Gastric cancer liver metastasis will reduce the efficacy of immunotherapy

Abstract

Immune checkpoint inhibitors augment the antitumor activity of T cells by inhibiting the negative regulatory pathway of T cells, leading to notable efficacy in patients with non-small cell lung cancer, melanoma, and other malignancies through immunotherapy utilization. However, secondary malignant liver tumors not only lower the liver's sensitivity to immunotherapy but also trigger systemic immune suppression, resulting in reduced overall effectiveness of immune therapy. Patients receiving immunotherapy for non-small cell lung cancer and melanoma experience reduced response rates, progression-free survival, and overall survival when secondary malignant tumors develop in the liver. Through Liu's retrospective analysis, valuable insights are provided for the future clinical management of these patients. Therefore, in patients with gastric cancer (GC), the occurrence of liver metastasis might be indicative of reduced efficacy of immunotherapy. Overcoming liver immune tolerance mechanisms and their negative impacts allows for the potential benefits of immunotherapy in patients with GC and liver metastasis.

Key Words: Immune checkpoint inhibitors; Gastric cancer; Gastric cancer with liver metastasis; Immunotherapy; Liver immune tolerance

Core Tip: Immunotherapy has found extensive application in the clinical management of advanced gastric cancer (GC), yielding notable clinical outcomes. In the context of advanced GC with liver metastasis, immunotherapy fails to elicit the desired response owing to the presence of hepatic immune tolerance mechanisms and the compromised physical condition of patients, leading to a reduction in immune response rates. Therefore, liver metastases may be associated with a lower likelihood of immunotherapy success in GC patients. Enhancing the response to immunotherapy in GC patients with liver metastases involves overcoming liver immune tolerance mechanisms and their adverse effects.

INTRODUCTION

Gastric cancer (GC) ranks among the prevalent malignancies affecting the digestive system globally. Based on the latest epidemiological data[1,2], it holds the fifth position for incidence and the fourth position for mortality among all malignant tumors. GC cases and fatalities in China make up roughly half of the worldwide figures. Earlier investigations[3] have demonstrated that the median overall survival (mOS) among advanced GC patients left untreated typically ranges from 3 to 4 months. Systemic chemotherapy recipients often experience a mOS of around one year, accompanied by a marked improvement in the quality of life among patients with advanced GC. The mainstay of treatment for advanced GC patients involves chemotherapeutic medications such as fluoropyrimidines, platinum compounds, and taxanes. However, their efficacy in tumor control is constrained by acquired resistance and primary resistance. The rise of personalized precision therapy has propelled immunotherapy into the spotlight as a crucial component of comprehensive treatment[4]. By blocking the negative regulatory pathways of T cells, immune checkpoint inhibitors (ICIs) boost the anti-tumor effect of T cells. Immunotherapy has brought about significant therapeutic benefits for patients diagnosed with non-small cell lung cancer, melanoma, and related illnesses[5,6], instilling newfound hope in those with advanced GC[7]. However, phase III clinical trial data[8-12] reveals that the incorporation of immunotherapy into chemotherapy regimens improves overall survival (OS) outcomes for patients with advanced GC. The liver's immune-exempt nature renders it less responsive to immunotherapy when secondary malignant tumors are present, fostering systemic immune suppression and yielding unfavorable outcomes in immune therapy[13-15]. In retrospective research[16-20] pertaining to non-small cell lung cancer and melanoma, it has been observed that the presence of secondary liver malignancies may lower the response rate, progression-free survival (PFS), and OS rates in patients treated with immunotherapy, independent of factors such as tumor mutation burden and PD-L1 expression. Despite this, there is a paucity of studies examining whether the existence of secondary malignant liver tumors affects the effectiveness of immunotherapy in patients diagnosed with advanced HER-2 negative GC.

EDITORIAL

The paper entitled " Analysis of the impact of immunotherapy efficacy and safety in patients with gastric cancer and liver metastasis"[21] in the latest issue of the World Journal of Gastrointestinal Surgery has aroused our great interest. The research conducted by Liu et al[21] sheds light on the effectiveness and safety of immunotherapy for individuals suffering from GC with liver metastasis. This retrospective study by Liu et al[21] investigated the clinical baseline parameters, treatment outcomes, and immune-related adverse events in 48 patients with advanced GC undergoing immunotherapy from February 2021 to January 2023. In patients with liver metastases from GC, 15.0% experienced partial remission (PR), 50.0% attained stable disease (SD), with objective response rate (ORR) and disease control rate (DCR) of 15.0% and 35.7%, respectively, as per RECIST 1.1 criteria; among patients diagnosed with GC but without liver metastases, improved clinical treatment efficacy was evident, showcasing PR and SD rates at 35.7% and 46.4%, correspondingly. Additionally, ORR and DCR reached 65.0% and 82.1%, respectively. Despite lacking statistical significance (P > 0.05), the study indicated a lower response rate to immunotherapy in patients with GC liver metastases compared to those without, implying considerable challenges in clinical management for this subgroup of advanced GC patients. The Kaplan-Meier survival analysis indicated that patients with liver metastasis had a median PFS of 5.0 months, notably lower than the 11.2 months seen in GC patients without liver involvement (HR = 0.40, P < 0.01). Despite this, the mOS for the two cohorts stood at 12.0 months and 19.0 months, respectively (P > 0.05). The long-term prognosis of patients with GC and liver metastases is adversely affected by immunotherapy, as opposed to patients without liver metastases, according to the study results. In both patient groups that didn't discontinue treatment or succumb to treatment-related adverse events, Liu et al[21] observed vomiting, nausea, and fatigue as the most frequent adverse effects. Patients with advanced GC are exhibiting varying degrees of decreased tolerance to tumor treatment, particularly among the elderly and frail, resulting in the accumulation of drug toxicity and more pronounced complications. However, this study indicates that employing immunotherapy in advanced GC patients can effectively manage drug-related adverse reactions, ensuring good safety profiles and laying a foundation for subsequent clinical utilization of immunotherapy in this patient cohort.

