Role of savolitinib in advanced gastric adenocarcinoma with meningeal carcinomatosis and cerebellar metastasis: A case report

Abstract

BACKGROUND

Brain metastases (BM) are very rare in gastric adenocarcinoma (GaC), and patients with BMs have a higher mortality rate due to stronger tumor aggressiveness. However, its pathogenesis remains unclear. Genetic testing revealed cellular-mesenchymal epithelial transition factor receptor (MET) amplification. Therefore, treatment with savolitinib, a small molecule inhibitor of c-Met, was selected.

CASE SUMMARY

A 66-year-old woman was diagnosed with advanced GaC 6 months prior to presentation due to back pain. Cerebellar and meningeal metastases were observed during candonilimab combined with oxaliplatin and capecitabine therapy. The patient experienced frequent generalized seizures and persistent drowsiness in the emergency department. Genetic testing of cerebrospinal fluid and peripheral blood revealed increased MET amplification. After discussing treatment options with the patient, savolitinib tablets were administered. After a month of treatment, the intracranial lesions shrank considerably.

CONCLUSION

BM is very rare in advanced GaC, especially in meningeal cancer, that is characterized by rapid disease deterioration. There are very few effective treatment options available; however, technological breakthroughs in genomics have provided a basis for personalized treatment. Furthermore, MET amplification may be a key driver of BM in gastric cancer; however, this conclusion requires further investigation.

Key Words: Cellular-mesenchymal epithelial transition factor receptor; Savolitinib; Meningeal carcinomatosis; Gastric adenocarcinoma; Case report

Core Tip: Common metastatic sites for gastric adenocarcinoma (GaC) occur in the lymph nodes, liver, and lungs. Additionally, brain metastases (BM) are rare. Interestingly, mesenchymal epithelial transition factor receptor (MET) amplification in GaC is rare, and its role in tumor metastasis remains unclear. Several previous reports have described the association between MET amplification and BM with GaC. This case highlights the unique phenomenon of rapid BM in advanced GaC after first-line treatment and the rapid short-term reduction of cerebellar metastases after the use of savolitinib. Therefore, it is hypothesized that MET amplification may be a key driver of BMs in GaC.

INTRODUCTION

The 2020 Global Cancer Statistics show that gastric cancer ranks fifth in global cancer incidence, with a prevalence of approximately 5.6%[1]. Advanced gastric adenocarcinoma (GaC) is the most predominant pathological type of gastric cancer, and is a multifactorial and heterogeneous disease. Approximately 1/3 of GaC patients have distant metastasis at the time of diagnosis; these patients have higher mortality rates due to stronger tumor aggressiveness[2]. Common metastatic sites of GaC include the peritoneum, lymph nodes, liver, and lungs. However, only 1%-2% of advanced GaC patients develop intracranial metastases and meningeal carcinomatosis (MC)[3].

A patient with advanced GaC harboring mesenchymal epithelial transition factor receptor (MET) amplification, intracranial metastases, and MC treated with savolitinib tablets is presented in this case study. The patient demonstrated rapid shrinkage of intracranial tumors in the short term.

CASE PRESENTATION

Chief complaints

A 66-year-old female presented to the emergency department due to frequent generalized seizures occurring within a week and persistent drowsiness.

History of present illness

In November 2023, the patient developed dizziness, headache, walking instability, tinnitus, and hearing loss. A head magnetic resonance imaging (MRI) indicated meningeal thickening and occupation of the cerebellum and occipital bone. The patient underwent lumbar puncture, which revealed an increase in cerebrospinal fluid (CSF) pressure of > 400 mm H₂O, indicating a rapid disease progression, seizures developed more gradually.

History of past illness

In November 2022, the patient underwent gastroscopy with no abnormality. In May 2023, the patient was treated at another hospital for lumbar pain, and lumbar MRI was performed. Abnormal vertebral signals were considered for tumor metastasis. After further examination by positron emission tomography/computed tomography and gastroscopy, the patient was diagnosed with advanced GaC with multiple metastases to the abdominal lymph nodes and lumbar vertebrae. In June 2023, the patient was treated with the regimen of Candonilimab + oxaliplatin and capecitabine (CAPEOX). After two courses of treatment, the patient showed elevated troponin and aminotransferase levels. Considering the adverse immune reactions, the above drugs were discontinued and gamma globulin and methylprednisolone were administered to suppress the immune system. In September 2023, the patient was administered another two courses of CAPEOX chemotherapy because of disease progression.

Personal and family history

The patient denied any family history of tumors or other notable medical history.

