Association of Tumor-Associated Collagen Signature With Prognosis and Adjuvant Chemotherapy Benefits in Patients With Gastric Cancer

Abstract

Importance: The current TNM staging system provides limited information for prognosis prediction and adjuvant chemotherapy benefits for patients with gastric cancer (GC).

Objective: To develop a tumor-associated collagen signature of GC (TACSGC) in the tumor microenvironment to predict prognosis and adjuvant chemotherapy benefits in patients with GC.

Design, setting, and participants: This retrospective cohort study included a training cohort of 294 consecutive patients treated between January 1, 2012, and December 31, 2013, from Nanfang Hospital, Southern Medical University, People's Republic of China, and a validation cohort of 225 consecutive patients treated between October 1, 2010, and December 31, 2012, from Fujian Provincial Cancer Hospital, Fujian Medical University, People's Republic of China. In total, 146 collagen features in the tumor microenvironment were extracted with multiphoton imaging. A TACSGC was then constructed using the least absolute shrinkage and selection operator Cox proportional hazards regression model in the training cohort. Data analysis was conducted from October 1, 2020, to April 30, 2021.

Main outcomes and measures: The association of TACSGC with disease-free survival (DFS) and overall survival (OS) was assessed. An independent external cohort was included to validate the results. Interactions between TACSGC and adjuvant chemotherapy were calculated.

Results: This study included 519 patients (median age, 57 years [IQR, 49-65 years]; 360 [69.4%] male). A 9 feature-based TACSGC was built. A higher TACSGC level was significantly associated with worse DFS and OS in both the training (DFS: hazard ratio [HR], 3.57 [95% CI, 2.45-5.20]; OS: HR, 3.54 [95% CI, 2.41-5.20]) and validation (DFS: HR, 3.10 [95% CI, 2.26-4.27]; OS: HR, 3.24 [95% CI, 2.33-4.50]) cohorts (continuous variable, P < .001 for all comparisons). Multivariable analyses found that carbohydrate antigen 19-9, depth of invasion, lymph node metastasis, distant metastasis, and TACSGC were independent prognostic predictors of GC, and 2 integrated nomograms that included the 5 predictors were established for predicting DFS and OS. Compared with clinicopathological models that included only the 4 clinicopathological predictors, the integrated nomograms yielded an improved discrimination for prognosis prediction in a C index comparison (training cohort: DFS, 0.80 [95% CI, 0.73-0.88] vs 0.78 [95% CI, 0.71-0.85], P = .03; OS, 0.81 [95% CI, 0.75-0.88] vs 0.80 [95% CI, 0.73-0.86], P = .03; validation cohort: DFS, 0.78 [95% CI, 0.70-0.87] vs 0.76 [95% CI, 0.67-0.84], P = .006; OS, 0.78 [95% CI, 0.69-0.86] vs 0.75 [95% CI, 0.67-0.84], P = .002). Patients with stage II and III GC and low TACSGC levels rather than high TACSGC levels had a favorable response to adjuvant chemotherapy (DFS: HR, 0.65 [95% CI, 0.43-0.96]; P = .03; OS: HR, 0.55 [95% CI, 0.36-0.82]; P = .004; dichotomized variable, P < .001 for interaction for both comparisons).

Conclusions and relevance: The findings suggest that TACSGC provides additional prognostic information for patients with GC and may distinguish patients with stage II and III disease who are more likely to derive benefits from adjuvant chemotherapy.

Figure 1.. Schematic of Tumor-Associated Collagen Signature of Gastric Cancer (TACS_GC)

A, Hematoxylin and eosin (H&E) and 2-photon excitation fluorescence (TPEF) and second harmonic generation (SHG) combined images. A representative region of interest with a field of view of 500 × 500 μm was selected in the H&E staining image. The corresponding multiphoton imaging was obtained. B, The SHG image was chosen for collagen feature extraction, including morphologic and textural features. C, Collagen feature selection used the least absolute shrinkage and selection operator Cox proportional hazards regression model with 10-fold cross-validation. Dashed vertical lines represent the optimal log(λ) value after the last step. D, Construction of the TACS_GC was based on the selected collagen features.

Figure 2.. Kaplan-Meier Survival Analysis of the Training and Validation Cohorts Grouped by the Tumor-Associated Collagen Signature of Gastric Cancer (TACS_GC)

Figure 3.. Association of Adjuvant Chemotherapy With Disease-Free Survival and Overall Survival in Patients With Stage II and III Gastric Cancer

TACS_GC indicates tumor-associated collagen signature of gastric cancer.