Introduction
Cervical cancer ranks as the fourth most common malignancy in women, with endocervical adenocarcinoma (ECA) accounting for ~20-25% of all cases (1-3). According to the World Health Organization (WHO) classification, ECA is divided into HPV-associated (HPVa) and HPV-independent (HPVi) types (4). Among HPVi subtypes, gastric-type endocervical adenocarcinoma (GEA) is the most prevalent, comprising 80% of all HPVi cases. In addition to being unrelated to high-risk HPV infection, GEA lesions mainly develop in the deep cervical canal, leading to a high failure rate using the current screening methods (high-risk HPV test and cervical cytology) (5,6). In the near future, with the implementation of large-scale HPV vaccination programs, a decline in the incidence of HPVa could be anticipated, potentially leading to an increased proportion of GEA.
In clinical practice, patients with GEA are more likely to present with bulky mass, deep stromal invasion, lymph node and ovarian metastasis, contributing to poor prognosis (7-9). Over the past decade, several studies have confirmed the poor prognosis of GEA in different populations. In a pivotal study conducted by Kojima et al (10), the post-operative survival outcomes of the patients with stage IB-IIB GEA [according to International Federation of Gynecology and Obstetrics (FIGO)] were compared with those of patients without GEA. It was reported that patients with GEA obtained a markedly worse five-year disease-free survival when compared with the patients without GEA (25 vs. 75%). Additionally, the five-year disease-specific survival rate was also lower in GEA group (30 vs. 77%) (10). In another study, Karamurzin et al (8) found that the five-year disease-specific survival rate for GEA was as low as 42%. Furthermore, in a retrospective analysis involving 95 patients with GEA and 233 patients with usual-type ECA (UEA) at FIGO stage IA-IIB and treated by the surgery, the median PFS for GEA was notably shorter than UEA (42 vs. 61.1 months) (7). Unfortunately, owing to its rarity, high-level evidences from prospective or randomized studies about GEA were not available yet. In clinical practice, current treatment strategies for GEA were mostly copied from that for common cervical cancers, while presented limited efficacy. Therefore, to explore individualized treatments based on the unique features of GEA becomes an urgent issue for our gynecologic oncologists.
In previous years, the immunotherapies represented by PD-1/PD-L1 inhibitors have achieved significant advancements in various human cancers, particularly among patients with positive PD-L1 expression (11-13). Pembrolizumab, the first commercial monoclonal antibody targeting PD-1, has demonstrated efficacy and manageable safety profiles in patients with persistent, recurrent, or metastatic cervical cancer (14,15). Based on the PFS and OS benefits observed in the KEYNOTE-826 study, NCCN recommend Pembrolizumab in combination with cisplatin/paclitaxel or carboplatin/paclitaxel and bevacizumab as a first-line treatment for PD-L1-positive recurrent or metastatic cervical cancer (16-18). Additionally, results from the KEYNOTE-158 study indicated that Pembrolizumab exhibits significant antitumor activity in previously treated patients with advanced cervical cancer, with an overall response rate of 12.2% (19). Furthermore, the recent KEYNOTE-A18 study reported that the combination of Pembrolizumab with radiotherapy and chemotherapy significantly enhanced PFS in newly diagnosed patients with high-risk locally advanced cervical cancer (20). Unfortunately, all these clinical trials focused on common histological patterns such as squamous cell carcinoma and UEA, while rarely recruiting patients with rare tumors including GEA and neuroendocrine carcinoma. Two reasons may account for this phenomenon: First, GEA was markedly more aggressive and progressed rapidly, making it an unsuitable candidate for most clinical trials; second, the incidence of GEA was notably lower than other subtypes, which introduced significant challenges in patients' recruitment. Therefore, a retrospective analysis may be a more feasible approach in clinical practice.
As two previous studies reported, positive expression of PD-L1 (CPS≥1) was detected in 87.5% (n=32) and 75.9% (n=58) patients with GEA, which strongly indicated that anti-PD-1/PD-L1 treatments might constitute a potent strategy for this lethal malignancy (21,22). In the present study, the survival benefits were retrospectively analyzed in a cohort of patients with GEA who received PD-1/PD-L1 inhibitors, aiming to provide the real-world evidence on this topic.
Discussion
Currently, the treatment strategy for GEA is similar to those for common cervical cancers, primarily involving surgery, radiotherapy and chemotherapy (18). However, owing to its significant aggressiveness and resistance to current therapies, the prognosis of GEA is considerably poorer (23). Thus, novel therapeutic approaches are urgently needed in clinical settings.
