Gastric cancer (GC) is the fifth most prevalent malignancy worldwide (1), with a generally poor prognosis (2). Following the landmark MAGIC trial (3–5), neoadjuvant therapy (NAT) has been recommended by numerous clinical practice guidelines (6–8), and has gradually becomes the standard treatment for patients with locally advanced gastric cancer (LAGC) (9). This transformation can be attributed to its multifaceted advantages, including a higher likelihood of achieving negative margins, tumor downstaging and improvements in both disease-free survival (DFS) and overall survival (OS) (10, 11).

Pathological complete response (pCR), defined as the absence of any viable tumor cells in the affected tissue (12), has been associated with improved survival in various cancers, including breast (13), rectal (14), esophageal (15), and bladder cancer (16). However, the prognostic significance of pCR in LAGC remains inadequately elucidated. In 2019, Wang reported on a cohort of 39 patients achieving pCR following NAT at the China National Cancer Center, revealing 3- and 5-year OS rates of 88.9% and 88.9%, respectively (17). While recent publications have summarized the characteristics and survival outcomes of pCR in LAGC patients, these studies were limited by small sample sizes and the inclusion of patients with lymph node metastasis (ypN+), which may affect the generalizability of their findings (18–20). Moreover, combined immunotherapy and chemotherapy showed prolonged OS and progression-free survival (PFS) compared to chemotherapy alone in patients with PD-L1 CPS ≥5 in CheckMate 649 (21) and ORIENT-169 (22). Ongoing investigations of neoadjuvant immunotherapy in LAGC hold the potential to further increase the pCR rate (23, 24).

This study aims to update our previous findings by including a larger cohort of 112 patients with pCR status between January 2004 and June 2023, providing a more robust analysis of long-term outcomes. Furthermore, we explored the potential benefits of postoperative adjuvant therapy and the early efficacy of neoadjuvant immunotherapy.

In the present study, we updated and expanded the previously published experience of our institution regarding the long-term outcomes of LAGC patients who achieved pCR after NAT. To our knowledge, this cohort of 112 patients represents the largest single-center study to date focusing on pCR in LAGC. Comparable to our institution’s previously published values, we reported 3- and 5-year OS rates of 90.2% and 83.3%, respectively, along with 3- and 5-year DFS rates of 86.8% and 82.0%, respectively. Moreover, we demonstrated that combining neoadjuvant immunotherapy with chemotherapy significantly improved pCR rate, while the administration of adjuvant therapy did not confer additional survival benefits for pCR patients.

Our study observed favorable survival outcomes among patients with pCR, consistent with findings reported by other researchers. Guo et al. revealed that patients achieving pCR following nCT had 3- and 5-year overall survival rates of 88.8% and 78.6%, respectively, along with 3- and 5-year progression-free survival rates of 86.5% and 75.8%, respectively (20). In a multicenter analysis involving 130 patients with LAGC who received nCT, Lin et al. reported that pCR was an independent prognostic factor for both OS and DFS (26). The survival benefit associated with pCR is theoretically attributed to the simultaneous eradication of the primary tumor, regional lymph node metastases, and potential distant micrometastases through neoadjuvant therapy (27). When pCR is achieved, neoadjuvant therapy may also eliminate occult micrometastatic disease, such as disseminated tumor cells within the peritoneal cavity, thereby exerting a potential curative effect (28). This mechanism may partially account for the long-term survival advantage observed in patients who achieve pCR following NAT.

Previous research has indicated a relatively low pCR rate following nCT, ranging from 4% to 9% (29, 30). Improving the pCR rate remains a critical challenge in clinical practice. In recent years, the emergence of immunotherapy has transformed the standards and principles of cancer treatment, representing the third paradigm shift in oncology after traditional chemotherapy and targeted therapies (31). The Checkmate-649 and ORIENT-16 trials have demonstrated significant clinical benefits and manageable safety profiles when using immune combination therapy as the first-line treatment for advanced gastric cancer (21, 22). The exploration of immune-based regimens in the NAT is currently underway and attracting considerable attention. A single-arm, phase II study evaluating XELOX combined with sintilimab as NAT for potentially resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma showed an R0 resection rate of 97.2%. Among the 36 patients enrolled in the study, 7 (19.4%) achieved a pathological complete response (pCR), with 17 (47.2%) exhibiting a major pathological response (32). Another study found that, in comparison to the SOX or FOLFOX neoadjuvant chemotherapy regimens, the addition of tislelizumab significantly elevated the rate of pCR (3.4% vs. 26.0%; p <0.001) and the rate of R0 resection (89.9% vs. 100%; p = 0.019) in patients with LAGC (33). Li et al. investigated the incorporation of an anti-angiogenic agent (apatinib) into neoadjuvant immunotherapy (carrelizumab) combined with chemotherapy (S-1 ± oxaliplatin), and reported complete and major pathological response rates of 15.8% and 26.3%, respectively (23). Our study yielded similar results, showing that neoadjuvant immunotherapy combined with chemotherapy elevated the pCR rate from 4.7% observed during neoadjuvant chemotherapy to 22.7% (p <0.001). Thus, the integration of neoadjuvant chemotherapy and immunotherapy presents a promising therapeutic approach for patients with gastric cancer.