Physical examination

The patient’s vital signs were as follows: Body temperature, 38 °C; blood pressure, 170/94 mmHg; heart rate, 95 beats/min; respiratory rate, 18 breaths/min. When receiving treatment, the patient was in a shallow coma, with left conjunctival congestion, and she demonstrated signs of mydriasis.

Laboratory examinations

Laboratory investigations revealed normocytic anemia (hemoglobin, 66 g/L), elevated leukocyte (14 × 10⁹/L), and elevated C-reactive protein (28.48 mg/L). Tumor markers, including carcinoembryonic antigen (56.2 ng/mL) and carbohydrate antigen 199 (139.4 U/mL), were above the reference range. Genetic testing of CSF and peripheral blood revealed an increased MET copy number and genetic mutations at the TP53p.R213 Locus.

Pathological diagnosis

Gastric mucosal pathology: Less differentiated adenocarcinoma, differentiated grades II–III, and mixed type Lauren classification.

The immunohistochemical results of the Gastric mucosal are as follows: Claudin18.2 (40% +); Her-2 (0); Met (90%); MLH (+); MSH2 (+); MSH6 (+); programmed death 1 (tumor-, interstitial 5% +); programmed death-ligand 1 (PD-L1) (tumor-, interstitial 5% +); PMS (+); TROP2 (100% +++); Ki67 (90% +); EBER (-).

Imaging examinations

MRI revealed thickening of the meninges and abnormal diffuse signals in the skull. A mass on the right cerebellar showed mixed-signal intensity. In December 2023 there was a decrease in the lesions, but the top right nodules increased (Figure 1).

Figure 1 Enhanced magnetic resonance imaging image of a patient with brain metastasis undergoing savolitinib treatment. A: Fluid attenuated inversion recovery image (November 11, 2023); B: T1 image (November 11, 2023); C: T2 image (November 11, 2023); D: Sagittal view of T2 image (November 11, 2023); E: Fluid attenuated inversion recovery image (December 26, 2023); F: T1 image (December 26, 2023); G: T2 image (December 26, 2023); H: Sagittal view of T2 image (December 26, 2023). Orange arrow shows the tumor.

FINAL DIAGNOSIS

The GaC invaded the surrounding tissues and caused pelvic implant metastasis accompanied by multiple metastases to the bone, liver, cerebellum, and meninges. The patient was diagnosed with GaC (cT4NxM1 IV) and was comatose at the time of admission.

TREATMENT

Considering the patient's poor health and comatose state with intracranial metastases and MC, the tumor was rapidly transferred after chemotherapy. After discussion, savolitinib tablets were administered to treat this patient.

OUTCOME AND FOLLOW-UP

After 4 d of oral administration of savolitinib, the patient regained autonomous consciousness and her lower limb muscle strength returned to grade IV after 2 wk. After one month of treatment, with the help of her family, she was able to walk normally. During hospitalization, MRI was used to examine the patient's brain, and the results showed that the cerebellar tumor had shrunk significantly, and the CSF pressure had returned to normal levels. After one month of treatment with savolitinib and a small-molecule MET kinase inhibitor, the patient's brain tumor was rapidly controlled in the short term, extending the patient's survival time.

DISCUSSION

Three major biomarkers, namely, HER2, PD-L1, and deficient mismatch repair/microsatellite instability-high group (dMMR/MSI-H), have been identified in advanced GaC to guide the main pathway of treatment decisions, and anti-angiogenesis large and small molecule targeting drugs can also be considered as second-line and above treatment. The accurate understanding of GaC has improved substantially over time, with considerable advancements made in treatment methods using molecule targeting drugs as compared to the era of chemotherapy. Despite this progress, there is still a gap between current clinical practices and ideal outcomes[4-6]. In reality, the proportion of patients with HER2-positive, PD-L1 CPS ≥ 5%, dMMR/MSI-H targets are small, thus they fall into a “high specific, low coverage” population. Although immune checkpoint inhibitors are used regardless of PD-L1 expression levels, their efficacy is limited with “wide coverage and low specificity”. Therefore, the examination of biomarkers to screen for beneficial traits and avoid ineffective treatments is required.

The MET gene is a proto-oncogene that encodes epithelial-mesenchymal transformation factor (c-Met), a receptor of hepatocyte growth factor. Under physiological conditions, the MET signaling pathway is involved in embryonic development and tissue regeneration, whereas in tumors, activation of the MET pathway can induce tumor occurrence, invasion, and metastasis[7]. Savolitinib is a selective MET inhibitor that prevents MET activation by disrupting the MET signal transduction pathway in an adenosine triphosphate competitive manner, resulting in the inhibition of tumor cell growth[8]. The proportion of MET amplification is low, constituting 4%–6% of GaC[9]. Furthermore, MET amplification includes two forms: primary amplification, defined as the activated MET signal at the time of tumor diagnosis, and secondary amplification, which refers to MET amplification detected after tumor treatment[10]. Patients with primary amplification have worse prognosis than those with secondary amplification[11]. Notably, GaC with MET amplification often appears more aggressive and advanced in the real world[12,13].

