The AGAMENON-SEOM model for prediction of survival in patients with advanced HER2-positive oesophagogastric adenocarcinoma receiving first-line trastuzumab-based therapy

Abstract

Background: Trastuzumab and chemotherapy is the standard first-line treatment in human epidermal growth factor receptor 2 (HER2)-positive advanced gastro-oesophageal cancer. The objective was to develop a predictive model for overall survival (OS) and progression-free survival (PFS) in patients treated with trastuzumab.

Methods: Patients with HER2-positive advanced gastro-oesophageal adenocarcinoma (AGA) from the Spanish Society of Medical Oncology (SEOM)-AGAMENON registry and treated first line with trastuzumab and chemotherapy between 2008 and 2021 were included. The model was externally validated in an independent series (The Christie NHS Foundation Trust, Manchester, UK).

Results: In all, 737 patients were recruited (AGAMENON-SEOM, n = 654; Manchester, n = 83). Median PFS and OS in the training cohort were 7.76 [95% confidence interval (CI), 7.13-8.25] and 14.0 months (95% CI, 13.0-14.9), respectively. Six covariates were significantly associated with OS: neutrophil-to-lymphocyte ratio, Eastern Cooperative Oncology Group performance status, Lauren subtype, HER2 expression, histological grade and tumour burden. The AGAMENON-HER2 model demonstrated adequate calibration and fair discriminatory ability with a c-index for corrected PFS/OS of 0.606 (95% CI, 0.578-0.636) and 0.623 (95% CI, 0.594-0.655), respectively. In the validation cohort, the model is well calibrated, with a c-index of 0.650 and 0.683 for PFS and OS, respectively.

Conclusion: The AGAMENON-HER2 prognostic tool stratifies HER2-positive AGA patients receiving trastuzumab and chemotherapy according to their estimated survival endpoints.

Keywords: HER2-positive; gastric cancer; nomogram; oesophageal cancer; survival; trastuzumab.

Figure 1.

Effect of AGAMENON-HER2 covariates on PFS (a) and OS (b). Adjusted TRs are derived from a multivariable log-normal AFT model and represent its exponentiated coefficients (Table 3). Interpretation of the adjusted TRs: TR > 1 means that an increase in the value of the covariate is associated with longer survival. TR < 1 means that an increase in the value of the covariate is associated with shorter survival. The criteria for overall tumour burden are specified in Table 1. AFT, accelerated failure time; CAPOX, capecitabine/oxaliplatin; CEA, carcinoembryonic antigen; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; FISH, fluorescence in situ hybridisation; FOLFOX, 5-fluorouracil/oxaliplatin; GEJ, gastroesophageal junction; HER2, human epidermal growth factor receptor-2; IHC, immunohistochemistry; OS, overall survival; PFS, progression-free survival; TRs, time ratios; XP, capecitabine/cisplatin.

Figure 2.

Calibration curves in the training cohort for PFS and OS. The term ‘predicted’ means the probability of PFS/OS at fixed points of time, whereas observed refers to the Kaplan–Meier survival estimate stratified by intervals. (a) 6-month PFS in the AGAMENON-SEOM cohort. (b) 6-Month PFS in the Christie Hospital cohort. (c) 12-month OS in the AGAMENON-SEOM cohort. (d) 12-month OS in the Christie Hospital cohort. OS, overall survival; PFS, progression-free survival.

Figure 3.

AGAMENON-HER2 nomograms for PFS (a) and OS (b). ECOG PS, Eastern Cooperative Oncology Group performance status; FISH, fluorescence in situ hybridisation; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; OS, overall survival; PFS, progression-free survival.