A recent breakthrough in the treatment of HER2-positive alpha-fetoprotein-producing gastric cancer (AFPGC) offers a new beacon of hope for patients suffering from this aggressive and historically poor-prognosis malignancy. A pioneering study conducted at Tianjin Medical University Cancer Institute reveals that combining anti-PD-1 antibodies with trastuzumab and chemotherapy may significantly enhance clinical outcomes. This single-center retrospective analysis sheds new light on tailored cancer immunotherapy, advancing the frontiers of precision medicine in oncology.
Alpha-fetoprotein-producing gastric cancer represents a rare yet notably aggressive subtype of gastric tumors, distinguished by elevated serum alpha-fetoprotein (AFP) levels. These cancers often exhibit rapid progression and dismal survival rates. Among these patients, those whose tumors overexpress human epidermal growth factor receptor 2 (HER2) fare even worse. The molecular intricacies underlying HER2-positive AFPGC create formidable therapeutic challenges, prompting oncologists to seek innovative combination regimens beyond standard chemotherapy.
This study analyzed 29 HER2-positive AFPGC patients selected from a pool of 259 individuals with confirmed elevated AFP levels, all treated between May 2017 and May 2022. By integrating comprehensive clinical data, treatment histories, and survival outcomes, researchers meticulously assessed the efficacy of various therapeutic strategies. Notably, 16 patients received a quadruple combination therapy consisting of doublet chemotherapy, trastuzumab—a monoclonal antibody targeting HER2—and an anti-PD-1 immune checkpoint inhibitor, a drug class revolutionizing cancer immunotherapy.
Immune checkpoint inhibitors disrupt the mechanisms tumors use to evade immune surveillance. Anti-PD-1 antibodies reinvigorate T-cell activity, thereby enhancing the body’s natural defenses. Trastuzumab targets HER2 receptors, impeding tumor growth and survival signals. By combining these agents with chemotherapy, which exerts cytotoxic effects on rapidly dividing cells, the researchers hypothesized a synergistic effect that could overcome the inherent resistance of HER2-positive AFPGC.
The clinical results affirm this hypothesis. Patients treated with the quadruplet combination achieved an objective response rate (ORR) of 80% and a disease control rate (DCR) of 93.3%, surpassing outcomes observed in the broader patient cohort. Across the entire study population, the median progression-free survival (mPFS) was 10.27 months, and median overall survival (mOS) was 20.50 months. Although mPFS and mOS in the quadruple therapy group measured slightly lower at 7.47 and 14.87 months respectively, this group contained patients experiencing prolonged survival, indicating potential durable responses.
Intriguingly, six patients on the quadruple regimen remained progression-free beyond the study’s follow-up, and eight were alive at the time of last contact. The wide range of progression-free and overall survival times, stretching as far as 41 months in some cases, underscores the heterogeneity of tumor biology and patient responses. These findings signal that even within a high-risk population like HER2-positive AFPGC, select individuals may derive substantial long-term benefits from this integrated treatment approach.
To elucidate the tumor microenvironment’s role in modulating these responses, the researchers employed multiple immunofluorescence staining techniques. This advanced cellular profiling revealed a pronounced deficit of critical immune effector populations—including CD3+ T cells, CD8+ cytotoxic T cells, CD56+ natural killer cells, and CD68+ macrophages—within both tumor parenchyma and stroma of HER2-positive AFPGC patients. Such immune cell paucity contrasts with patterns observed in HER2-negative and AFP-normal gastric cancers, hinting at unique immunosuppressive landscapes that may influence therapeutic success.
These immune profiling insights deliver powerful mechanistic clues. The diminished presence of immune infiltrates in HER2-positive AFPGC could partly explain its aggressive nature and resistance to monotherapies. Consequently, incorporating immune checkpoint blockade into treatment regimens appears particularly justified, as it can potentially restore antitumor immunity missing in these tumors. The synergy noted with trastuzumab and chemotherapy further supports combined targeting of proliferative and immune evasion pathways.
The study’s retrospective real-world design offers valuable evidence reflective of routine clinical practice, complementing controlled clinical trials. Despite limitations inherent to single-center analyses and relatively small sample sizes, the data underscore the transformative potential of precision immuno-oncology strategies tailored to molecular tumor characteristics such as HER2 status and AFP production.
Importantly, these findings advocate for routine AFP monitoring alongside HER2 evaluation in gastric cancer diagnostics. Identifying patients with this dual biomarker profile may enable clinicians to stratify those who stand to benefit most from quadruple combination regimens, optimizing resource allocation and personalized care. As therapeutic options expand, such biomarker-driven approaches will be instrumental in refining treatment algorithms.
Future prospective investigations with larger cohorts and multi-institutional collaboration are warranted to validate these observations and elucidate mechanisms underpinning varied patient responses. Additionally, explorations into combinatorial biomarkers capturing both tumor and immune parameters could further refine prognostic models and guide adaptive treatment adjustments.
In conclusion, this seminal analysis signifies a critical step toward overcoming the formidable challenge posed by HER2-positive AFPGC. By employing a multipronged therapeutic approach integrating chemotherapy, HER2-targeted monoclonal antibodies, and immune checkpoint inhibitors, clinicians can now envision improved prognoses for a subset of these otherwise poor-outcome patients. The marriage of molecular oncology and immunotherapy heralds a new era of hope and scientific progress in the fight against this refractory cancer subtype.
As novel immuno-modulatory agents gain approval and refine existing therapeutic modalities, precision medicine strategies tailored to unique tumor-immune landscapes will likely become standard care for complex gastric cancers. This study shines a spotlight on the imperative to innovate beyond one-size-fits-all paradigms, encouraging continued exploration of combinatorial regimens that pragmatically harness the immune system’s power to eradicate malignant cells.
Undoubtedly, the reported survival benefits and profound immunological insights provided by this Tianjin Medical University team will catalyze further research and clinical trials, paving the way for improved quality of life and extended survival among patients burdened by HER2-positive alpha-fetoprotein-producing gastric cancer worldwide.
Subject of Research: HER2-positive alpha-fetoprotein-producing gastric cancer and the efficacy of combination therapy involving anti-PD-1 antibodies, trastuzumab, and chemotherapy.
Article Title: The combination of anti-PD-1 antibodies, trastuzumab and chemotherapy may improve the outcome of some patients with HER2-positive alpha-fetoprotein-producing gastric cancer: a retrospective real-world analysis from a single center.
Article References:
Ge, S., Wang, F., Li, H. et al. The combination of anti-PD-1 antibodies, trastuzumab and chemotherapy may improve the outcome of some patients with HER2-positive alpha-fetoprotein-producing gastric cancer: a retrospective real-world analysis from a single center. BMC Cancer 25, 1549 (2025). https://doi.org/10.1186/s12885-025-14808-3
Image Credits: Scienmag.com
