Gastric cancer (GC) is the sixth most common cancer and has the third-highest global mortality rate in 2018 (1). In Korea, the stomach is the second most common site of cancer following lung, and GC is the fifth-highest mortality following lung, liver, colorectal, and pancreas cancers (2). The frequency of human epidermal growth factor receptor 2 (HER2) overexpression in gastric and gastroesophageal cancer varies by study, with a mean of 18%, and is a significant predictor of poor survival (3–5). Trastuzumab, a monoclonal antibody targeting HER2, inhibits HER2-mediated signaling and prevents cleavage of the extracellular domain of HER2 (6). In a previous study, trastuzumab plus chemotherapy showed a survival advantage in HER2-positive advanced gastric and gastroesophageal junction cancers (7). However, the overall response rate (ORR) was 47%, with a complete response (CR) of only 5%, and the available data demonstrated that high dose trastuzumab is not associated with efficacy improvement (7, 8). Thus, there is a need for potential biomarkers regarding the efficacy of anti-HER2 therapy.

Tumor mutational burden (TMB) means the total number of mutations per coding area of a tumor genome. There is a strong relationship between the TMB and the activity of immune checkpoint inhibitors (ICIs) across multiple cancers (9–12). Hu et al. suggested that TMB could predict the response to trastuzumab rather than HER2 status in patients with advanced gastric cancer (AGC) (13). However, few studies have been performed on the relationship between TMB and the efficacy of anti-HER2 therapies.

Herein, we analyzed the efficacy of anti-HER2 therapy in patients with HER2-positive AGC according to TMB.

In this study, we retrospectively analyzed the relationship between TMB and response to trastuzumab plus chemotherapy as first-line treatment in metastatic or recurrent GC. There was no difference in ORR and OS between the TMB-high and low groups (P=0.546 and 0.117, respectively). However, PFS in the TMB-high group was longer than that in the TMB-low group with statistically a significant difference (P=0.019).

GC has a molecular heterogeneity and has been classified to diffuse and intestinal subtypes according to Lauren classification (14). In 2014, The Cancer Genome Atlas (TCGA) genomically separated GC into four subtypes, such as EBV-associated tumors, microsatellite instability-high (MSI-H) tumors, genomically stable tumors, and tumors with chromosomal instability (15). In the era of immunotherapy, pembrolizumab, PD-L1 monoclonal antibody, showed a durable response rate in patients with advanced gastric or gastroesophageal cancer that had progressed after second-line treatment (16). Especially in a previous study, EBV-positive and/or MSI-high GC had a higher response to an anti-PD-L1 therapy compared to other subtypes according to TCGA (17). A recent study showed that nivolumab, the first programmed cell death-1 (PD-1) inhibitor, plus chemotherapy had superior OS and PFS with tolerable toxicity profile in patients with previously untreated advanced gastric, gastroesophageal junction, or esophageal adenocarcinoma (18). However, this study included only non-HER2-positive disease, and the importance of trastuzumab is still emphasized in patients with HER2-positive gastric or gastroesophageal cancers.

Despite the development of targeted therapy, surgical resection is still the only curable treatment option for GC, and preoperative chemo-radiotherapy or perioperative chemotherapy is needed to improve the outcomes for locally advanced disease (clinically T2-4 or positive lymph node). In the metastatic setting, the first-line chemotherapy consists of platinum-based doublet or triplet with or without trastuzumab according to HER2 status (19). In ToGA (Trastuzumab for Gastric Cancer) trial, trastuzumab plus chemotherapy showed significantly longer OS (18.6 versus 17.1 months; HR 0.74 [95% CI 0.60-0.91]; P=0.0046) than the chemotherapy alone for HER2-positive gastric or gastroesophageal junction cancer. And the ORR and CR were 47% (n=139/294) and 5% (n=16/294), respectively (7).

Considering that high TMB correlates with a greater probability of displaying tumor neoantigens on human leukocyte antigen molecules on the surface of tumor cells (20, 21), it was suggested that the tumors with higher TMB are more likely to respond to immunotherapy. In several previous studies, the benefit of high TMB on response to immunotherapy has been reported in many cancer types, including melanoma, non-small cell lung cancer, and bladder cancer (9–12). Furthermore, a previous case report suggested that TMB could be a predictor of the response to trastuzumab in patients with HER2-positive AGCs (13). However, as far as we know, there was no clinical trial to evaluate the value of TMB as a predictor of efficacy of trastuzumab in HER2-positive AGCs.

This study had several limitations. First, it had a small sample size, was retrospective in nature, and utilized a heterogeneous population, all conductive to bias. Second, in patients with low TMB, anti-HER2 therapy showed a useful effect. This suggests that the status of TMB is not a sufficient biomarker for selecting patients likely to benefit from HXP. Third, only Asian patients with HER2-positive AGC were analyzed in the study, limiting the generalizability because of differences in molecular profiles and clinical features between Western and Eastern patients with HER2-positive AGC.

Therefore, study findings for high TMB as a novel biomarker should be interpreted with caution and make it difficult to draw definite conclusions. Further prospective clinical trials are required to determine whether high TMB could be a novel predictive or prognostic biomarker for anti-HER2 therapy in HER2-positive AGC. Furthermore, as next-generation sequencing (NGS) is available in the biomarker-based trials are in practice (22).

The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by the Institutional Review Board Samsung Medical Center. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

The conception and design of the study: HRK and STK. Acquisition of data: HRK, SA, HJ, HK, JH, JL, H-YL, WK, and STK. Analysis and interpretation of data: HRK and STK. Drafting the article or revising it critically for important intellectual content: HRK and STK. Final approval of the version to be submitted: HRK and STK. All authors contributed to the article and approved the submitted version.

This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HR20C0025).

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.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.