaC with good local control and few side effects, and dose-escalated approaches may improve local control rates (59–61). Radiosurgery appears a nice alternative to surgical resection for cases with BM from advanced gastric cancer (62); gamma-knife radiosurgery and recursive partitioning analysis class 2 may contribute to more favorable clinical outcomes (63). Resection and stereotactic radiosurgery for BM contributed to long-term survival in two Japanese people with BM identified more than 1 year after the removal of primary GaC, who remained alive after 6.5 years and died of non-GaC causes 4 years after surgery, respectively (64). Stereotactic radiotherapy is also associated with better outcomes and longer overall survival after brain relapse (65). Cumulative intracranial tumor volume is a vital prognostic factor in cases with stereotactic radiosurgery-managed gastrointestinal tract cancer BM (66). A case report described a patient with advanced gastric cancer and multiple brain and abdominal LN involvements who was successfully treated through an abscopal effect, which refers to the phenomenon where local radiation therapy is correlated with the regression of metastatic tumor, which is located distantly from the irradiated site, through brain radiation and anti-PD-1 therapies (67). Combined therapy with nivolumab and gamma-knife radiosurgery appeared effective for treating another 55-year-old male with gastric cancer and BM (68). A 68-year-old man with gastric cancer and BM was also reported to be successfully treated with nivolumab (69). Another 63-year-old man with gastroesophageal junction cancer and brain, bone, and gastric intramural metastases was reported to be responsive to combined modality therapy (70). Notably, acquired mutation of CTNNB1 may drive immune checkpoint inhibitor (ICI)-acquired resistance in microsatellite instability (MSI)-high esophagogastric adenocarcinoma with BM (71).

Agents targeting HER2, pSTAT3, EGFR, and angiogenesis-associated molecules may be feasible for the treatment of BM from gastric cancer (72–78). The combination of apatinib and continual nutritional support may be another option for the treatment of BM from gastric cancer, which may prolong survival (27). HER2+ patients with gastroesophageal adenocarcinoma may have an increased risk to develop brain metastasis (15), and patients with HER2+ gastric cancer may have a higher susceptibility to disease recurrence in the central nervous system (79). The proportion of HER2+ status in patients with gastroesophageal adenocarcinoma and brain involvement appeared higher than expected (80). In cases with gastrointestinal cancer and brain metastases, HER2+ status was more frequent intracranially compared to prior disease sites, suggesting that examining HER2 in brain metastases of those patients might offer additional treatment options, irrespective of HER2 status in previously examined tissues (81). Trastuzumab deruxtecan showed efficacy for the management of a 65-year-old man with BM originating from advanced HER2-positive gastric cancer (82). It would be desirable to investigate if other HER2-targeting antibody-drug conjugates (ADCs; e.g., GQ1001 and T-DM1 (7)) could show similar efficacies against BM from GaCs. BM from advanced gastric cancer was correlated with VEGF expression, and metformin therapy might be helpful for modulating the metastasis capacity via reducing the expression of VEGF and blocking epithelial-to-mesenchymal transition (EMT) (83). Arterial infusion chemotherapy with tegafur, epirubicin, and lobaplatin appeared effective for the management of a 73-year-old man with advanced gastric cancer affecting the brain (84). Irinotecan plus cisplatin and irradiation appeared effective for the management of another two Japanese cases with BM from gastric cancer (85). Paclitaxel may also be effective for GaC with BM (86, 87). Accordingly, we found that cases receiving chemotherapy had lower death rates.

The treatment scheme for this specific patient subpopulation should be individualized and based on expected survival, performance status, symptoms, the number, location, and size of metastases, the status of the primary tumor, and dissemination to other organs (61, 88–91). QoL should also be factored into management decisions, especially in the setting of aggressive treatment (17). Searching for ideal treatment pathways for this specific patient subgroup would be greatly desired.

This observational investigation shared some common limitations with other registry-based population-based studies. Information on some other variables that were potentially correlated with BM (e.g., genetic and environmental risk factors) and prognostic variables [e.g., health conditions and comorbidities (92–94)] were not available. HER2 status was not available in the analyzed database. Nonetheless, the majority of the common prognostic and risk factors had been included in multivariable-adjusted models. A few variables (e.g., cancer differentiation grade, local invasion, and LN metastasis) had missing data; they were not initially included in the main multivariable-adjusted analyses but were separately added into the main multivariable-adjusted models to assess the associations with them. Nonsurgical therapies were under-ascertained and registered with low sensitivity but high specificity (35), and detailed data on management [e.g., agents and courses (95)] were not available. Accordingly, they were not included in the main multivariable-adjusted survival analyses, and subgroup analyses for cases having chemotherapy or radiation therapy were specifically done. Furthermore, the findings were based on the US cases and might not be well generalizable to patients from other countries, particularly Asians, in which gastric cancer would be much more prevalent. We would strongly encourage analyses of databases from other nations.

To our knowledge, this report appears to be the largest real-world population-based investigation utilizing robust statistics and patient-level data to address BM in GaC patients. The strict and careful case selection, utilization of comprehensive multivariable-adjusted CR analysis methods, and meticulous stratified investigations enable this study to offer useful, valid, and robust references for personalized management of cases with GaC and BM.

Among patients with GaC, brain metastasis was correlated with several clinical and pathological factors, which included ethnicity, age, cancer histology, location, LN involvement, and metastases to other sites. Cases with brain involvement had poor survival, which was correlated with age, cancer location, LN metastasis, and management. The findings offer clinically relevant and helpful clues and evidence for individualized treatment of cases with GaC and brain metastasis and future mechanistic explorations.

Publicly available datasets were analyzed in this study after signing the appropriate agreement and obtaining the data use approval. This data can be found here: Surveillance, Epidemiology, and End Results Program Research Data (www.seer.cancer.gov).

Ethical review and approval was not required for this study using the Surveillance, Epidemiology, and End Results Program database after signing the appropriate agreement and obtaining the data use approval in accordance with the local legislation and institutional requirements. New written informed consent was not required for this study in accordance with the national legislation and the institutional requirements.

Conception or design: LH, WH, and JZ. Acquisition, analysis, or interpretation of data: LH, LW, YS, YZ, CX, WH, and JZ. Drafting of the manuscript: LH. Critical revision of the manuscript for important intellectual content: LW, YS, YZ, CX, WH, and JZ. Statistical analysis: LH. Administrative, technical, or material support: WH and JZ. All authors have given final approval of the manuscript for submission and publication.

This study was supported by the Fund for Medical Center on Aging (GB202103), and the Start-up Fund for the Introduction of High-Level Talents by Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. The funders had no involvement in the study design; in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.

We are very grateful to the staff of the Surveillance, Epidemiology, and End Results Program for their great work in data collection and delivery and to the members of the Chinese Anti-Cancer Association (CACA), Chinese Society of Clinical Oncology (CSCO), and Chinese Medical Association for all their great support.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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