Targeting HER-2 is significant in tumor therapy, with Trastuzumab yielding effective responses in HER-2-positive GC patients. Given the low proportion of HER-2 positive GC cases, HER-2 targeted therapy remains largely inaccessible for the majority of patients with advanced GC, impeding potential clinical gains. Pembrolizumab's efficacy and benefits were validated in cancer patients with non-colorectal microsatellite instability-high and deficient mismatch repair through the KEYNOTE-158 study[22], highlighting the importance of precise population screening for GC immunotherapy. Nivolumab, in combination with either SOX or CapeOX, was evaluated as the first-line treatment regimen for unresectable advanced or recurrent GC in the ATTRACTION-04 study[23], exhibiting well-tolerated side effects and positive clinical responses. The CheckMate649 study, noted as[10], compared the efficacy of combining nivolumab monoclonal antibody with chemotherapy vs chemotherapy alone in the first-line treatment of HER-2 negative advanced gastric or gastroesophageal junction adenocarcinoma patients through a randomized phase III clinical study. The results showed that patients with combined positive score (CPS) ≥ 5 demonstrated improved OS and PFS when treated with the combination of nivolumab monoclonal antibody and chemotherapy compared to those receiving chemotherapy alone. Meanwhile, it remains efficacious in improving OS among patients with CPS ≥ 1. The RATIONALE-305 study[24] revealed that utilizing tislelizumab alongside chemotherapy in the primary management of advanced GC resulted in substantial enhancements in ORR, OS, and PFS, establishing a novel milestone in first-line therapeutic efficacy for advanced GC. While the aforementioned studies highlight the clinical benefits of immunotherapy in advanced GC patients, GC tends to be less responsive to immunotherapy compared to other solid tumors, especially in the presence of liver metastases, which often correlates with a poor prognosis for this specific patient cohort. GC frequently metastasizes to the liver[12,25]. However, the advent of ICIs has sparked fresh optimism for individuals afflicted with advanced GC. It has been demonstrated in prior research[26] that the occurrence of liver metastases in individuals with melanoma and non-small cell lung cancer during immunotherapy can trigger systemic immune suppression, leading to diminished efficacy of the treatment. So, is the efficacy of immunotherapy compromised by the presence of liver metastases in these patients? In the author's study, patients with GC and liver metastases had poor physical status, leading to decreased immunotherapy response rate and shortened PFS in these patients. The reasons for this difference were elaborated by the authors through the mechanism of liver immune tolerance[13-15]. Evidence from research[27] suggests that non-small cell lung cancer patients with liver metastases manifest a decreased absolute lymphocyte count. The sequencing of primary tumors from metastatic patients reveals a notable decrease in T cell clonality and diversity, as well as impaired T cell effector function, particularly in cases involving liver metastases. Research results by Yu et al[20] indicate that T cell apoptosis in the liver leads to systemic immune suppression, ultimately resulting in poor efficacy of immunotherapy. Meanwhile, research results[14] also suggest that liver metastases can exacerbate the overall tumor burden, leading to a decline in patients' physical condition; however, other studies[28,29] show that the prolonged time and frequent use of corticosteroids needed to achieve a response to immunotherapy are also associated with lower clinical efficacy of immunotherapy, but this still needs further research to confirm.

According to Lin et al[30], a retrospective study in real-world settings revealed the favorable safety profile and oncological efficacy of immune combination chemotherapy in patients with synchronous GC liver metastasis, significantly improving long-term prognosis and providing opportunities for surgical resection. However, it is important to acknowledge that GC liver metastasis patients generally exhibit a limited response to immunotherapy due to the immunosuppressive characteristics present in the hepatic immune microenvironment[31]. In clinical practice, multidisciplinary and individualized treatment strategies should be considered to achieve optimal treatment outcomes by selecting appropriate treatment plans based on specific patient conditions and tumor characteristics.

CONCLUSION

From the results of this study, it can be concluded that the presence of liver metastases in GC patients is associated with a decline in immune response, leading to a diminished efficacy of immunotherapy. Therefore, liver metastases may serve as an adverse predictive factor for immunotherapy effectiveness in GC. Overcoming liver immune tolerance mechanisms and addressing their adverse effects could potentially amplify the efficacy of immunotherapy in GC patients with liver metastases.

ACKNOWLEDGEMENTS

The authors acknowledge and appreciate our colleagues for their valuable suggestions and assistance for this editorial.