As previously reported, a substantial proportion of GEA cases exhibit positive PD-L1 expression, suggesting that immunotherapy targeting the PD-1/PD-L1 axis may offer therapeutic benefits. in the present study, by retrospectively analyzing GEA cases in our centers, preliminary evidences to support the potential benefits of immunotherapy for this lethal cancer were provided. However, it is important to note that GEA has previously been reported to have a low median tumor mutational burden and a high proportion of KRAS and STK11 mutations, suggesting that GEA may exhibit resistance to checkpoint inhibitors. However, it was concluded that checkpoint inhibitors have a therapeutic effect on GEA. Several factors may account for this discrepancy. From a sampling perspective, the participants in the present study are drawn from the Chinese population, whereas the sample source in the previous study differs (23). Variations in genetic background, regional characteristics, living environment and other factors among patients may influence the tumor’s response to immunotherapy. Regarding treatment options, the majority of patients in the present study received a combination of chemotherapy or radiotherapy, and PD-1/PD-L1 inhibitors, which may produce a synergistic effect that enhances the efficacy of immunotherapy. By contrast, earlier studies may not have adequately addressed the effects of combination therapy. Future studies should aim to expand the sample size and further investigate the mechanisms by which these factors influence the efficacy of immunotherapy, in order to more accurately evaluate the role of checkpoint inhibitors in the treatment of GEA. The present findings supported that PD-1/PD-L1 inhibitors were beneficial for patients with PD-L1-positive GEA and who started immunotherapy as part of their primary treatment. Interestingly, among patients with GEA who initiated immunotherapy following tumor recurrence/metastasis, it was observed that immunotherapy significantly prolonged OS while having limited effects on PFS. After reviewing the data, it was hypothesized that subsequent treatments following PD-1/PD-L1 inhibition may partially account for this unexpected finding (data not shown), which will be further explored in our future work.
To the best of our knowledge, this is the first case series study aimed at exploring the efficacy of immunotherapy in GEA, which might shed some light on treating this rare and lethal malignancy. As a preliminary study, several limitations should be acknowledged. First, the retrospective nature and small sample size limited the statistical power of the analysis and may not adequately mitigate potential biases; second, the majority of patients in our cohort received a combination of treatments, including chemotherapy, radiotherapy and PD-1/PD-L1 inhibitors, which might not fully reveal the efficacy of immunotherapy and introduce unpredicted interference for the evaluation of tumor response.
Besides immunotherapies, the latest studies also reported two candidates for target therapy of GEA, HER2 and Claudin 18.2. In a Chinese GEA cohort, Wang et al (24) revealed that 17.2 and 15.5% patients presented HER2 overexpression and amplification, which was closely related with a worse prognosis. Shi et al (25) also reported that HER2 amplification/over-expression was more common in GEA comparing to UEA (14.7 vs. 4.5%). Interestingly, several studies have also indicated potential benefits of anti-HER2 treatment in other gynecologic malignancies such as ovarian mucinous carcinoma and uterine serous carcinoma (26,27). These findings support that anti-HER2 therapy might be a candidate choice for GEA and warrant further investigations.
As a member of the claudins family, Claudin18.2 primarily regulates the tight junctions on the cell surface and is typically expressed in cancers originating from the digestive system. In recent years, a series of clinical trials have demonstrated that targeting Claudin18.2 can lead to significant improvements in PFS and OS in advanced gastric, gastroesophageal junction and esophageal carcinomas. Notably, a recent study found that Claudin18.2 was positively stained in 95.2% of gastroesophageal adenocarcinoma tissues, with 58.0% of cases exhibiting moderate to strong staining (28), while it was rarely detected in common cancers or normal cervical tissues. These findings suggest that targeting Claudin18.2 may represent a viable strategy for treating advanced GEA.
As a member of the claudins family, Claudin18.2 mainly participates in regulating the tight junctions on cell surface, which is usually specifically expressed in cancers originated from the digestive system (29,30). Recently, a series of clinical trials have demonstrated that targeting Claudin18.2 can lead to significant improvements in PFS and OS in advanced gastric, gastroesophageal junction and esophageal carcinomas (31,32). Notably, a latest study proved that Claudin18.2 was positively stained in 95.2% GEA tissues (58.0% cases presented a moderate or strong staining), while scarcely detected in common cancers or normal tissues of cervix (28). This result proposed that targeting Claudin18.2 might be a reasonable strategy for treating advanced GEA.
In conclusion, the present study provides the first case series about the efficacy of PD-1/PD-L1 inhibitors for treating GEA. The present results suggest that immunotherapy could be given as part of the primary treatments and patients with high expression of PD-L1 would obtain more survival benefits. These findings are helpful for guiding our clinical practice, which warrants further investigations in large populations.