The most interesting aspect of this case was the rare intracranial metastasis and meningeal cancer. Therefore, to determine the factors associated with GaC brain metastases (BM), a comprehensive cohort study was carried out[14]. The results showed that BMs occurred less frequently in patients with antrum/pylorus tumors, and that patients with bone and lung metastases were more likely to develop BMs. However, this phenomenon is rare in liver metastases. In addition, there was a /significant negative correlation between BMs and age. Octogenarians had significantly fewer BMs compared to patients aged 60–69 years. BMs are very rare in GaC, and the clinical data of the 11 patients are summarized in Table 1. A review of these data revealed that the age of these patients was generally higher, mainly related to the target of HER2. Further, 10 of the 11 patients opted for radiation therapy and surgical resection as their treatment choice.

Table 1 Summary of previously published series of cases.

Ref.	Case No.	Age/sex	BM	Therapy	Target point	Ending	Survival (month)
Cinar et al[19]	1	55/M	+	Gamma-knife; Irinotecan + trastuzumab	HER2	Dead	1
Cinar et al[19]	2	60/M	+	Radiotherapy; Trastuzumab + capecitabine + carboplatin; Clinical trial	HER2	Dead	24
Katayanagi et al[20]	3	77/M	+	X-knife + surgical resection	Unknown	PR	> 12
Kitayama et al[21]	4	76/M	+	Paclitaxel + surgical resection + radiation therapy	Unknown	PR	5
Sakurai et al[22]	5	78/F	+	Radiation therapy	Unknown	Dead	4
Rino et al[23]	6	63/M	+	Irinotecan + cisplatin + radiation therapy	Unknown	PR	No specified
Rino et al[23]	7	78/M	+	Irinotecan + cisplatin + Cyber-knife	Unknown	PR	No specified
Kostoglou et al[24]	8	69/F	+	Radiation therapy + surgical resection	HER2	Dead	4
Ahn et al[25]	9	38/M	+	Stereotactic radiosurgery + anti-PD-1	Unknown	PR	> 26
Kosco et al[26]	10	73/F	+	Radiation therapy + surgical resection + pharmacological intervention	Unknown	CR	> 26
Murakami et al[27]	11	65/M	+	Supportive care	Unknown	Dead	1

BM: Brain metastases; PR: Partial response; CR: Complete response; HER2: Human epidermal growth factor receptor 2.

It has been reported that patients with HER2+ GaC may have an increased risk of developing BM; however, the role of MET amplification in BM is unclear[15]. According to the well-known “seed and soil” hypothesis, tumor cells can survive and thrive only after adapting to the brain microenvironment microenvironment[16]. Pericytes, brain microvascular endothelial cells, and astrocytes are the three major components of blood–brain barrier[17]. For cancer cells to grow in the brain, they must acquire two key properties: overcoming the tumor-killing ability of glial cells and altering the brain microenvironment to create a suitable environment for tumor cells to survive. Activation glial cells and altering the brain microenvironment to create a suitable environment for tumor cells to survive. Activation of the c-Met signaling pathway can induce the secretion of interleukin (IL) 8 and CXCL1, which promotes the adhesion of tumor cells to brain endothelial cells and stimulates the formation of micro vessels. In addition, this signaling pathway secretes additional IL1β, causing astrocytes to secrete the ligand hepatocellular growth factor (HGF) of c-MET. This vicious feed-forward c-Met/HGF loop generates a favorable microenvironment for metastatic cells astrocytes to secrete the ligand HGF of c-MET. This vicious feed-forward c-Met/HGF loop generates a favorable microenvironment for metastatic cells[18]. However, this conclusion was reached during a search for breast cancer. In this case, the patient developed BM in the short term and achieved partial remission quickly after administration of savolitinib. Therefore, it is speculated that intracranial tumor subsets may be driven mainly by c-MET amplification.

CONCLUSION

BM are rare in advanced GaC, casing a rapid deterioration in these patients, especially in MC. There are very few effective treatment options available; however, technological breakthroughs in genomics have provided a basis for personalized treatment. Therefore, MET amplification may be a key driver of BMs in gastric cancer; however, this conclusion requires further investigation.