We also observed an unfavorable prognosis among pCR patients who experienced postoperative recurrence in our clinical practice, with 8 individuals developing recurrence within a median period of less than 2 years. Fields et al. found that despite achieving pCR following NAT, patients still face a significant risk of recurrence and cancer-specific death after resection (34). Therefore, we conducted univariate and multivariate Cox analyses, which revealed that nCT was an independent protective factor for long-term survival, while nCRT was associated with poorer outcomes even with pCR achieved. Previous investigations similarly suggested that nCRT was associated with a higher incidence of pCR compared to nCT, but this improvement did not translate into better prognosis (35). The JCOG1109 NExT study demonstrated that in locally advanced oesophageal squamous cell carcinoma (OSCC), the pCR rate was significantly higher in the NeoCF+RT (cisplatin/fluorouracil + radiotherapy) group compared to the NeoCF (cisplatin/fluorouracil) group (32.5% vs 2.0%), whereas no significant differences were observed in OS (68.3% vs 62.6%, p = 0.12) or PFS (58.5% vs 47.7%) (36). Similarly, the German POET study reported a higher pCR rate in the nCRT group for gastric cancer, but 3-year DFS was comparable between the two groups (37). The potential reason for this discrepancy in outcomes may be attributed to the distinct mechanisms of chemotherapy and chemoradiotherapy. Chemotherapy is a systemic therapy, while chemoradiotherapy offers targeted and localized therapy. Gastric cancer recurrences primarily occur at distant sites, particularly peritoneal implantation metastasis, rather than local recurrence (38). This disparity may explain the improved survival observed after nCT due to its systemic effects. With the advent of the immunotherapy era, it remains unclear whether the increased pCR rates achieved with neoadjuvant immunotherapy will ultimately translate into survival benefits (39). The multicenter phase III KEYNOTE-585 trial demonstrated that perioperative pembrolizumab combined with FOLFOX or FLOT significantly increased the pCR rate compared with FLOT alone (13.4% vs. 2.0%) in patients with resectable locally advanced gastric or gastroesophageal junction cancer, although the improvement in overall survival remained limited (71.8 vs. 55.7 months; HR: 0.86, 95% CI: 0.71–1.06) (40). Similarly, a multicenter study reported a lower early recurrence rate in the neoadjuvant immunochemotherapy group than in the chemotherapy-alone group (29.7% vs. 40.8%, P=0.047), with immunotherapy identified as an independent protective factor (OR: 0.62, 95% CI: 0.41–0.92, P=0.018) (41). However, the limited follow-up duration in this retrospective study warrants further validation of its long-term outcomes.

Another important consideration is whether adjuvant therapy is necessary following pCR. Some data suggested that patients with gastroesophageal cancer who underwent NAT followed by resection benefited from adjuvant chemotherapy (42), but there is no established consensus regarding the benefit and indications of adjuvant therapy in pCR patients. Our analysis showed no significant difference in OS and DFS between patients who received adjuvant therapy and those who did not, indicating that adjuvant therapy might not confer additional survival benefit in patients achieving pCR. Similarly, He et al. observed that adjuvant chemotherapy was unnecessary for patients with locally advanced rectal cancer who achieved pCR through NAT, as it did not improve survival (43). In the real world, the causal relationship between pCR and long-term oncological outcomes is confounded by factors such as neoadjuvant therapy pattern and the biological behavior of the patients. The crucial issue in optimizing treatment strategies for pCR patients is the identification of individuals who are truly cured. The evaluation of minimal residual disease (MRD) through circulating tumor DNA (ctDNA) testing has been preliminarily applied to various solid tumors (44–46). Studies have shown that postoperative ctDNA can reflect the presence of MRD and predict the risk of recurrence in solid tumors, with MRD-positive gastric cancer patients exhibiting a significantly higher risk of recurrence than MRD-negative patients (47, 48). MRD detection can also predict the risk of recurrence in patients undergoing NAT. A phase Ib trial enrolled 32 patients with resectable stage II/III gastroesophageal cancer who underwent neoadjuvant immunotherapy combined with chemoradiotherapy. Patients with undetectable ctDNA at postoperative time points had longer recurrence-free survival (RFS) compared to those with detectable ctDNA (not reached vs. 7.8 months, P = 0.007), with a similar trend observed for OS (49). These findings suggest that ctDNA testing may serve as a valuable tool for assessing MRD status in pCR patients, thereby identifying those who are truly cured and guiding subsequent treatment decisions.

Our study has several limitations. Firstly, it was a single-center study with considerable heterogeneity in treatment regimens. Secondly, although our cohort represented the largest to date, the number of pCR patients receiving neoadjuvant immunotherapy remained limited, and no endpoint events were observed in this subgroup. Further large-scale investigations with extended follow-up are warranted to validate the survival benefits of pCR after neoadjuvant immunotherapy.

In conclusion, patients with LAGC who achieved pCR exhibited favorable long-term survival outcomes, and adjuvant therapy did not confer additional survival benefits. Although neoadjuvant immunotherapy increased the pCR rate, its impact on the prognosis of pCR patients requires further investigation.